CN102918047A - 具有假儿茶酚基团的头孢烯类化合物 - Google Patents

具有假儿茶酚基团的头孢烯类化合物 Download PDF

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CN102918047A
CN102918047A CN201180027756XA CN201180027756A CN102918047A CN 102918047 A CN102918047 A CN 102918047A CN 201180027756X A CN201180027756X A CN 201180027756XA CN 201180027756 A CN201180027756 A CN 201180027756A CN 102918047 A CN102918047 A CN 102918047A
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山胁健二
杉本英基
佐野将之
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Shionogi and Co Ltd
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Abstract

公开了式(I)所示的化合物;其酯;或其被保护的产物(其中7位侧链中的环上的氨基是被保护的);所述化合物、酯或被保护的产物的药学上可接受的盐;以及所述化合物、酯或被保护的产物的溶剂化物。(在所述式中,X为-N=、-CH=等;W为-CH2等;U为-S-等;R1和R2各自独立地为氢原子、卤素、任选取代的低级烷基等;Q为单键等;R3为氢原子等;环A为具有1~3个氮原子的六元杂芳族基团;每个R4独立地为氢原子、卤素等;m为0~2的整数;G为C(=O)-等;D为单键、-NH-等;并且E为环状季铵基团。)

Description

具有假儿茶酚基团的头孢烯类化合物
技术领域
本发明化合物涉及抗菌谱广,特别是对产β-内酰胺酶的革兰氏阴性菌显示强抗菌活性的头孢烯类化合物以及包含其的药物组合物。
背景技术
迄今为止,已开发出多种β-内酰胺类药物,且β-内酰胺类药物已经成为临床上非常重要的抗菌药物。但是,越来越多的菌种已经通过产生降解β-内酰胺类药物的β-内酰胺酶获得了对β-内酰胺类药物的耐药性。
根据Ambler分子分类法,β-内酰胺酶主要被分为四类。具体而言,这些为A类(TEM型、SHV型、CTX-M型等)、B类(IMP型、VIM型、L-1型等)、C类(AmpC型等)和D类(OXA型等)。其中,A类、C类和D类型主要被归入丝氨酸-β-内酰胺酶,而另一方面,B类型被归入金属-β-内酰胺酶(metallo-beta-lactamase)。已知两者在水解β-内酰胺类药物的水解方面分别具有不同的机制。
近年来,由于通过产生具有扩大范围的底物谱的A类(ESBL)和D类型的丝氨酸-β-内酰胺酶和具有扩大范围的底物谱的B类型的金属-β-内酰胺酶而变得对包括头孢烯类和碳青霉烯类在内的大量β-内酰胺类药物高度耐受的革兰氏阴性菌的存在,已经出现了临床上的问题。特别地,已知金属-β-内酰胺酶是革兰氏阴性菌获得多药耐药性的一个原因。对产金属-β-内酰胺酶的革兰氏阴性菌显示出中等活性的头孢烯类化合物是已知的(例如:专利文献1和非专利文献1)。然而,仍然存在开发显示出更强的抗菌活性,特别是对各种产β-内酰胺酶的革兰氏阴性菌更加有效的头孢烯类化合物的需要。
一种已知的具有高的抗革兰氏阴性菌活性的抗菌药物是具有分子内儿茶酚基团的头孢烯类化合物(例如:非专利文献2~4)。其作用是儿茶酚基团与Fe3+形成螯合物,由此所述化合物通过细胞膜上的Fe3+转运体系(依赖tonB的铁转运体系)被有效地结合至细菌体内。因此,已经针对具有儿茶酚或与其类似的结构的化合物的头孢烯骨架的3位侧链或7位侧链的部分进行了研究。
专利文献2~5中描述了在头孢烯骨架上的3位侧链部分上具有羟基吡啶酮基团的假儿茶酚型衍生物。非专利文献2~11以及16中公开了在头孢烯骨架上的3位侧链部分上具有儿茶酚基团或与其类似的结构的化合物。
专利文献6和非专利文献12~15中公开了在头孢烯骨架上的7位侧链部分上具有儿茶酚基团或假儿茶酚结构的化合物。
非专利文献7、9、10以及12~15中记载了已经对β-内酰胺酶稳定化的头孢烯类化合物。
但是,这些文献并未描述本发明化合物。此外,这些描述了具有分子内儿茶酚基团的头孢烯类化合物的文献没有关于B类型的金属-β-内酰胺酶或对包括B类型在内的众多的革兰氏阴性菌的抗菌活性的具体描述。
专利文献7和8中没有具体公开具有儿茶酚型取代基的头孢烯类化合物。然而,本申请的申请人提交了具有儿茶酚型取代基的头孢烯类化合物的专利申请(专利文献9)。
现有技术文献
专利文献
专利文献1:WO 2007/119511 A1
专利文献2:JP 2-15090 A
专利文献3:JP 2-28187 A
专利文献4:JP 6-510523 A
专利文献5:JP 5-213971 A
专利文献6:JP 6-345776 A
专利文献7:WO 2007/09674
专利文献8:WO 2003/078440 A1
专利文献9:国际专利申请第PCT/JP2009/068400号
非专利文献
非专利文献1:The Journal of Antibiotics, vol.61, pp.36-39 (2008)
非专利文献2:The Journal of Antibiotics, vol.43, pp.1617-1620 (1990)
非专利文献3:The Journal of Antibiotics, vol.42, pp.795-806 (1989)
非专利文献4:The Journal of Antibiotics, vol.46, pp.833-839 (1993)
非专利文献5:The Journal of Antibiotics, vol.46, pp.840-849 (1993)
非专利文献6:The Journal of Antibiotics, vol.46, pp.850-857 (1993)
非专利文献7:The Journal of Antibiotics, vol.46, pp.1458-1470 (1993)
非专利文献8:The Journal of Antibiotics, vol.48, pp.1371-1374 (1995)
非专利文献9:The Journal of Medicinal Chemistry, vol.35, pp.2631-2642 (1992)
非专利文献10:The Journal of Medicinal Chemistry, vol.35, pp.2643-2651 (1992)
非专利文献11:Bioorganic & Medicinal Chemistry Letters, vol.5, pp.963-966 (1995)
非专利文献12:The Journal of Antibiotics, vol.48, pp.417-424 (1995)
非专利文献13:The Journal of Antibiotics, vol.41, pp.377-391 (1988)
非专利文献14:The Journal of Antibiotics, vol.49, pp.496-498 (1996)
非专利文献15:The Journal of Antibiotics, vol.46, pp.1279-1288 (1993)
非专利文献16:Applied Microbiology and Biotechnology, vol.40, pp.892-897 (1994)。
发明概述
发明解决的技术问题
本发明提供对包括革兰氏阴性菌和/或革兰氏阳性菌在内的多种细菌显示出强的抗菌谱的头孢烯类化合物。
优选地,本发明提供对产β-内酰胺酶的革兰氏阴性菌显示出强抗菌活性的头孢烯类化合物。
更优选地,本发明提供对多药耐药菌,特别是B类型的产金属-β-内酰胺酶的革兰氏阴性菌显示出强抗菌活性的头孢烯类化合物。
仍更优选地,本发明提供对产超广谱型β-内酰胺酶(ESBL)的细菌显示出有效抗菌活性的头孢烯类化合物。
最优选地,本发明提供对已知的头孢烯类药物或碳青霉烯类药物不显示出交叉耐药性的头孢烯类化合物。
解决所述技术问题的手段
本发明提供解决了上述问题的,至少基于以下结构特征的头孢烯类化合物:
1)本发明化合物在3位侧链上具有环状季铵基团(-E-),并且在该侧链末端具有假儿茶酚基团(环A)。优选地,所述化合物在环A的芳香杂环上具有一个氯原子;
2)本发明化合物在季铵基团(-E-)和假儿茶酚基团(环A)之间有间隔基部分(-D-C(=O)-);
3)在间隔基部分(-D-C(=O)-)中,D特别优选为链状结构;
4)本发明化合物在7位侧链上具有氨基噻二唑环或氨基噻唑环,并且在肟部分的末端具有羧基(carboxylic group);并且
5)本发明化合物的另一实施方案的特征为在3位侧链上具有非环状季铵基团,并且在该侧链末端具有假儿茶酚基团(环A)。在此情况下,间隔基部分(-D-C(=O)-)的D为环状基团。
具体而言,本发明提供如下发明:
(项目1)
下式的化合物:
[式1]
Figure 607952DEST_PATH_IMAGE001
或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,
其中
X为–N=、-CH=、-C(-R5)=、-C(-Br)=或-C(-Cl)=;
R5为低级烷基或卤代(低级)烷基;
W为-CH2-、-S-或-O-;
当W为-CH2-时,U是-CH2-、-S-或-O-,并且当W为-S-或-O-时,U为-CH2-;
R1和R2独立地为氢原子、卤素、羟基、羧基、任选取代的低级烷基、任选取代的碳环基或任选取代的杂环基;或者
R1和R2与相邻原子一起形成任选取代的碳环基或任选取代的杂环基;
Q为单键、任选取代的碳环基或任选取代的杂环基;
环A为具有1-3个氮原子的六元芳香杂环基;
R3为氢原子、-OCH3或-NH-CH(=O);
k为从0到2的整数;
m为从0到2的整数;
每个R4独立地为氢原子、卤素、羟基、-CN、-C(=O)-R6、-C(=O)-OH或-OR6
R6为低级烷基或卤代(低级)烷基;
关于D和E,
a)D为单键、-N(R8)-或-R7-N(R8)-,其中R7为任选取代的低级亚烷基,R8为氢或低级烷基,并且E为任选取代的选自下式(1)~(40)的环状基团;或者
b)D为下式:
[式2]
其中q为0或1,并且
E为取代基E的下式中式(10)或式(41)的基团:
[式3]
Figure 73941DEST_PATH_IMAGE004
Figure 888313DEST_PATH_IMAGE005
Figure 648458DEST_PATH_IMAGE006
Figure 915492DEST_PATH_IMAGE007
[式4]
Figure 114392DEST_PATH_IMAGE008
Figure 720954DEST_PATH_IMAGE009
Figure 714317DEST_PATH_IMAGE010
Figure 406330DEST_PATH_IMAGE011
Figure 143342DEST_PATH_IMAGE012
Figure 102945DEST_PATH_IMAGE013
其中p为从1到3的整数;n为1或2;并且Rx为任选取代的低级烷基。
(项目2)
根据项目1所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中D为单键、-NH-或-R7-NH-,R7为低级亚烷基,并且E选自式(1)~(40)。
(项目3)
根据项目2所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中D为-NH-、-CH2-NH-或-CH2-CH2-NH-。
(项目4)
根据项目3所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中E为选自式(5)、(6)、(10)、(11)、(26)、(29)~(34)、(36)和(37)的基团。
(项目5)
根据项目3所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中E为式(26)或(31)的基团。
(项目6)
根据项目2所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中D为单键。
(项目7)
根据项目6所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中E为选自式(1)~(4)、(7)、(12)~(25)、(27)和(28)的基团。
(项目8)
根据项目6所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中E 为选自式(1)~(3)、(7)和(12)的基团。
(项目9)
根据项目1所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中D为下式:
[式5]
Figure 532790DEST_PATH_IMAGE014
其中q如项目1中的定义。
(项目10)
根据项目1~9任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中U为-S-。
(项目11)
根据项目1~10任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中W为-CH2-。
(项目12)
根据项目1~11任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中R3为氢原子或-OCH3
(项目13)
根据项目1~12任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中X为-N=、-CH=或–C(-Cl)=。
(项目14)
根据项目1~13任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中下式:
[式6]
Figure 712098DEST_PATH_IMAGE015
选自下式:
[式7]
Figure 987222DEST_PATH_IMAGE016
Figure 568376DEST_PATH_IMAGE017
Figure 903542DEST_PATH_IMAGE018
Figure 570147DEST_PATH_IMAGE019
Figure 648961DEST_PATH_IMAGE020
(项目15)
根据项目1~13任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中下式:
[式8]
Figure 583157DEST_PATH_IMAGE021
选自下式:
[式9]
Figure 292487DEST_PATH_IMAGE022
Figure 243125DEST_PATH_IMAGE023
Figure 63314DEST_PATH_IMAGE024
(项目16)
根据项目1~15任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中Q为单键或任选取代的亚苯基。
(项目17)
根据项目16所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中R1为任选取代的低级烷基并且R2为氢原子。
(项目18)
根据项目16所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中R1为氢原子并且R2为任选取代的低级烷基。
(项目19)
根据项目16所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中R1和R2独立地为低级烷基。
(项目20)
根据项目17所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中m为0。
(项目21)
药物组合物,其包含根据项目1~18任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物。
(项目22)
根据项目20所述的药物组合物,其具有抗菌活性。
(项目23)
用于治疗感染性疾病的方法,其特征在于给予根据项目1~20任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物。
(项目24)
用于治疗感染性疾病的根据项目1~20任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物。
(项目25)
根据项目1~20任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物在制备用于治疗感染性疾病的治疗剂中的应用。
在另一实施方案中,本发明还提供如下发明:
根据项目1~18任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,条件是下面的化合物(B-1)、(B-2)和(B-3)被从式(I)中排除:
[式10]
Figure 296029DEST_PATH_IMAGE026
发明的效果
本发明化合物由于具有至少一种的下述特点从而可用作药品:
1)所述化合物对包括革兰氏阴性菌和/或革兰氏阳性菌在内的多种细菌显示出强效抗菌谱;
2)所述化合物对产β-内酰胺酶的革兰氏阴性菌显示出强效抗菌活性;
3)所述化合物对多药耐药菌,特别是产B类型的金属-β-内酰胺酶的革兰氏阴性菌显示出强效抗菌活性;
4)所述化合物对产超广谱β-内酰胺酶(ESBL)的细菌显示出强效抗菌活性;
5)所述化合物与已知的头孢烯类药物和/或碳青霉烯类药物之间不显示出交叉耐药性;并且
6)所述化合物在给药至身体后不显示出副作用,例如发热。
用于实施本发明的实施方案
本文中使用的各个术语被单独定义或与如下的其它术语组合定义:
“卤素”包括氟、氯、溴和碘。优选地,卤素为氟、氯或溴,更优选卤素为氯。
“低级烷基”包括具有1~8个碳,优选1~6个碳,更优选1~4个碳的直链或支链烷基,并且包括,例如,甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、己基、异己基、正庚基、异庚基、正辛基等。
“低级亚烷基”包括具有1~8个碳,优选1~6个碳,更优选1~4个碳,最优选1个或2个碳原子的直链亚烷基,并且包括,例如,亚甲基、亚乙基、亚正丙基、亚正丁基、亚正戊基、亚正己基等。
“卤代(低级)烷基”是指所述“低级烷基”的至少一个位置被上述“卤素”取代的基团,并且包括,例如,单氟甲基、二氟甲基、三氟甲基、单氯甲基、二氯甲基、三氯甲基、单溴甲基、单氟乙基、单氯乙基、氯二氟甲基等。优选地,卤代(低级)烷基为三氟甲基或三氯甲基。
“任选取代的低级烷基”中所述的取代基包括选自取代基群α的至少一个基团。当被多个取代基群α的基团取代时,这样的基团可以相同也可以不同。
“任选取代的低级亚烷基”中所述的取代基包括任选取代的低级烷基和选自取代基群α的至少一种基团。当被多个取代基取代时,这样的取代基可以相同也可以不同。
“任选取代的亚苯基”中所述的取代基包括任选取代的低级烷基和选自取代基群α的至少一个基团。当被多个取代基取代时,这样的取代基可以相同也可以不同。
此处,“取代基群α”是由卤素、羟基、低级烷氧基、羟基(低级)烷氧基、低级烷氧基(低级)烷氧基、羧基、氨基、酰基氨基、低级烷氨基、亚氨基、羟基亚氨基、低级烷氧基亚氨基、低级烷硫基(alkylthio)、氨甲酰基、低级烷基氨甲酰基、羟基(低级)烷基氨甲酰基、氨磺酰基、低级烷基氨磺酰基、低级烷基亚磺酰基、氰基、硝基、碳环基和杂环基组成的群。
“低级烷氧基”、“羟基(低级)烷氧基”、“低级烷氧基(低级)烷氧基”、“低级烷氨基”、“低级烷氧基亚氨基”、“低级烷硫基”、“低级烷基氨甲酰基”、“羟基(低级)烷基氨甲酰基”和“低级烷基氨磺酰基”中的低级烷基部分如上文“低级烷基”中的定义。
“任选取代的低级烷基”中所述取代基的优选实施方案包括氟原子、氯原子、溴原子、羟基、羧基、甲氧基、乙氧基、羟基甲氧基、羟基乙氧基、甲氧基甲氧基、甲氧基乙氧基、氨基、乙酰氨基、甲氨基、二甲氨基、亚氨基、羟亚氨基、甲氧基亚氨基、甲硫基(methylthio)、氨甲酰基、甲基氨甲酰基、羟甲基氨甲酰基、氨磺酰基、甲基氨磺酰基、低级烷基氨磺酰基、氰基、硝基、苯基、环丙基、环丁基、环己基、吡啶基、吗啉基等。
“任选取代的低级烷基”的优选实施方案包括甲基、乙基、异丙基、叔丁基、单氟甲基、二氟甲基、三氟甲基、羧甲基、羧乙基、氨甲酰基甲基、氨甲酰基乙基、羟基甲基、羟基乙基、甲氧基甲基、乙氧基甲基、甲氧基乙基、乙氧基乙基、甲基硫基甲基(methylthiomethyl)、乙基硫基甲基、苄基、苯乙基、4-羟基苄基、4-甲氧基苄基、4-羧基苄基等。
“碳环基”包括环烷基、环烯基、芳基和非芳香稠合碳环基等。该术语包括二价基团(例如,环亚烷基、环亚烯基、亚芳基)和前面提到的一价基团。
“环烷基”为具有3~10个碳,优选3~8个碳,更优选4~8个碳的碳环基,并且包括,例如,环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基等。
“环烯基”包括在环烷基环中的任何位置处具有至少一个双键的那些,并且具体包括,例如,环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基和环己二烯基等。
“芳基”包括苯基、萘基、蒽基、菲基等,并且特别地,优选苯基。
“非芳香稠合碳环基”包括其中两个或更多的选自“环烷基”、“环烯基”和“芳基”的环状基团是稠合的的基团,并且具体包括,例如,茚满基、茚基、四氢萘基和芴基等。
“杂环基”包括在其环中具有至少一个选自O、S和N的杂原子的杂环基,并且具体包括,例如,五元或六元杂芳基,诸如吡咯基、咪唑基、吡唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三唑基、三嗪基、四唑基、异噁唑基、噁唑基、噁二唑基、异噻唑基、噻唑基、噻二唑基、呋喃基、噻吩基等;二环稠合杂环基,诸如吲哚基、异吲哚基、吲唑基、吲嗪基、二氢吲哚基、异二氢吲哚基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、萘啶基、喹喔啉基、嘌呤基、蝶啶基、苯并吡喃基、苯并咪唑基、苯并三唑基、苯并异噁唑基、苯并噁唑基、苯并噁二唑基、苯并异噻唑基、苯并噻唑基、苯并噻二唑基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、苯并三唑基、咪唑并吡啶基、吡唑并吡啶基、三唑并吡啶基、咪唑并噻唑基、吡嗪并哒嗪基、喹唑啉基、喹啉基、异喹啉基、萘啶基、二氢苯并呋喃基、四氢喹啉基、四氢异喹啉基、二氢苯并噁嗪基、四氢苯并噻吩基等;三环稠合杂环基,诸如咔唑基、吖啶基、呫吨基、phenothiadinyl、苯并吩噁噻基(phenoxathiinyl)、苯并噁嗪基、二苯并呋喃基、咪唑并喹啉基等;非芳香杂环基,诸如二噁烷基、硫杂丙环基、环氧乙烷基、氧硫杂环戊烷基、氮杂环丁烷基、硫杂环己烷基、噻唑烷基、吡咯烷基、吡咯啉基、咪唑烷基、咪唑啉基、吡唑烷基、吡唑啉基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、硫代吗啉代(thiomorpholino)、二氢吡啶基、二氢苯并咪唑基、四氢吡啶基、四氢呋喃基、四氢吡喃基、四氢噻唑基、四氢异噻唑基、二氢噁嗪基、六氢氮杂䓬基、四氢二氮杂䓬基等。优选地,杂环基为五元或六元杂芳基或非芳香族杂环基,并且更优选地,为五元或六元杂芳基。
这些包括二价杂环基,以及前文提到的一价杂环基。
“任选取代的碳环基”和“任选取代的杂环基”中所述的取代基包括任选取代的低级烷基和选自取代基群α的至少一种基团。
“任选取代的碳环基”和“任选取代的杂环基”中的取代基的优选实施方案包括甲基、乙基、异丙基、叔丁基、氟原子、氯原子、溴原子、羟基、羧基、甲氧基、乙氧基、羟基甲氧基、羟基乙氧基、甲氧基甲氧基、甲氧基乙氧基、氨基、乙酰氨基、甲氨基、二甲氨基、亚氨基、羟基亚氨基、甲氧基亚氨基、甲硫基、氨甲酰基、甲基氨甲酰基、羟甲基氨甲酰基、氨磺酰基、甲基氨磺酰基、低级烷基氨磺酰基、氰基、硝基、苯基、环丙基、环丁基、环己基、吡啶基、吗啉基等。
“具有1~3个氮原子的六元芳香族杂环基”包括吡啶、嘧啶、哒嗪、吡嗪、1,3,5-三嗪、1,2,4-三嗪、1,2,3-三嗪等。
情况“R1和R2与相邻原子一起形成任选取代的碳环基或任选取代的杂环基”的实例包括下式的情况:
[式11]
Figure 733964DEST_PATH_IMAGE027
其中每个符号如项目1中的定义,为环烷基、环烯基或非芳香族杂环基,例如,下式中的基团:
[式12]
Figure 590799DEST_PATH_IMAGE028
其环上任选具有选自取代基群α的取代基。
在部分“E”中,“选自式(1)~式(40)的任选取代的环状基团”包括其中每个环状基团的碳原子上的氢原子被一个或多个相同的或不同的并且选自任选取代的低级烷基或取代基群α的基团取代的基团。所述取代基的优选实施方案包括甲基、乙基-异丙基、叔丁基、氟原子、氯原子、溴原子、羟基、羧基、甲氧基、乙氧基、羟基甲氧基、羟基乙氧基、甲氧基甲氧基、甲氧基乙氧基、氨基、乙酰氨基、甲氨基、二甲氨基、亚氨基、羟亚氨基、甲氧基亚氨基、甲硫基、氨甲酰基、甲基氨甲酰基、羟甲基氨甲酰基、氨磺酰基、甲基氨磺酰基、低级烷基氨磺酰基、氰基、硝基、苯基、环丙基、环丁基、环己基、吡啶基、吗啉基等。更优选的实施方案为不取代。
式(I)中各部分的实例或实施方案如下所示。但是,本发明的范围并不仅限于下面描述的那些。
“X”的实例包括-N=、-CH=、-C(-CH3)=、-C(-CF3)=、-C(-Br)=、-C(-Cl)=等。优选地,“X”为-N=、-CH=和-C(-Cl)=。
在优选的实施方案中,“W”为-CH2-,并且“U”为-CH2-、-S-或-O-。更优选地,“W”为-CH2-,并且“U”为-S-或-O-。仍更优选地,“W”为-CH2-,并且“U”为-S-。
“R1和R2”的实例包括氢原子、氟原子、氯原子、羟基、羧基、甲基、乙基、异丙基、叔丁基、单氟甲基、二氟甲基、三氟甲基、羧甲基、羧乙基、氨甲酰甲基、氨甲酰乙基、羟甲基、羟乙基、甲氧基甲基、乙氧基甲基、甲氧基乙基、乙氧基乙基、甲基硫基甲基、乙基硫基甲基、苄基、4-羟基苄基、4-甲氧基苄基、4-羧基苄基、苯基、萘基、环丙基、环丁基、环戊基、环己基、吡咯基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、吡嗪基、三唑基、三嗪基、四唑基、异噁唑基、噁唑基、噁二唑基、异噻唑基、噻唑基、噻二唑基、呋喃基、噻吩基等。
R1和R2的优选组合包括,(R1、R2)为(氢原子、氢原子)、(甲基、氢原子)、(氢原子、甲基)、(甲基、甲基)、(乙基、氢原子)、(氢原子、乙基)、(乙基、乙基)、(苯基、氢原子)、(氢原子、苯基)、(羧甲基、氢原子)、(氢原子、羧甲基)、(羧乙基、氢原子)、(氢原子、羧乙基)、(羟乙基、氢原子)、(氢原子、羟乙基)、(氨甲酰甲基、氢原子)、(氢原子、氨甲酰甲基)、(三氟甲基、氢原子)、(羧基、氢原子)、(氨甲酰乙基、氢原子)、(苄基、氢原子)、(4-羟基苄基、氢原子)等。
情况“R1和R2与相邻原子一起形成任选取代的碳环基或任选取代的杂环基”的优选的实施方案包括任选取代的三元至八元环烷基、任选取代的三元至八元环烯基或三元至八元非芳香族杂环基。更优选的实施方案包括下式的情况:
[式13]
Figure 63369DEST_PATH_IMAGE029
其中每个符号如项目1中的定义,为下式中的任何一种:
[式14]
“R3”优选为氢原子或-OCH3
“R4”的实例包括氢原子、氯原子、氟原子、溴原子、氰基、羟基、乙酰基、甲氧基、乙氧基、三氟甲基等。优选地,R4为氢原子、羟基或氯原子。
“-E-D-(C=O)-”的实例包括下式(1A)~(41A):
[式15]
Figure 39732DEST_PATH_IMAGE031
Figure 201723DEST_PATH_IMAGE032
Figure 263220DEST_PATH_IMAGE033
Figure 485254DEST_PATH_IMAGE034
Figure 897781DEST_PATH_IMAGE035
[式16]
Figure 361998DEST_PATH_IMAGE036
Figure 670936DEST_PATH_IMAGE038
Figure 570759DEST_PATH_IMAGE039
Figure 74553DEST_PATH_IMAGE040
Figure 376221DEST_PATH_IMAGE041
其中p为从1到3的整数;n为1或2;并且Rx为任选取代的低级烷基。
此处,Rx的优选实例包括甲基、乙基、三氟甲基、羧甲基、氨甲酰甲基、羟乙基等。
“-E-D-(C=O)-”的优选实施方案包括下式(1B)~(41B):
[式17]
Figure 867617DEST_PATH_IMAGE044
Figure 695896DEST_PATH_IMAGE045
Figure 492951DEST_PATH_IMAGE046
[式18]
Figure 39470DEST_PATH_IMAGE047
Figure 150645DEST_PATH_IMAGE048
Figure 565501DEST_PATH_IMAGE050
Figure 310920DEST_PATH_IMAGE052
“-E-D-(C=O)-”的仍更优选的实施方案包括下式:
[式19]
Figure 252648DEST_PATH_IMAGE054
在优选的实施方案中,下式的环A:
[式20]
Figure 23475DEST_PATH_IMAGE056
其中每个符号如项目1中的定义,为具有1~3个氮原子的六元芳香族杂环基。
在优选的实施方案中,R4为氢原子、氯原子或羟基。
优选k为0或1。
在更优选的实施方案中,下式:
[式21]
Figure 8749DEST_PATH_IMAGE057
其中每个符号如项目1中的定义,
具有下式:
[式22]
Figure 754726DEST_PATH_IMAGE058
Figure 825450DEST_PATH_IMAGE059
在仍更优选的实施方案中,下式:
[式23]
其中每个符号如项目1中的定义,
具有下式:
[式24]
Figure 161884DEST_PATH_IMAGE064
Figure 943950DEST_PATH_IMAGE066
在优选的实施方案中,Q为单键或亚苯基。在更优选的实施方案中,Q为单键。
式(I)的头孢烯骨架上取代位置的命名法如下所示。如本文所用,7位侧链和3位侧链分别指结合至如下所示的头孢烯骨架的7位和3位上的基团。
[式25]
Figure 926950DEST_PATH_IMAGE067
式(I)的酯优选包括在7位侧链和/或在4位上的羧基处的那些酯。在7位侧链上的羧基处的酯是指具有其中肟基末端处的羧基按下式所示被酯化的结构的化合物:
[式26]
Figure 259842DEST_PATH_IMAGE068
其中每个符号如项目1中的定义,并且Ra表示酯残基,例如羧基保护基团。这样的酯包括在体内容易代谢形成羧基态的那些酯。
在式(I)的4位上的羧基处的酯是具有其中头孢烯骨架的4位处的羧基按下式所示被酯化的结构的化合物:
[式27]
Figure 808635DEST_PATH_IMAGE069
其中每个符号如项目1中的定义,并且Rb为酯残基,例如羧基保护基团。这样的酯包括在体内容易代谢形成羧基态的那些酯。
前面提到的羧基保护基团可为任何基团,只要其可以通过例如在Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons)中描述的方法用于保护和/或脱保护即可,并且其例如包括低级烷基(如,甲基、乙基、叔丁基)、低级烷基羰基氧基甲基(如,特戊酰基)、任选取代的芳烷基(如,苄基、二苯甲基、苯乙基、对-甲氧基苄基、对-硝基苄基)、甲硅烷基(叔丁基二甲基甲硅烷基、二苯基(叔丁基)甲硅烷基)等。
在式(I)的7位侧链上的氨基处被保护的化合物是指其中环上的氨基已经被保护的结构,所述结构如下式所述:
[式28]
其中每个符号如项目1中的定义,并且Rc表示氨基保护基团。这样的氨基保护基团包括在体内容易代谢形成氨基的那些基团。前面提到的氨基保护基团可以为任何基团,只要其可以通过例如在Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons)中描述的方法用于保护和/或脱保护即可,并且其例如包括低级烷氧基羰基(如,叔丁氧基羰基、苄氧基羰基、对-硝基苄氧基羰基)、任选取代的芳烷酰基(aralkanoyl)(如苯甲酰基、对-硝基苯甲酰基)、酰基(如,甲酰基、氯乙酰基)等。
式(1)的盐包括在4位处的羧基、在7位侧链处的羧基和/或吡啶酮衍生物的羟基上的氢原子解离后与抗衡阳离子(多个阳离子)形成的那些盐;由7位侧链上的氨基与无机酸或有机酸形成的那些盐;以及由3位侧链中的季胺部分与抗衡阴离子形成的那些盐。
式(I)的药学上可接受的盐包括,例如,与无机碱、氨、有机碱、无机酸、有机酸、碱性氨基酸、卤素离子等形成的盐或分子内盐。这样的无机碱包括,例如,碱金属(Na、K等)和碱土金属(Mg等)。有机碱包括,例如,普鲁卡因、2-苯乙基苄胺、二苄基乙二胺(dibenzylethylenediamine)、乙醇胺、二乙醇胺、三羟基甲基氨基甲烷、聚羟基烷基胺、N-甲基葡糖胺等。无机酸包括,例如,盐酸、氢溴酸、硫酸、硝酸、磷酸等。有机酸包括,例如,对-甲苯磺酸、甲磺酸、甲酸、乙酸、三氟乙酸、马来酸等。碱性氨基酸包括,例如,赖氨酸、精氨酸、鸟氨酸、组氨酸等。
如本文所用,“溶剂化物”是指与水或有机溶剂(例如,甲醇、乙醇、异丙醇、丙酮)形成的溶剂化物,并且优选为水合物。
本发明的化合物(I)不限于特定的异构体,但是包括如下所例示的任何可能的异构体、外消旋体以及共振结构(resonance structures):
例如,式(I)中的式:
[式29]
Figure 101393DEST_PATH_IMAGE071
其中每个符号如项目1中的定义,
其包括:
[式30]
Figure 736512DEST_PATH_IMAGE072
Figure 139811DEST_PATH_IMAGE073
其中每个符号如项目1中的定义。
例如,式(I)中的式:
[式31]
Figure 336437DEST_PATH_IMAGE074
其中每个符号如项目1中的定义,
其包括下面的共振结构:
[式32]
Figure 90767DEST_PATH_IMAGE075
Figure 765462DEST_PATH_IMAGE076
Figure 226530DEST_PATH_IMAGE077
Figure 92076DEST_PATH_IMAGE079
Figure 632779DEST_PATH_IMAGE080
其中R4如项目1中的定义,
等等。
本发明的式(I)表示的化合物可以例如通过下述的一般合成方法来制备。
[式33]
Figure 213933DEST_PATH_IMAGE081
其中X、U、Ra、Rb和Rc如上面所定义;P-为季胺的抗衡阴离子;
K具有下式:
[式34]
Figure 549100DEST_PATH_IMAGE082
其中每个符号如上面所定义;
下式:
[式35]
Figure 215704DEST_PATH_IMAGE083
为包括3-位侧链的季铵基团部分的式(I)中的下述部分:
[式36]
其中每个符号如上面所定义;
LG和Y为离去基团(例如,羟基、卤素(Cl、Br、I)、任选取代的氨甲酰氧基、酰氧基、甲磺酰氧基和甲苯磺酰氧基等);
Rd为氢或羧基保护基;并且
Re氢或氨基保护基。
1)7-位侧链的原料:化合物(VI)的合成
第一步:
在化合物(II)(LG为羟基)和Mitsunobu试剂的存在下,或在化合物(II)(LG为另一离去基)和碱(例如氢氧化钠、甲醇钠)的存在下,通过使N-羟基酞酰亚胺反应得到化合物(III)。
相对于化合物(II),N-羟基酞酰亚胺的用量通常为1~5摩尔当量,优选1~2摩尔当量。
反应溶剂的实例包括醚类(如,二噁烷、四氢呋喃、乙醚、叔丁基甲醚、二异丙醚)、卤代烃类(如,二氯甲烷、氯仿、四氯化碳)、烃类(如,正己烷、苯、甲苯)、酰胺类(如,甲酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮)等,及其混合溶剂等。
反应温度通常为约-50~100℃,优选为约-40~50℃,并且更优选为约-30~0℃。
第二步:
加入N-甲基肼或肼并与化合物(III)反应以得到化合物(IV)。
相对于化合物(III),N-甲基肼或肼的用量为约1~10摩尔当量,优选1~5摩尔当量,并且更优选1~2摩尔当量。
反应溶剂的实例包括醚类(如,二噁烷、四氢呋喃、乙醚、叔丁基甲醚、二异丙醚)、酯类(如,甲酸乙酯、乙酸乙酯、乙酸异丙酯)、卤代烃类(如,二氯甲烷、氯仿、四氯化碳)、烃类(如,正己烷、苯、甲苯)、醇类(如,甲醇、乙醇、异丙醇)、酰胺类(如,甲酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮)、酮类(如,丙酮、甲乙酮)、腈类(如,MeCN、丙腈)、二甲亚砜、水等,及其混合溶剂。
反应温度通常为约0~100℃,优选为约0~50℃,更优选为约10~30℃。
第三步:
加入市售或通过已知方法得到的化合物(V)并与化合物(IV)反应以得到化合物(VI)。(如,在Bioorganic & Medicinal Chemistry, vol.15, pp.6716-6732 (2007)中描述的那样)。
加入化合物(III)并与N-甲基肼或腈反应以得到化合物(IV)。
反应溶剂的实例包括醚类(如,二噁烷、四氢呋喃、乙醚、叔丁基甲醚、二异丙醚)、酯类(如,甲酸乙酯、乙酸乙酯、乙酸异丙酯)、卤代烃类(如,二氯甲烷、氯仿、四氯化碳)、烃类(如,正己烷、苯、甲苯)、醇类(如,甲醇、乙醇、异丙醇)、酰胺类(如,甲酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮)、酮类(如,丙酮、甲乙酮)、腈类(如,MeCN、丙腈)、二甲亚砜、水等,及其混合溶剂。
反应温度通常为约0~100℃,优选为约0~50℃,更优选为约10~30℃。
2)7-位酰胺化以及3-位侧链的形成;化合物(X)的合成
第四步(7-位酰胺化反应):
化合物(IX)可以通过将化合物(VI)与化合物(VII)反应得到,后者可以通过市售获得或根据文献(如,JP 60-231684 A、JP 62-149682 A等)中描述的方法合成。在这种情况下,优选地,Ra和Rb为羧基保护基,Rc为氨基保护基,并且Rd和Re为氢。
相对于1摩尔的化合物(VII),化合物(VI)的用量通常为约1~5摩尔,优选1~2摩尔。
反应溶剂的实例包括醚类(如,二噁烷、四氢呋喃、乙醚、叔丁基甲醚、二异丙醚)、酯类(如,甲酸乙酯、乙酸乙酯、乙酸异丙酯)、卤代烃类(如,二氯甲烷、氯仿、四氯化碳)、烃类(如,正己烷、苯、甲苯)、酰胺类(如,甲酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮)、酮类(如,丙酮、甲乙酮)、腈类(如,MeCN、丙腈)、二甲亚砜、水等,及其混合溶剂等。
反应温度通常为约-40~80℃,优选为约-20~50℃,更优选为约-10~30℃。
上述酰胺化反应可以在羧基部分转化成反应性衍生物(如,无机碱盐、有机碱盐、酰卤、酰基叠氮化物、酸酐、混合酸酐、活性酰胺、活性酯和活性硫酯)后进行。这样的无机碱的实例包括碱金属(如,Na、K等)、碱土金属(如,Ca、Mg)等。有机碱的实例包括三甲胺、三乙胺、叔丁基二甲胺、二苄基甲胺、苄基二甲胺、N-甲基吗啉、二异丙基乙胺等。酰卤的实例包括酰氯、酰溴等。混合酸酐的实例包括单烷基碳酸酯(mono-alkyl carbonates)的混合酸酐、脂肪族羧酸的混合酸酐、芳香族羧酸的混合酸酐、有机磺酸的混合酸酐等。活性酰胺的实例包括与含氮杂环化合物形成的酰胺等。活性酯的实例包括有机磷酸酯(如,二乙氧基磷酸酯、二苯氧基磷酸酯等)、对-硝基苯基酯、2,4-二硝基苯基酯、氰基甲基酯等。活性硫酯的实例包括与芳香族杂环硫醇化合物形成的酯(如,2-吡啶基硫酯)等。此外,在上述的反应中,可以根据需要使用合适的缩合剂(condensing agent)。例如,1-二甲氨基丙基-3-乙基碳二亚胺盐酸盐(WSCD·HCl)、N,N’-二环己基碳二亚胺、N,N’-羰二咪唑、N,N’-硫基羰二咪唑(N,N’-thiocarbonyldiimidazole)、N-乙氧基羰基-2-乙氧基-1,2-二氢喹啉、三氯氧磷、烷氧基乙炔、2-氯甲基吡啶鎓碘化物、2-氟甲基吡啶鎓碘化物、三氟乙酸酐等可用作缩合剂。
第五步(3-位侧链形成反应):
化合物(X)是通过将化合物(IX)与相应的叔胺反应得到的。在这种情况下,优选地,Ra和Rb为羧基保护基,并且Rc为氨基保护基。
相对于1摩尔化合物(IX),相应的叔胺的用量通常为1~5摩尔,优选1~2摩尔。
反应溶剂的实例包括醚类(如,二噁烷、四氢呋喃、乙醚、叔丁基甲醚、二异丙醚)、酯类(如,甲酸乙酯、乙酸乙酯、乙酸异丙酯)、卤代烃类(如,二氯甲烷、氯仿、四氯化碳)、烃类(如,正己烷、苯、甲苯)、酰胺类(如,甲酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮)、酮类(如,丙酮、甲乙酮)、腈类(如,MeCN、丙腈)、二甲亚砜、水等,及其混合溶剂等。
反应温度通常为-20~60℃,优选为约-10~40℃,更优选为约0~20℃。
此外,可以通过还原其中U为SO的化合物(X)得到其中U为SO的化合物(X)。还原剂的实例包括碘化钾-乙酰氯等。
3)3-位侧链形成和7-位酰胺化;化合物(X)的合成
第六步(3-位侧链形成反应):
化合物(VIII)是通过将化合物(VII)与相应的叔胺反应得到的。在这种情况下,优选地,Rb为羧基保护基,并且Re为氨基保护基。
相对于1摩尔化合物(VII),相应的叔胺用量通常为1~5摩尔,优选1~2摩尔。
反应溶剂的实例包括醚类(如,二噁烷、四氢呋喃、乙醚、叔丁基甲醚、二异丙醚)、酯类(如,甲酸乙酯、乙酸乙酯、乙酸异丙酯)、卤代烃类(如,二氯甲烷、氯仿、四氯化碳)、烃类(如,正己烷、苯、甲苯)、酰胺类(如,甲酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮)、酮类(如,丙酮、甲乙酮)、腈类(如,MeCN、丙腈)、二甲亚砜、水等,及其混合溶剂等。
反应温度通常为-20~60℃,优选为约-10~40℃,更优选为约0~20℃。
在第五步和第六步的3-位侧链形成反应中用到的两种叔胺部分(相应于项目1中的部分E)可以作为市售试剂,通过已知方法和/或通过本文中描述的方法得到。
第七步(7-位酰胺化反应):
化合物(X)是通过将化合物(VIII)和化合物(VI)反应得到的。在这种情况下,优选地,Ra和Rb为羧基保护基,Rc为氨基保护基,Rd和Re为氢。
相对于1摩尔化合物(VIII),化合物(VI)的用量通常为约1~5摩尔,优选1~2摩尔。
反应溶剂的实例包括醚类(如,二噁烷、四氢呋喃、乙醚、叔丁基甲醚、二异丙醚)、酯类(如,甲酸乙酯、乙酸乙酯、乙酸异丙酯)、卤代烃类(如,二氯甲烷、氯仿、四氯化碳)、烃类(如,正己烷、苯、甲苯)、酰胺类(如,甲酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮)、酮类(如,丙酮、甲乙酮)、腈类(如,MeCN、丙腈)、二甲亚砜、水等,及其混合溶剂。
反应温度通常为-40~80℃,优选为约-20~50℃,更优选为约-10~30℃。
上述酰胺化反应可以在羧基部分转化成反应性衍生物(如,无机碱盐、有机碱盐、酰卤、酰基叠氮化物、酸酐、混合酸酐、活性酰胺、活性酯和活性硫酯)后进行。这样的无机碱的实例包括碱金属(如,Na、K等)、碱土金属(如,Ca、Mg)等。有机碱的实例包括三甲胺、三乙胺、叔丁基二甲胺、二苄基甲胺、苄基二甲胺、N-甲基吗啉、二异丙基乙胺等。酰卤的实例包括酰氯、酰溴等。混合酸酐的实例包括单烷基碳酸酯的混合酸酐、脂肪族羧酸的混合酸酐、芳香族羧酸的混合酸酐、有机磺酸的混合酸酐等。活性酰胺的实例包括与含氮杂环化合物形成的酰胺等。活性酯的实例包括有机磷酸酯(如,二乙氧基磷酸酯、二苯氧基磷酸酯等)、对-硝基苯基酯、2,4-二硝基苯基酯、氰基甲基酯等。活性硫酯的实例包括与芳香族杂环硫醇化合物形成的酯(如,2-吡啶基硫酯)等。此外,在上述的反应中,可以根据需要使用合适的缩合剂。例如,1-二甲氨基丙基-3-乙基碳二亚胺盐酸盐(WSCD·HCl)、N,N’-二环己基碳二亚胺、N,N’-羰二咪唑、N,N’-硫基羰二咪唑、N-乙氧基羰基-2-乙氧基-1,2-二氢喹啉、三氯氧磷、烷氧基乙炔、2-氯甲基吡啶鎓碘化物、2-氟甲基吡啶鎓碘化物、三氟乙酸酐等可用作缩合剂。
此外,可以通过使用其中U为O的化合物(VII)得到其中U为O的化合物(X)。
4)脱保护反应
第八步:
根据本领域技术人员公知的方法将化合物(X)经历脱保护反应以得到化合物(I)。
反应溶剂的实例包括醚类(如,苯甲醚、二噁烷、四氢呋喃、乙醚、叔丁基甲醚、二异丙醚)、酯类(如,甲酸乙酯、乙酸乙酯、乙酸正丁酯)、卤代烃类(如,二氯甲烷、氯仿、四氯化碳)、烃类(如,正己烷、苯、甲苯)、酰胺类(如,甲酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮)、酮类(如,丙酮、甲乙酮)、腈类(如,MeCN、丙腈)、硝基化合物类(nitros)(如,硝基甲烷、硝基乙烷、硝基苯)、二甲亚砜、水等。这些溶剂可单独使用或在使用两种或多种这样的溶剂的组合中使用。
反应温度通常为-30~100℃,优选为约0~50℃,更优选为约0~10℃。
可使用路易斯酸(如,AlCl3、SnCl4、TiCl4)、质子酸(如HCl、HBr、H2SO4、HCOOH)等作为催化剂。
可以对得到的化合物(I)进一步化学修饰以得到其酯,或其在噻唑环上的7-位的氨基被保护的化合物,或其药学上可接受的盐或其溶剂化物。
本发明化合物具有广谱抗菌活性,并且可以用于预防和治疗由包括人在内的哺乳动物中的病原菌引起的各种疾病,例如,气道感染性疾病、泌尿系统感染性疾病、呼吸系统感染性疾病、败血病、肾炎、胆囊炎、口腔感染性疾病、心内膜炎、肺炎、骨髓膜性脊髓炎(bone marrow membrane myelitis)、中耳炎、肠炎、积脓、创伤感染性疾病、机会性感染等。
本发明化合物尤其对革兰氏阴性菌,优选肠道细菌的革兰氏阴性菌(大肠杆菌(E. coli)、克雷伯杆菌属(Klebsiella)、灵杆菌(Serratia)、肠道细菌属(Enterobacter)、柠檬酸细菌属(Citrobacter)、摩根菌属(Morganella)、普罗威登斯菌属(Providencia)、变形菌(Proteus)等)、寄居于呼吸系统中的革兰氏阴性菌(嗜血杆菌属(Haemophilus)、莫拉菌属(Moraxella)等)以及葡萄糖非发酵的革兰氏阴性菌(绿脓杆菌(Pseudomonas aeruginosa)、除绿脓杆菌外的假单胞菌属(Pseudomonas other than P. aeruginosa)、寡养单胞菌属(Stenotrophomonas)、伯克氏菌属(Burkholderia)、不动杆菌属(Acinetobacter)等)显示出高的抗菌活性。这些化合物对这些革兰氏阴性菌产生的A类、B类、C类和D类的β-内酰胺酶稳定,并且对多种耐β-内酰胺类药物的革兰氏阴性菌(诸如产ESBL菌等)具有高的抗菌活性。这些对属于特别是包括IMP型、VIM型、L-1型等在内的B类的金属-β-内酰胺酶极其稳定,因而对耐多种β-内酰胺类药物(包括头孢烯类和碳青霉烯类)的革兰氏阴性菌有效。此外,本发明化合物还对革兰氏阳性菌,包括耐甲氧西林的金黄色葡萄球菌(MRSA)、耐青霉素的肺炎链球菌(PRSP)等具有抗菌活性。仍更优选的化合物具有关于体内动力学的特征,诸如血药浓度高、起效时间长和/或组织迁移性显著。更优选的化合物在副作用方面是安全的。同时,更优选的化合物具有高的水溶解度,并且因而特别适于可注射制剂。
化合物(I)可以作为可注射制剂、胶囊剂、片剂和颗粒剂胃肠外或口服给药,并且优选作为可注射制剂给药。基于每1kg的患者或动物的体重,剂量可以通常为约0.1~100mg/天,优选为约0.5~50mg/天,并且可以任选每天将剂量分成2~4次。在可注射制剂中使用的载体可以为,例如,蒸馏水、盐水等,并且可以另外使用碱来调节pH值。在胶囊剂、颗粒剂或片剂中使用的载体包括已知的赋形剂(如,淀粉、乳糖、蔗糖、碳酸钙、磷酸钙等)、粘合剂(如,淀粉、阿拉伯胶、羧甲基纤维素、羟丙基纤维素、微晶纤维素等)、润滑剂(如,硬脂酸镁、滑石等)等。
实施例
在下文中,采用工作实施例和实验实施例更详细地描述本发明。然而,本发明并不限于此。
在实施例中,各个缩写的含义如下所述。
ODS:十八烷基甲硅烷基
MeCN:乙腈
WSCD∙HCl:N-乙基-N’-(3-二甲基氨基丙基)碳二亚胺的盐酸盐
Me:甲基
Et:乙基
Pr:丙基
Ph:苯基
PMB:对甲氧基苄基
t-Bu:叔丁基
i-Pr:异丙基
Boc:叔丁氧羰基
BH:二苯甲基
Ms:甲磺酰基
Trt:三苯甲基
TBS:叔丁基二甲基甲硅烷基
Bn:苄基
实施例1
化合物(I-1)的合成
[式37]
Figure 730179DEST_PATH_IMAGE085
步骤(1):化合物1a → 化合物1b
向冰冷却的四氢呋喃(40 mL)中加入氢化铝锂(1.52 g,40 mmol),接着加入化合物1a(2.72 g,20 mmol)。回流加热45分钟后,在冰浴中冷却反应溶液。然后向其中加入十水合硫酸钠直到没有气泡产生。然后加入无水硫酸钠(5.0g),随后在室温搅拌1小时。经硅藻土过滤除去不溶物后,浓缩得到的滤液然后干燥,得到为无色液体的化合物1b(2.61 g,93% 收率)。
1H-NMR (CDCl3) δ: 1.36 (6H, t, J = 7.5 Hz), 2.43 (2H, s), 2.91 (6H, q, J = 7.5 Hz)。
步骤(2):化合物1c → 化合物1d
将亚氯酸钠(3.87 g,42.7 mmol)溶于水(20 mL)中。在冰冷却下向其中加入氨基硫酸(amidosulfuric acid)(4.15 g,42.7 mmol)和化合物1c(4.45 g,17.1 mmol)在甲醇(50 mL)中的溶液,然后在相同温度搅拌3小时。将反应溶液用水(150 mL)稀释后,过滤掉不溶物,然后用异丙醇/乙醚(1/1)洗涤。将过滤后的残留物在减压下干燥,得到化合物1d(3.98 g,84% 收率)。
1H-NMR (d6-DMSO) δ: 3.76 (3H, s), 4.90 (2H, s), 6.92-6.97 (3H, m), 7.50 (2H, d, J = 8.7 Hz), 8.33 (1H, s)。
步骤(3):化合物1d → 化合物1e
向化合物1d(829 mg,3.0 mmol)的乙醇(6.0 mL)溶液中加入28%的氨水溶液(aqueous 28% ammonium solution)(3.46 mL,45 mmol)。在室温搅拌12小时后,将混合物在室温静置过夜。真空蒸发溶剂,然后向其中加入水。随后,用1N的盐酸调节pH至2.5,并过滤掉沉淀的不溶物。将过滤后的残留物真空干燥,得到化合物1e(798 mg,97% 收率)。
1H-NMR (d6-DMSO) δ: 3.75 (3H, s), 5.09 (2H, s), 6.94 (2H, d, J = 8.4 Hz), 7.18 (1H, brs), 7.37 (2H, d, J = 8.4 Hz), 7.90 (1H, brs)。
步骤(4):化合物1e → 化合物1f
在冰冷却搅拌条件下,向化合物1e(1.69 g,6.14 mmol)的N,N-二甲基甲酰胺(18 mL)溶液中加入N-乙基-N’-(3-二甲基氨基丙基)碳二亚胺的盐酸盐(1.69 g,6.14 mmol)和1-羟基苯并三唑(954 mg,7.06 mmol)。在室温搅拌1小时后,再次将混合物用冰冷却,历时5分钟向其中加入化合物1b(1.03 g,7.37 mmol)的N,N-二甲基甲酰胺(6 mL)溶液。在相同温度搅拌2小时后,真空蒸发溶剂。将残留物加入到冷水中,然后用20%的碳酸钠水溶液调节pH到10。过滤掉沉淀,然后真空干燥,得到化合物1f(1.38 g,57% 收率)。
1H-NMR (d6-DMSO) δ: 0.90 (6H, t, J = 8.1 Hz), 2.34 (6H, t, J = 8.1 Hz), 2.63 (2H, d, J = 6.6 Hz), 3.33 (3H, s), 4.72 (2H, s), 6.52 (2H, d, J = 8.7 Hz), 6.95-6.98 (3H, m), 7.62 (1H, s), 7.89 (1H, t, J = 6.6 Hz)。
步骤(5):化合物1g → 化合物(I-1)
在冰冷却下,向化合物1g(506 mg,0.6 mmol) 的N,N-二甲基甲酰胺(2.0 mL)的溶液中加入化合物1f(262 mg,0.66 mmol)和溴化钠(123 mg,1.2 mmol)。将反应溶液在15℃的水浴中搅拌3小时后,向其中加入N,N-二甲基甲酰胺(4 mL),然后冷却到-40℃。在-40℃,向其中加入三溴化磷(phosphorus tribromide)(113 μl,1.2 mmol),然后在相同温度搅拌1小时。将反应溶液倒入到5%盐水(100 mL)中,并搅拌15分钟,然后过滤沉淀。沉淀真空干燥,得到浅棕色固体。将该固体的二氯甲烷(5 mL)溶液在搅拌下加入到冰浴冷却的苯甲醚(553 mL)三氟乙酸(7.0 mL)溶液中。将反应溶液在室温搅拌1.5小时并真空蒸发溶剂。这时,将水浴中的温度设定在不超过25℃。将残余物在搅拌下加入到冰冷却的二异丙醚(80 mL)中,然后过滤沉淀。干燥得到的固体,将其溶解在碳酸氢钠水溶液中,然后进行ODS柱色谱,用水-乙腈洗脱。将含有目标化合物的洗脱的级分真空浓缩以及冻干浓缩的溶液,得到为粉末的化合物I-1(185 mg,30%收率)。
1H-NMR (D2O) δ: 1.52 (3H, s), 1.53 (3H, s), 1.92 (6H, m), 3.36-3.49 (9H, m), 3.84-3.91 (2H, m), 4.59 (1H, m), 5.34 (1H, d, J = 5.1 Hz), 5.88 (1H, d, J = 5.1 Hz), 7.09 (1H, s), 7.70 (1H, s)。
C30H33N9Na2O10S2·8.7 H2O的元素分析
计算值:C, 37.96;H, 5.21;N, 13.13;S, 7.80;Na, 4.51 (%)
实测值:C, 37.07;H, 5.37;N, 13.32;S, 6.78;Na, 4.86 (%)。
实施例2
化合物(I-2)的合成
[式38]
Figure 236247DEST_PATH_IMAGE086
步骤(1):化合物2a → 化合物(I-2)
化合物I-2(305 mg,52% 收率)通过按照如实施例1中描述的方法使用化合物2a(637 mg,0.80 mmol)得到。
1H-NMR (D2O) δ: 1.48 (3H, s), 1.50 (3H, s), 1.92 (6H, t, J = 7.5 Hz), 3.36-3.49 (9H, m), 3.85-3.91 (1H, m), 4.57 (1H, d, J = 13.5 Hz), 5.34 (1H, d, J = 5.1 Hz), 5.86 (1H, d, J = 5.1 Hz), 6.96 (1H, s), 7.09 (1H, s), 7.72 (1H, s)。
C31H35N8NaO10S2·6.1 H2O·0.4NaHCO3的元素分析
计算值:C, 41.38;H, 5.33;N, 12.55;S, 7.29;Na, 3.68 (%)
实测值:C, 41.43;H, 5.27;N, 12.31;S, 7.05;Na, 3.54 (%)。
实施例3
化合物(I-3)的合成
[式39]
Figure 888683DEST_PATH_IMAGE087
步骤(1):化合物3a → 化合物3c
向化合物3a(561 mg,4.0 mmol)的乙醇(0.5 mL)溶液中加入化合物3b(404 mg),然后在回流下加热20小时。蒸发溶剂后,将残余物用氯仿稀释,然后用水洗涤。将有机层用无水硫酸镁干燥,过滤,然后浓缩。向残余物中加入乙酸异丙酯。过滤得到的沉淀的固体,然后干燥,得到化合物3c(312 mg,48%收率)。
1H-NMR (CDCl3) δ: 1.22 (6H, t, J = 8.4 Hz), 2.91 (6H, t, J = 8.4 Hz), 3.44 (2H, s), 5.22 (2H, s), 6.41 (1H, d, J = 7.5 Hz), 6.66 (1H, d, J = 2.1 Hz), 6.98 (1H, dd, J = 2.1, 7.5 Hz), 7.26-7.39 (5H, m)。
步骤(2):化合物3d → 化合物(I-3)
在冰浴冷却下,向化合物3d(444 mg,0.50 mmol)的N,N-二甲基甲酰胺(2.0 mL)溶液中加入化合物3c(162 mg,0.50 mmol)。将反应溶液在15℃水浴中搅拌3小时后,向其中加入N,N-二甲基甲酰胺(4 mL),然后用冰冷却至-40℃。在-40℃,向其中加入三溴化磷(47 μl,0.50 mmol),然后在相同温度搅拌1小时。将反应溶液倒入5%盐水(100 mL)中。搅拌15分钟后,过滤沉淀。将过滤的残余物真空干燥,得到浅棕色固体。向该固体的二氯甲烷(10 mL)溶液中加入苯甲醚(657 μl),然后冷却至-40℃。接着,在相同温度向该溶液中加入氯化铝(3.01 mL,2.0 M的硝基甲烷溶液),然后在室温搅拌3小时。将反应溶液在搅拌下倒入冰冷却的水(30 mL)、乙腈(30 mL)和二异丙醚(50 mL)的混合溶液中。分离水层,然后将有机层用水/乙腈/稀盐酸的混合溶液萃取。向合并的水层中加入HP20SS,然后浓缩至20 mL。将浓缩的悬浮液进行HP20SS柱色谱,用水-乙腈洗脱。将含有目标化合物的洗脱的级分真空浓缩,冻干浓缩的溶液,得到粉末状的化合物I-3(201 mg,42%收率)。
1H-NMR (D2O) δ: 1.48 (3H, s), 1.49 (3H, s), 1.90 (6H, m), 3.38-3.49 (7H, m), 3.81-4.10 (4H, m), 4.58 (1H, d, J = 13.2 Hz), 5.34 (1H, brs), 5.80 (1H, brs), 6.70 (1H, d, J = 6.3 Hz), 6.92 (1H. Brs), 7.30 (1H, brs), 7.58 (1H, d, J = 6.3 Hz)。
C30H35N7O10S2·9.3 H2O的元素分析
计算值:C, 41.17;H, 5.52;N, 11.54;S, 8.21 (%)
实测值:C, 41.45;H, 6.21;N, 11.28;S, 7.38 (%)。
实施例4
化合物(I-4)的合成
[式40]
Figure 771188DEST_PATH_IMAGE088
步骤(3):化合物4a → 化合物4b
将化合物4a(963 mg,3.5 mmol)的N,N-二甲基甲酰胺(7 mL)溶液冷却至0℃,然后加入N-(2-氨基乙基)-吡咯烷(480 mg,4.20 mmol)、N-乙基-N’-(3-二甲基氨基丙基)碳二亚胺的盐酸盐(738 mg,3.85 mmol)和1-羟基苯并三唑(520 mg,3.85 mmol),接着在室温搅拌1小时。蒸发溶剂,然后进行HP20SS柱色谱,用水-乙腈洗脱。将含有目标化合物的洗脱的级分真空浓缩,得到化合物4b(256 mg,20%收率)。
1H-NMR (DMSO) δ:1.66-1.70(4H, m), 2.40-2.60(4H, m), 3.10-3.80(4H, m), 3.75(3H, s), 5.15(2H, s), 6.92-7.00(2H, m), 7.37-7.39(2H, m), 7.44(1H, s), 8.11(1H, s), 8.43-8.50(1H, br)。
步骤(4):化合物4c + 化合物4b → 化合物4d → 化合物(I-4)
在将化合物4c(635 mg,0.68 mmol)的N,N-二甲基甲酰胺(3 mL)溶液冷却至0℃后,向其中加入化合物4b(253 mg,0.68 mmol),然后在室温搅拌1小时。将反应溶液用N,N-二甲基甲酰胺(6 mL)稀释,然后冷却至-40℃。接着,向其中加入三溴化磷(0.189 mL,2 mmol),接着搅拌1小时。将反应溶液加入到冷却的5%盐水中,过滤沉淀的固体,用水洗涤,然后空气干燥,得到化合物4d。
将化合物4d溶于二氯甲烷(10 ml)和苯甲醚(0.7 ml)中,然后冷却至-40℃。向其中加入2 mol/L-氯化铝/硝基甲烷溶液(3.4 ml),然后在0℃搅拌50分钟。向反应溶液中加入2N的盐酸水溶液(60 mL)、乙腈(50 mL)和乙醚(100 mL)。将分离的水层用乙醚洗涤,真空浓缩,然后进行ODS柱色谱,用乙腈-水洗脱。将含有所需化合物的洗脱的级分减压浓缩。向浓缩的溶液中,加入7%碳酸氢钠水溶液,然后再次进行ODS柱色谱,用乙腈-水洗脱。将含有所需化合物的洗脱的级分减压浓缩。将浓缩的溶液进一步进行ODS柱色谱,用乙腈-0.02 N盐酸水溶液洗脱。将含有所需化合物的洗脱的级分减压浓缩。将浓缩的溶液进一步进行ODS柱色谱,用乙腈-水洗脱。向含有所需化合物的级分中加入0.02 N氢氧化钠水溶液以调节至pH = 6并形成钠盐。减压浓缩得到的溶液,然后冻干,得到白色粉末状化合物I-4。收率69.9 mg (14%)。
1H-NMR (D2O) δ: 1.47(3H, s), 1.48(3H, s), 2.00-2.15(4H, m), 3.40-4.18(12H, m), 5.34(1H, d, J=5.1Hz), 5.85(1H, d, J=5.1Hz), 6.94(1H, s), 7.01(1H, s), 7.74(1H, s)。
C29H33N8O10S2Na·7.8H2O的元素分析
计算值:C, 39.36;H, 5.42;N, 12.73;S, 7.61;Na, 2.88 (%)
实测值:C, 39.52;H, 5.56;N, 12.72;S, 7.28;Na, 2.61 (%)。
实施例5
化合物(I-5)的合成
[式41]
Figure 61355DEST_PATH_IMAGE089
步骤(1):化合物5a → 化合物5b
向化合物5a(6.94g,30 mmol)中加入乙腈(120 mL)。向其中加入N-氯代琥珀酰亚胺(6.01g,45 mmol),然后在80℃搅拌90分钟。过滤沉淀的固体,先用乙腈再用水洗涤,然后空气干燥,得到化合物5b。收率5.21g (65%)。
1H-NMR (CDCl3) δ:3.15-3.70(1H, br), 4.54(1H, s), 5.03(1H, s), 7.22-7.50(6H, m)。
步骤(2):化合物5b → 化合物5c
将化合物5b(5.21 g,19.61 mmol)溶于氯仿(80 mL)中。向其中加入二氧化锰(6.82g,78 mmol),然后回流3小时。静置过夜后,进一步加入二氧化锰(13.6g,156 mmol),然后回流4小时。经硅藻土过滤后,向其中加入甲醇/氯仿。向其中加入二氧化锰(6.82g,78 mmol),然后进一步回流3小时。经硅藻土过滤后,减压蒸发溶剂,得到化合物5c。收率4.0g (77%)。
步骤(3):化合物5c → 化合物5d
将化合物5c(4g,15.17 mmol)悬浮于水(5 mL)中,然后向其中加入氨基硫酸(3.68g,37.9 mmol)。冷却至0℃后,向其中逐滴加入甲醇(40 mL)和亚氯酸钠(3.43g,37.9 mmol)水溶液(35 mL)。在室温搅拌1小时后,减压蒸发溶剂。将残余物进行HP20SS色谱,用水-乙腈洗脱。浓缩含有所需化合物的洗脱的级分,得到化合物5d。收率2.34g (55.2%)。
1H-NMR (DMSO) δ:5.17(2H, s), 7.30-7.50(6H, m), 7.60-7.80 (1H, br)。
步骤(4):化合物5d → 化合物5e
向化合物5d(839 mg,3 mmol)和N-(2-氨基乙基)-吡咯烷(514 mg,4.5 mmol)的N,N-二甲基甲酰胺(8 mL)溶液中加入O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐(1.37g,3.60 mmol)和三乙胺(0.499 mL,3.60 mmol),然后静置过夜。真空蒸发溶剂后,进行HP20SS柱色谱,用乙腈-水洗脱。收集含有所需化合物的级分,并浓缩,得到化合物5e。收率530 mg (47%)。
1H-NMR (DMSO) δ:1.80-2.00(4H, m), 3.00-4.00 (8H, m), 5.24(2H, s), 7.12-7.50(5H, m), 7.90(1H, s), 8.79-8.82 (1H, br)。
步骤(5):化合物4c + 化合物5e → 化合物5f → 化合物(I-5)
将化合物4c(934 mg,1.0 mmol)的N,N-二甲基甲酰胺(3 mL)溶液冷却至0℃。向其中加入化合物5e(376 mg,1.0 mmol),然后在室温搅拌2小时。将反应溶液用N,N-二甲基甲酰胺(6 mL)稀释,然后冷却至-40℃。接着,向其中加入三溴化磷(0.189 mL,2 mmol),然后搅拌1小时。在将反应溶液加入到预先冷却至0℃ 的5%盐水中后,过滤沉淀的固体,用水洗涤,并空气干燥,得到化合物5f。
将化合物5f溶于二氯甲烷(10 ml)和苯甲醚(1.1 ml)中,然后冷却至-40℃。接着,向其中加入2 mol/L-氯化铝/硝基甲烷溶液(5 ml),然后在0℃搅拌50分钟。向反应溶液中加入2N的盐酸水溶液(60 mL)、乙腈(50 mL)和乙醚(100 mL)。将分离的水层用乙醚洗涤,减压浓缩,然后进行HP-20SS柱色谱,用乙腈-水洗脱。向含有所需化合物的洗脱的级分中加入0.02 N的氢氧化钠水溶液以调节pH = 6。将得到的溶液真空浓缩,然后冻干得到白色粉末状化合物I-5。收率26 mg (3%)。
1H-NMR (D2O) δ: 1.48(3H, s), 1.50(3H, s), 2.00-2.20(4H, m), 3.20-4.00(11H, m), 5.20(1H, d, J=4.5Hz), 5.28(1H, d, 16.2Hz), 5.84(1H, d, J=4.5Hz), 6.98(s, 1H), 7.75(s, 1H)。
C29H32ClN8O10S2Na·7.4H2O (NaHCO3)0.4的元素分析
计算值:C, 37.30;H, 4.86;Cl, 3.90;N, 11.80;S, 7.39;Na, 3.75(%)
实测值:C, 37.48;H, 5.05;Cl, 3.76;N, 11.89;S, 6.81;Na, 3.42(%)。
实施例6
化合物(I-6)的合成
[式42]
步骤(1):化合物4c + 化合物6a → 化合物6b → 化合物6c
在15℃,向化合物4a(28.0g,30 mmol)的N,N-二甲基乙酰胺(45 mL)溶液中逐滴加入化合物6a(8.04g,30 mmol)的N,N-二甲基甲酰胺(45 mL)溶液。在室温搅拌2小时后,向其中加入N,N-二甲基甲酰胺(180 mL),然后冷却至-40℃。接着,向反应溶液中加入三溴化磷(5.66 mL,60 mmol),然后搅拌1小时。将反应溶液加入到预先冷却至0℃的5%亚硫酸钠水溶液中,然后过滤沉淀的固体。将过滤出的残余物悬浮在水中,然后冻干。
将得到的化合物6b用类似于实施例4中对4d的方法处理,得到化合物6c。
将化合物6b溶于二氯甲烷(300 ml)和苯甲醚(33 ml)中,然后冷却至-40℃。向其中加入2 mol/L-氯化铝/硝基甲烷溶液(150 mL,300 mmol),然后在0℃搅拌50分钟。向反应溶液中加入2 N的盐酸水溶液(60 mL)、乙腈(50 mL)和乙醚(100 mL)。将分离的水层用乙醚洗涤,真空浓缩,并进行ODS柱色谱,用乙腈-水洗脱。将含有所需化合物的洗脱的级分减压浓缩,然后冻干,得到白色粉末状化合物6c。收率4.84g (28%)。
1H-NMR (D2O) δ:1.50(3H,s), 1.51(3H, s), 2.10-2.40(4H, m), 3.40-3.80(10H, m), 3.90(1H, d, J=16.8Hz), 4.11(1H, d, J=16.8Hz), 5.37(1H, d, J=5.1Hz), 5.86(1H, d, J=5.1Hz), 6.98 (1H, s)。
步骤(2):化合物6c + 化合物6d → 化合物6e
向化合物6d的四氢呋喃(8 mL)溶液中加入三乙胺(0.22 mL,1.59 mmol)。冷却至15℃后,加入五氯化磷(267 mg,1.28 mmol),然后搅拌1小时以制备酰氯。同时,向化合物6c(582 mg,1 mmol)的水和四氢呋喃(8 mL)溶液中加入三乙胺(1.25 mL,9 mmol),然后冷却至0℃。向得到的溶液中一次性加入之前制备的酰氯,然后在0℃搅拌1小时。在加入稀盐酸并确定该混合液为酸性后,将混合物进行HP-20SS柱色谱,用乙腈-水洗脱所需化合物。加入0.02 N氢氧化钠水溶液以调节pH = 6并形成钠盐。将溶液真空浓缩,然后冻干,得到白色粉末状化合物6e。收率226 mg (26%)。
1H-NMR (DMSO) δ:1.39(3H, s), 1.46(3H, s), 1.90-2.20(4H, m), 3.00-3.60(12H, m), 3.75(3H, s), 5.04(2H, s), 5.11-5.12(1H, m), 5.70-5.80(1H, m), 6.73(1H, s), 6.80-7.50(6H, m)。
步骤(3):化合物6e → 化合物(I-6)
向三氟乙酸(5.5 mL)中加入苯甲醚(0.38 mL),并冷却至0℃,然后加入化合物6e的二氯甲烷溶液。在0℃搅拌1小时后,减压蒸发溶剂。然后向反应溶液中加入2 N的盐酸水溶液(60 mL)、乙腈(50 mL)和乙醚(100 mL)。将分离的水层用乙醚洗涤,减压浓缩,然后进行HP-20SS柱色谱,用乙腈-水洗脱所需化合物。向溶液中加入0.02 N的氢氧化钠水溶液以调节pH = 6以形成钠盐。减压浓缩溶液,然后冻干,得到白色粉末状化合物I-6。收率115 mg (43%)。
1H-NMR (D2O) δ:1.50(3H, s), 1.51(3H, s), 2.00-2.15(4H, m), 3.40-4.20(12H, m), 5.37(1H, d, J=4.8Hz), 5.89(1H, d, J=4.8Hz), 6.99(1H, s), 7.38(1H, s), 7.99(1H, s)。
C29H33N8O11S2Na·6H2O (NaHCO3)的元素分析
计算值:C, 38.20;H, 5.08;N, 12.12;S, 7.29;Na, 5.17(%)
实测值:C, 37.98;H, 4.89;N, 11.81;S, 6.76;Na, 4.85(%)。
实施例7
化合物(I-7)的合成
[式43]
Figure 379521DEST_PATH_IMAGE091
步骤(1):化合物7a → 化合物7c
向化合物7a(851 mg,2.0 mmol)的N,N-二甲基乙酰胺(8 mL)溶液中加入三乙胺(665 μl,4.8 mmol)。冷却至-15℃后,加入甲磺酰氯(187 μl,2.4 mmol)。在-15℃搅拌1小时后,向其中加入化合物7b(303 mg,2.4 mmol),然后在-15℃搅拌3.5小时。真空蒸发溶剂,然后将5%碳酸氢钠水溶液加入到得到的浓缩残余物中,接着用乙酸乙酯萃取。将有机层先用5%碳酸氢钠水溶液洗涤,再用饱和盐水洗涤,然后用无水硫酸钠干燥。通过过滤除去无机物质,接着真空浓缩。将得到的粗产物经硅胶柱色谱纯化,得到棕色泡沫状化合物7c。收率373 mg,(35%)。
MS (m+1) = 534.25。
步骤(2):化合物7d + 化合物7c → 化合物7e → 化合物(I-7)
在将化合物7d(648 mg,0.69 mmol)的N,N-二甲基乙酰胺(2 mL)溶液冷却至15℃后,历时10分钟向其中逐滴加入7c(370 mg,0.69 mmol)的N,N-二甲基乙酰胺(1 mL)溶液,然后在15℃搅拌7.5小时。向反应溶液中加入N,N-二甲基甲酰胺(1.6 mL),然后冷却至-40℃。接着,加入三溴化磷(131 μl,1.4 mmol),然后在-40℃下搅拌30分钟。将反应混合物慢慢的加入到预先冰冷却的5%的盐水中。过滤沉淀的固体,然后用水洗涤。将残余物悬浮在水中,然后冻干得到棕色固体化合物7e。将得到的化合物7e不经过纯化直接用于下一步反应。
将得到的全部量的化合物7e溶于二氯甲烷(7 ml)中,然后冷却至-40℃。向其中先加入苯甲醚(757 μl,6.9 mmol),接着加入2 mol/L-氯化铝/硝基甲烷溶液(3.45 mL,6.9 mmol),然后在0℃搅拌45分钟。向反应溶液中加入2 N的盐酸水溶液、乙腈、和二异丙醚,然后搅拌。通过倾析将不溶物从上清液分离,然后从上清液分离出水层。同时,将水和乙腈加入到粘有不溶物的容器中,然后搅拌。在不溶物全部溶解后,向其中加入二异丙醚,然后分离水层。然后将有机层用水萃取。合并所有的水层,向其中加入HP20-SS树脂,然后减压浓缩含有乙腈的溶液。将得到的混合悬浮液经ODS柱色谱纯化。向得到的含有目标化合物的级分中加入0.2 N的氢氧化钠水溶液以调节pH = 6.0,然后加入一块干冰。将得到的溶液真空浓缩,然后冻干,得到黄色粉末状化合物I-7。收率111 mg,(21%)。
1H-NMR (D2O) δ:1.43 (3H, s), 1.45 (3H, s), 2.16 (4H, br), 3.40-4.26 (13H, m), 5.29 (1H, d, J=4.5 Hz), 5.82 (1H, d, J=4.8 Hz), 6.71 (1H, br), 6.91 (1H, s), 7.71 (1H, s)
MS (m+1) = 731.33。
实施例8
化合物(I-8)的合成
[式44]
Figure 800138DEST_PATH_IMAGE092
步骤(1):化合物8a → 化合物8c
向化合物8a(851 mg,2.0 mmol)的N,N-二甲基乙酰胺(9 mL)溶液中加入三乙胺(665 μl,4.8 mmol)和化合物8b(252 mg,2.0 mmol),在冰冷却下加入O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐(913 mg,2.4 mmol),然后在室温搅拌45分钟。减压蒸发溶剂后,将5%碳酸氢钠水溶液加入到得到的浓缩残余物中,接着用乙酸乙酯和四氢呋喃的混合溶剂萃取。将有机层用5%碳酸氢钠水溶液洗涤,再用饱和盐水洗涤,然后用无水硫酸钠干燥。通过过滤除去无机物质,接着减压浓缩。将得到的粗产物经硅胶柱色谱纯化,得到棕色泡沫状化合物8c。收率565 mg,(53%)。
MS (m+1) = 534.25。
步骤(2):化合物8d + 化合物8c → 化合物8e → 化合物(I-8)
向化合物8d(1.02g,1.0 mmol)的N,N-二甲基乙酰胺(3 mL)溶液中加入溴化钠(204 mg,2.0 mmol),然后在室温搅拌30分钟。在将反应溶液冷却至15℃后,历时10分钟逐滴加入化合物8c(534 mg,1.0 mmol)的N,N-二甲基乙酰胺(1.5 mL)溶液,然后在相同温度搅拌7小时。向反应溶液中加入N,N-二甲基甲酰胺(2.5 mL),然后冷却至-40℃。接着,加入三溴化磷(189 μl,2.0 mmol),然后在-40℃搅拌30分钟。将反应混合物缓慢加入到预先冰冷却的5%的盐水中。过滤沉淀的固体,用水洗涤,悬浮在水中,然后冻干,得到棕色固体状化合物8e。将得到的化合物8e不经过纯化直接用于下一步反应。
将得到的全部量的化合物8e溶于二氯甲烷(10 ml)中,然后冷却至-40℃。向其中先加入苯甲醚(1.09 mL,10 mmol),接着加入2 mol/L-氯化铝/硝基甲烷溶液(5.0 mL,10 mmol),然后在-40℃搅拌1小时。向反应溶液中加入2 N的盐酸水溶液、乙腈和二异丙醚,然后搅拌。通过倾析将不溶物从上清液分离。从上清液分离出水层。同时,将水和乙腈加入到粘有不溶物的容器中,然后搅拌。在将不溶物全部溶解后,向其中加入二异丙醚,然后分离水层。然后将有机层用水萃取。合并所有的水层,向其中加入HP20-SS树脂,然后浓缩。将得到的混合悬浮液经ODS柱色谱纯化。向含有目标化合物的得到的级分中加入0.2 N的氢氧化钠水溶液以调节pH = 5.2,然后真空浓缩溶液。将浓缩的溶液冻干,得到黄色粉末状化合物I-8。收率122 mg,(16%)。
1H-NMR (D2O) δ:1.42 (3H, s), 1.44 (3H, s), 2.29 (4H, br), 3.36-4.32 (13H, m), 5.29 (1H, d, J=4.8 Hz), 5.80 (1H, d, J=4.8 Hz), 6.70 (1H, s), 6.90 (1H, s), 7.69 (1H, s)。
MS (m+1) = 731.22。
C30H33N8O10S2Na·0.1NaHCO3·6.6H2O的元素分析:
计算值:C, 41.08;H, 5.30;N, 12.73;S, 7.29;Na, 2.87 (%)
实测值:C, 40.89;H, 5.19;N, 12.78;S, 8.08;Na, 3.02 (%)。
实施例9
化合物(I-9)的合成
[式45]
Figure 210391DEST_PATH_IMAGE093
步骤(1):化合物9a + 化合物9b → 化合物9c → 化合物(I-9)
向化合物9a (720 mg,0.75 mmol)的N,N-二甲基乙酰胺(2 mL)溶液中加入碘化钠(225 mg,1.5 mmol),然后在室温搅拌10分钟。冷却至15℃后,历时5分钟向其中逐滴加入化合物9b(534 mg,1.0 mmol)的N,N-二甲基乙酰胺(1 mL)溶液,然后在室温搅拌6小时。向反应溶液中加入N,N-二甲基甲酰胺(2 mL),然后冷却至-40℃。接着,向其中加入三溴化磷(141 μl,1.5 mmol),然后在-40℃搅拌30分钟。将反应混合物慢慢地加入到预先冰冷却的5%的盐水中。过滤沉淀的固体,用水洗涤,悬浮在水中,然后冻干,得到浅橙色固体状化合物9c。将得到的化合物9c不经过纯化直接用于下一步反应。
将得到的全部量的化合物9c溶于二氯甲烷(10 ml)中,然后冷却至-40℃。向其中先加入苯甲醚(735 μl,6.73 mmol),接着加入2 mol/L-氯化铝/硝基甲烷溶液(3.36 mL,6.73 mmol),然后在0℃搅拌1小时。向反应溶液中加入2 N的盐酸水溶液、乙腈和二异丙醚,然后搅拌。然后分离水层。将有机层用水/乙腈/稀盐酸的混合溶液萃取。合并所有的水层,向其中加入HP20-SS树脂,然后减压浓缩含有乙腈的溶液。将得到的混合悬浮液经ODS柱色谱纯化。向含有目标化合物的得到的级分中加入0.2 N的氢氧化钠水溶液以调节pH = 6.0,然后加入一块干冰。将得到的溶液真空浓缩,然后冻干,得到黄色粉末状化合物I-9。收率45.6 mg,(8%)。
1H-NMR (D2O) δ: 7.79 (1H, s), 7.03 (1H, s), 6.78 (1H, s), 5.91 (1H, d, J = 5.20 Hz), 5.37 (1H, d, J = 4.70 Hz), 4.38-3.86 (7H, m), 3.72-3.47 (5H, m), 2.14 (4H, d, J = 51.53 Hz), 1.47 (3H, d, J = 7.05 Hz)。
C29H31N8O10S2Na·0.15NaHCO3·6.5H2O的元素分析:
计算值:C, 40.32;H, 5.12;N, 12.90;S, 7.38;Na, 3.04 (%)
实测值:C, 40.53;H, 4.90;N, 12.65;S, 7.52;Na, 3.04 (%)。
实施例10
化合物(I-10)的合成
[式46]
Figure 58261DEST_PATH_IMAGE094
步骤(1):化合物10a + 化合物10b → 化合物10c
向化合物10a (952 mg,1 mmol)的N,N-二甲基乙酰胺(3 mL)溶液中加入碘化钠(300 mg,2 mmol),然后将混合物在室温搅拌10分钟。将混合物冷却至0℃后,并加入化合物10b(534 mg,1 mmol)和碳酸氢钠(336 mg,4 mmol)。将混合物在15℃搅拌1.5小时。向得到的混合物中加入DMF(6mL)并冷却至-40℃。加入乙酰氯(0.5 mL,7 mmol)、碘化钾(830 mg,5 mmol)和三溴化磷(0.189 mL,2 mmol)并将混合物搅拌1小时。将得到的混合物倒入冷却的5%的亚硫酸氢钠(sodium hydrigensulfite)水溶液(30 mL)中,然后通过过滤收集沉淀的物质,用水洗涤并干燥,得到化合物10c,将其不经过进一步纯化而直接用于下一步反应。
步骤(2):化合物10c → 化合物(I-10)
向化合物10c的二氯甲烷(10 ml)溶液中加入苯甲醚(1.0 mL,10 mmol),然后将混合物冷却至-40℃。向混合物中加入2 mol/L-氯化铝/硝基甲烷溶液(5.0 mL)。将混合物在0℃搅拌50分钟,然后在室温再搅拌1小时。向得到的混合物中加入2 mol/L的HCl /水(60 mL)、乙腈(50 mL)和乙醚(100 mL)。浓缩有机层,然后将残余混合物经HP-20SS柱色谱用水-乙腈洗脱纯化。向含有所需化合物的级分中加入0.2 N氢氧化钠水溶液以调节pH = 6.0并形成其钠盐。真空浓缩,接着冻干,得到粉末状化合物I-10。收率(196 mg,26%)。
1H-NMR(D2O) δ:0.97(3H, t), 1.80-2.60(6H, m), 3.40-4.40(13H, m), 5.36(1H, d, J=5.1Hz), 5.88(1H, d, J=5.1Hz,), 6.85-6.95(1H, br), 7.00(1H, s), 7.79(1H, s)。
C30H33N8O10S2Na·5.8H2O·(NaHCO3)0.2的元素分析
计算值:C, 41.50;H, 5.17;N, 12.82;S, 7.34;Na, 3.16 (%)
实测值:C, 41.40;H, 5.10;N, 12.81;S, 7.49;Na, 3.36 (%)。
实施例11
化合物(I-11)的合成
[式47]
Figure 419710DEST_PATH_IMAGE095
步骤:化合物11a + 化合物10b → 化合物(I-11)
化合物I-11是通过如针对化合物I-10的合成所描述的方法从化合物11a和化合物10b得到的 (收率: 283 mg,35%)。
1H-NMR(D2O) δ:1.90-4.20 (20H,m), 5.33 (1H, J=4.8Hz, d), 5.82 (1H, J=4.8Hz, d), 6.79-6.80 (1H, br), 7.01 (1H, s), 7.80 (1H, s)。
C30H30N8O12S2Na2·7H2O的元素分析
计算值:C, 38.71;H, 4.76;N, 12.04;S, 6.89;Na, 4.94 (%)
实测值:C, 38.67;H, 4.78;N, 11.93;S, 6.88;Na, 4.67 (%)。
实施例12
化合物(I-12)的合成
[式48]
Figure 644018DEST_PATH_IMAGE096
步骤(1):化合物12a → 化合物12b
将化合物12a(1.03 g,2.5 mmol)溶于乙酸乙酯(10 mL)中并加入4 mol/L盐酸/乙酸乙酯溶液(3.75 mmol,15 mmol)。加入乙醚并通过倾析除去溶剂。与甲苯共沸蒸馏并真空干燥,得到残余物,化合物12b(550 mg,定量)。
1H-NMR(D2O) δ: 2.98(3H, s), 2.99-4.20(10H, m)。
步骤(2):化合物12b + 化合物12c → 化合物12d
向化合物12c(2.55 g,6 mmol)的DMF(25 mL)溶液中加入WSCD-HCl (1.38 g,7.20 mmol)和HOBt水合物(1.10 g,7.20 mmol)。将混合物在室温搅拌30分钟。将得到的混合物冷却至0℃,然后加入化合物12b(1.49 g,7.5 mmol)的DMF(25mL)溶液和三乙胺(1.66mL,12mmol)。经蒸发除去溶剂。加入乙酸乙酯和四氢呋喃,并将有机层用水和盐水洗涤,然后用MgSO4干燥并过滤。减压除去溶剂。经硅胶柱色谱纯化,得到化合物12d(2.44 g,76%)。
1H-NMR(CDCl3) δ: 1.80-2.80(9H, m), 3.0-4.20(15H, m), 5.08(1H, s), 6.25-7.35(9H,m)。
步骤(3):化合物12e + 化合物12d → 化合物(I-12)
化合物I-12是通过与化合物I-10类似的方法从化合物12e和化合物12d制备得到的 (收率:39%)。
1H-NMR(D2O) δ: 1.49(3H,s), 1.51(3H,s), 3.00-4.20(17H,m), 5.37-5.39(1H,m), 5.86-5.89(1H,m), 6.82(1H,s), 6.98(1H,s), 7.77(1H,s)。
C30H33N8O10S2Na·6.7H2O的元素分析
计算值:C, 41.25;H, 5.35;N, 12.83;S, 7.34;Na, 2.63 (%)
实测值:C, 41.22;H, 5.26;N, 12.80;S, 7.48;Na, 2.74 (%)。
实施例13
化合物(I-13)的合成
[式49]
Figure 908777DEST_PATH_IMAGE097
步骤:化合物13a + 化合物13b → 化合物13c → 化合物(I-13)
化合物I-13是通过与针对化合物I-10的合成所描述的方法从化合物13a和化合物13b得到的(收率:480 mg,34%)。
1H-NMR (D2O) δ: 7.75 (1H, s), 6.97 (1H, s), 6.72 (1H, s), 5.85 (1H, s), 5.38 (1H, d, J = 5.0 Hz), 4.08-3.88 (4H, m), 3.72 (1H, t, J = 12.0 Hz), 3.49 (1H, d, J = 16.6 Hz), 3.39-3.25 (1H, m), 3.08 (3H, br s), 2.98 (3H, br s), 2.46-2.17 (2H, m), 2.03-1.80 (2H, m), 1.51 (3H, s), 1.50 (3H, s)。
C30H35N8O10S2Na 7.2H2O 0.2NaOH的元素分析
计算值:C,40.37;H,5.60;N,12.56;Na,3.09;S,7.19 (%)
实测值:C,40.29;H,5.44;N,12.66;Na,3.20;S,7.44 (%)。
实施例14
化合物(I-14)的合成
[式50]
Figure 193128DEST_PATH_IMAGE098
步骤:化合物14a + 化合物14b → 化合物14c → 化合物(I-14)
化合物I-14是通过与针对化合物I-10的合成所描述的方法从化合物14a和化合物14b得到的(收率:560 mg,27%)。
1H-NMR (D2O) δ: 7.77-7.75 (1H, m), 6.96 (1H, s), 6.90-6.81 (1H, m), 5.92-5.83 (1H, m), 5.38 (1H, dd, J = 13.2, 5.0 Hz), 4.97-4.60 (0H, m), 4.50-3.60 (7H, m), 3.49 (1H, t, J = 14.7 Hz), 3.25-2.87 (7H, m), 2.65-2.31 (2H, m), 1.59-1.39 (6H, m)。
C29H33N8O10S2Na(H2O)7.1的元素分析
计算值:C, 40.10;H, 5.48;N, 12.90;S, 7.38;Na, 2.65 (%)
实测值:C, 40.04;H, 5.34;N, 12.89;S, 7.42;Na, 2.81 (%)。
实施例15
化合物(I-15)的合成
[式51]
Figure 543338DEST_PATH_IMAGE099
步骤:化合物15a + 化合物15b → 化合物15c → 化合物(I-15)
化合物I-15是通过与针对化合物I-10的合成所描述的方法从化合物15a和化合物15b得到的(收率:27mg,3%)。
质谱:
计算值:738.15,
实测值:[M+1] = 739.39。
实施例16
化合物(I-16)的合成
[式52]
Figure 305758DEST_PATH_IMAGE100
步骤(1):化合物16a → 化合物16b
将已知的化合物16a(Bioorganic & Medicinal Chemistry 17 (2009) 6106-6122))溶解在N,N-二甲基甲酰胺(30mL)中并加入碳酸钾(2.99g,21.62mmol)、对甲氧基苄基氯(2.99g,21.62mmol)和碘化钠(3.24g,21.62mmol)。将混合物在室温搅拌直到反应结束,然后将水加入到反应混合物中。将水层用乙酸乙酯萃取。用水和盐水洗涤有机层,用硫酸镁干燥,过滤,并真空浓缩。残余物经硅胶色谱纯化,得到化合物16b(4.44g,15.35mmol)。
1H-NMR (CDCl3) δ: 7.98 (1H, d, J = 2.5 Hz), 7.79 (1H, dd, J = 9.4, 2.5 Hz), 7.34 (2H, dt, J = 9.5, 2.5 Hz), 6.89 (2H, dt, J = 9.2, 2.5 Hz), 6.64 (1H, d, J = 9.5 Hz), 5.24 (2H, s), 3.81 (3H, s), 3.81 (3H, s)。
步骤(2):化合物16b → 化合物16c → 化合物16d
将化合物16b(4.4g,14mmol)溶于四氢呋喃(20mL)和甲醇(20mL)中并加入2 mol/L的氢氧化钠水溶液(23mL)。将混合物在室温搅拌1小时。向反应混合物中加入2mol/L的盐酸水溶液(22mL),然后减压除去溶剂。通过过滤收集得到的沉淀,用水洗涤,并真空干燥,得到化合物16c(3.98g,14.46mmol)。
将化合物16c(1.376g,5mmol)溶于二氯甲烷中。加入2-(吡咯烷-1-基)乙胺(0.685g,6mmol)、1-羟基苯并三唑和1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐 (1.15g,6mmol),并将混合物在室温搅拌。将水加入到混合物中,将水层用2 mol/L的氢氧化钠水溶液碱化并用乙酸乙酯萃取。将有机层用水和盐水洗涤,用硫酸镁干燥,过滤,并在真空中除去溶剂。残余物经色谱纯化,得到化合物16d。
1H-NMR (CDCl3) δ: 7.95 (1H, d, J = 2.6 Hz), 7.62 (1H, dd, J = 9.6, 2.5 Hz), 7.35 (2H, dt, J = 9.6, 2.5 Hz), 6.89 (2H, dt, J = 8.7, 2.4 Hz), 6.67-6.64 (2H, m), 5.23 (2H, s), 3.81 (3H, s), 3.45 (2H, dd, J = 4.7, 10.9 Hz), 2.65 (2H, t, J = 6.4 Hz), 2.58-2.50 (4H, m), 2.22 (2H, br s), 1.84-1.77 (4H, m)。
步骤(3):化合物16e → 化合物16f → 化合物(I-16)
将化合物16e(0.842g,1mmol)溶解于N,N-二甲基乙酰胺(3.3 mL)中。加入碘化钠(0.3g,2mmol)和化合物16d(659mg,1mmol),并将混合物在10℃搅拌。向混合物中加入水并用乙酸乙酯萃取。将有机层用水和盐水洗涤,用硫酸镁干燥,过滤,并在真空中除去溶剂,得到化合物16f。
将化合物16f溶于二氯甲烷(15 mL)中并冷却至-40℃。加入三溴化磷(0.189mL,2mmol)并在相同温度搅拌1小时。然后向混合物中加入苯甲醚(1.09mL,10mmol)和2 mol/L-氯化铝/硝基甲烷溶液(5.0 mL,10 mmol)并在0℃搅拌。向溶液中加入水(30mL)和二异丙醚(50 mL)。加入乙腈和2 mol/L的盐酸以溶解(solbilize)沉淀,然后分离水层。将有机层用水/乙腈/稀HCl 混合物萃取。将HP-20SS树脂加入水层中,浓缩,然后进行HP20SS/ODS柱色谱,用水-乙腈洗脱。向含有所需化合物的级分中加入0.2 mol/L的氢氧化钠水溶液以形成钠盐。真空浓缩,然后冻干,得到粉末状化合物I-16(178 mg,24%)。
1H-NMR (D2O) δ: 8.62 (1H, s), 8.04 (1H, d, J = 9.9 Hz), 7.07-6.94 (2H, m), 5.84-5.76 (1H, m), 5.40-5.29 (1H, m), 4.79 (1H, d, J = 14.1 Hz), 3.99-3.47 (11H, m), 2.21 (4H, s), 1.55-1.44 (6H, m)。
元素分析
计算值:C, 39.93;H, 5.50;N, 12.85;S, 7.35;Na, 2.64 (%)
实测值:C, 39.91;H, 5.22;N, 12.80;S, 7.39;Na, 2.92 (%)。
实施例17
化合物(I-17)的合成
[式53]
Figure 425023DEST_PATH_IMAGE101
步骤(1):化合物17a + 化合物17b → 化合物17c
使用1-羟基苯并三唑、1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐和二异丙基乙胺将化合物17a(1.28 g,6.00 mmol)和化合物17b(2.13 g,5.00 mmol)反应。将含有化合物的液体进行氨基硅胶柱色谱,用氯仿洗脱。减压浓缩含有所需化合物的级分,得到化合物17c(1.43g,52%)。
1H-NMR (DMSO-d6) δ: 8.37 (1H, d, J = 4.70 Hz), 7.55 (1H, s), 7.29 (2H, d, J = 8.73 Hz), 6.90 (2H, d, J = 8.73 Hz), 6.85 (1H, d, J = 8.39 Hz), 6.52 (1H, d, J = 2.43 Hz), 6.41 (1H, dd, J = 8.39, 2.43 Hz), 6.15 (1H, s), 5.10 (2H, s), 4.95 (2H, s), 3.75 (3H, s), 3.74 (3H, s), 3.70 (3H, s), 2.93 (2H, br s), 2.11 (3H, s), 2.00-1.69 (6H, m), 1.60 (1H, br s), 1.56 (1H, br s)。
步骤(2):化合物17d + 化合物17c → 化合物(I-17)
使用化合物17d(796 mg,1.000 mmol)和化合物17c(602 mg,1.100 mmol)经与上述相同的方法制备化合物I-17。
产量:221.2 mg,(23%)。
1H-NMR (D2O) δ: 7.78 (1H, s), 7.10 (1H, s), 6.98 (1H, s), 5.89 (1H, d, J = 4.88 Hz), 5.38 (1H, d, J = 4.88 Hz), 4.63 (1H, d, J = 14.18 Hz), 4.25 (1H, t, J = 7.02 Hz), 4.10-3.94 (4H, m), 3.51 (1H, d, J = 16.93 Hz), 3.10 (3H, br s), 2.81-2.70 (2H, m), 2.59-2.36 (4H, m), 2.25 (1H, br s), 2.19 (1H, br s), 1.52 (3H, s), 1.50 (3H, s)。
元素分析:C31H35N8O10S2Na(H2O)8.4
计算值:C,40.55;H,5.69;N,12.20;S,6.99;Na,2.50 (%)
实测值:C,40.59;H,5.62;N,12.05;S,6.80;Na,2.57 (%)。
实施例18
化合物(I-18)的合成
[式54]
Figure 880276DEST_PATH_IMAGE102
步骤:化合物18a + 化合物17c → 化合物(I-18)
使用化合物18a(1.26 g,1.000 mmol)和化合物17c(602 mg,1.100 mmol)经与上述相同的方法制备化合物I-18。
产量:268.1 mg,(26%)。
1H-NMR (D2O) δ: 7.76 (1H, s), 7.08 (1H, s), 6.99 (1H, s), 5.84 (1H, d, J = 4.88 Hz), 5.34 (1H, d, J = 4.88 Hz), 4.98 (1H, dd, J = 8.16, 5.11 Hz), 4.61 (1H, d, J = 14.03 Hz), 4.24 (1H, t, J = 7.17 Hz), 4.13-3.89 (4H, m), 3.50 (1H, d, J = 16.62 Hz), 3.10 (3H, br s), 2.79-2.71 (4H, m), 2.59-2.32 (4H, m), 2.24 (1H, br s), 2.18 (1H, br s)。
元素分析:C31H32.1N8O12S2Na1.9(H2O)9.2
计算值:C,37.90;H,5.18;N,11.41;S,6.53;Na,4.45 (%)
实测值:C,38.14;H,5.20;N,11.16;S,6.38;Na,4.46 (%)。
实施例19
化合物(I-19)的合成
[式55]
Figure 216317DEST_PATH_IMAGE103
步骤(1):化合物19a + 化合物19b → 化合物19c
化合物19c是由化合物19a(0.147 g,0.32 mmol)经与上述相同的方法合成的(0.122 g,68%)。
1H-NMR (DMSO-d6) δ: 8.14 (1H, s), 7.52-7.25 (12H, m), 7.10-7.07 (1H, m), 6.99 (2H, d, J = 8.6 Hz), 6.77-6.71 (1H, m), 5.19 (2H, s), 3.77 (3H, s), 3.05-1.62 (13H, m)。
步骤(2):化合物19d + 化合物19c → 化合物19e →化合物(I-19)
化合物I-19是由化合物19d(0.155 g,0.194 mmol)和19c(0.110 g,0.194 mmol)经与上述相同的方法合成的(0.021 g,22%)。
HPLC纯度:97.1%,
MS:747.18 (M+H)。
1H-NMR (DMSO-d6) δ: 9.48 (1H, d, J = 6.9 Hz), 7.78-7.76 (1H, m), 7.31 (2H, s), 6.83-6.77 (1H, m), 6.71 (1H, s), 5.89-5.84 (1H, m), 5.24-5.20 (1H, m), 4.83-3.37 (16H, m), 2.18-2.03 (4H, m), 1.45-1.43 (6H, m)。
实施例20
化合物(I-20)的合成
[式56]
Figure 782427DEST_PATH_IMAGE104
步骤(1):化合物20a → 化合物20b
向在冰浴中的化合物20a(1.87 g)的二甲基甲酰胺(20 mL)溶液中加入咪唑和叔丁基二甲基氯硅烷(6.0 g),并搅拌混合物,然后在室温静置过夜。通过蒸发除去溶剂。将残余物用水和乙酸乙酯稀释。将有机层用水和盐水洗涤。用MgSO4干燥,过滤并浓缩。将残余物从甲醇中结晶,得到化合物20b(2.34 g,72%收率)。
1H-NMR(DMSO-d6) δ: 0.18 (6H, s), 0.94 (9H, s), 7.12 (1H, d, J = 2.4 Hz), 7.65 (1H, brs), 12.1 (1H, brs), 12.7 (1H, brs)。
步骤(2):化合物20c → 化合物20d
向在冰浴中的化合物20c(1.26 g)的二氯甲烷(20 mL)溶液中加入二碳酸二叔丁酯(2.40 g)的二氯甲烷(10 mL)溶液。将混合物在室温搅拌2小时。通过蒸发除去溶剂,并将残余物经硅胶柱色谱纯化,得到化合物20d(1.83 g,81%收率)。
1H-NMR(CDCl3) δ: 1.46 (9H, s), 1.81 (4H, m), 2.11 (2H, m), 2.55 (1H, m), 3.02 (3H, m), 4.05 (3H, m), 12.7 (1H, brs)。
步骤(3):化合物20e + 化合物20d → 化合物20g →化合物(I-20)
由化合物20e和化合物20d经与上述类似的方法制备化合物20g。
向在冰浴中的化合物20b(189 mg)的N,N-二甲基甲酰胺(5 mL)溶液中加入N-甲基吗啉(0.165 mL)、1-羟基苯并三唑(73 mg)和WSCD-HCl (104 mg)。将混合物在室温搅拌30分钟。在冰冷却下将化合物20g加入到混合物中,然后将所有混合物在冰浴中搅拌2.5小时。将得到的混合物倒入乙醚中。通过过滤收集沉淀的物质。将固体用稀HCl/乙腈溶解。加入HP20SS,并将混合物浓缩至20 mL。残余物经HP20SS反相柱色谱纯化并冻干,得到I-20(102 mg)。
1H-NMR (D2O+NaHCO3) δ: 1.53 (3H, s), 1.55 (3H, s), 2.01 – 2.45 (5H, m), 3.40 – 3.85 (5H, m), 3.80 – 4.35 (6H, m), 5.36 (1H, d, J = 5.1 Hz), 5.86 (1H, d, J = 5.1 Hz), 7.07 (1H, m), 7.39 (1H, m)。
实施例21
化合物(I-21)的合成
[式57]
Figure 756200DEST_PATH_IMAGE105
步骤(1):化合物21a → 化合物(I-21)
化合物21a(0.627g,0.633mmol)经与上述类似的方法处理,得到化合物I-21。收率0.086g,(16%)。
MS:777.20 (M+H)。
1H-NMR (D2O) δ: 7.68-7.66 (1H, m), 7.01 (1H, s), 6.71-6.64 (1H, m), 5.85-5.82 (1H, m), 5.35-5.31 (1H, m), 4.98-4.94 (1H, m), 4.40-4.35 (1H, m), 3.94-3.49 (12H, m), 2.74-2.70 (2H, m), 2.39-2.22 (4H, m)。
实施例22
化合物(I-22)的合成
[式58]
步骤(1):化合物22a + 化合物22b → 化合物22c
化合物22a(1.10g,2.40mmol)和化合物22b(0.424g,3.36mmol)经与上述类似的方法处理,得到化合物22c。
收率0.895g,(66%)。
1H-NMR (DMSO-d6) δ: 8.13-8.11 (1H, m), 7.44-7.22 (12H, m), 7.12-7.07 (1H, m), 6.99 (2H, d, J = 8.7 Hz), 6.76-6.75 (1H, m), 5.77-5.75 (2H, m), 5.18 (2H, s), 4.39 (1H, s), 4.13-4.10 (2H, m), 3.77 (3H, s), 3.18-1.44 (8H, m)。
步骤(2):化合物22d → 化合物22f →化合物(I-22)
化合物22d(0.637g,0.800mmol)经与上述类似的步骤处理,得到化合物I-22。
收率0.075g,(12%)。
质谱:747.25 (M+H)。
1H-NMR (D2O) δ: 7.66-7.64 (1H, m), 6.98-6.98 (1H, m), 6.66-6.63 (1H, m), 5.90-5.87 (1H, m), 5.38-5.36 (1H, m), 4.21-3.43 (13H, m), 2.37-2.23 (4H, m), 1.51-1.50 (7H, m)。
实施例23
化合物(I-23)的合成
[式59]
步骤:化合物23a → 化合物23c →化合物I-23
化合物23a(0.757g,0.800mmol)经如上所述的类似方法处理,得到化合物I-23。
收率0.035g,(5%)。
MS:777.17 (M+H)。
1H-NMR (D2O) δ: 7.66-7.63 (1H, m), 7.02 (1H, s), 6.64 (1H, s), 5.85-5.82 (1H, m), 5.37-5.33 (1H, m), 4.96-4.90 (2H, m), 4.23-3.42 (12H, m), 2.74-2.70 (2H, m), 2.39-2.24 (4H, m)。
实施例24
化合物(I-24)的合成
[式60]
Figure 811377DEST_PATH_IMAGE108
步骤:化合物24a → 化合物24c →化合物(I-24)
化合物24a经如上所述的类似方法处理,得到化合物I-24。
收率0.097g,(13%)。
1H-NMR (DMSO-d6) δ: 9.54-9.52 (1H, m), 8.64 (1H, s), 7.92 (1H, s), 7.47 (1H, s), 7.29-7.27 (2H, m), 6.81 (1H, s), 5.71 (1H, dd, J = 8.2, 4.9 Hz), 5.08 (1H, d, J = 4.9 Hz), 4.84-4.73 (2H, m), 3.82-2.68 (17H, m), 1.78-1.74 (6H, m)。
元素分析:C31H34N8O12S2(H2O)5.9
计算值:C,42.26;H,5.24;N,12.72;S,7.28 (%)
实验值:C,42.20;H,5.13;N,12.85;S,7.37 (%)。
实施例25
化合物(I-25)的合成
[式61]
步骤:化合物25a → 化合物25c →化合物(I-25)
化合物25a(0.726g,0.800mmol)经如上所述的类似方法处理,得到化合物I-25。
收率0.025g,(4%)。
1H-NMR (DMSO-d6) δ: 9.48 (1H, d, J = 8.4 Hz), 8.63 (1H, s), 7.96-7.93 (1H, m), 7.48-7.43 (1H, m), 7.29-7.26 (2H, m), 6.75 (1H, s), 5.80-5.75 (1H, m), 5.12-5.10 (1H, m), 4.84-4.71 (1H, m), 4.44 (1H, t, J = 6.3 Hz), 3.84-3.20 (14H, m), 1.85-1.71 (8H, m), 0.95 (3H, t, J = 7.5 Hz)。
元素分析:C31H36N8O10S2(H2O)6.6(NaCl)0.2
计算值:C,42.53;H,5.67;N,12.80;S,7.33;Cl,0.81 (%)
实验值:C,42.47;H,5.42;N,12.27;S,7.53;Cl,0.74 (%)。
实施例26
化合物(I-26)的合成
[式62]
Figure 702290DEST_PATH_IMAGE110
步骤:化合物26a → 化合物26c →化合物(I-26)
化合物26a(0.852g,0.900mmol)经如上所述的类似方法处理,得到化合物I-26。
收率0.093g,(13%)。
MS:749.12 (M+H)。
1H-NMR (D2O) δ: 7.77 (1H, s), 7.09 (1H, s), 7.00 (1H, s), 5.85-5.81 (1H, m), 5.36-5.33 (1H, m), 5.00-4.95 (1H, m), 4.16 (1H, d, J = 14.5 Hz), 3.95-3.52 (11H, m), 2.78-2.66 (2H, m), 2.23-2.07 (4H, m)。
实施例27
化合物(I-27)的合成
[式63]
Figure 747344DEST_PATH_IMAGE111
步骤:化合物27a → 化合物27c →化合物(I-27)
化合物27a(0.726g,0.800mmol)经如上所述的类似方法处理,得到化合物I-27。
收率0.192g,(32%)。
MS:719.17 (M+H)。
1H-NMR (D2O) δ: 7.77 (1H, s), 7.09 (1H, s), 6.99 (1H, s), 5.88 (1H, d, J = 5.3 Hz), 5.37 (1H, s), 4.53 (1H, t, J = 5.9 Hz), 4.12 (1H, d, J = 13.6 Hz), 4.00-3.48 (11H, m), 2.24-2.20 (4H, m), 1.92-1.82 (2H, m), 0.97 (3H, t, J = 7.2 Hz)。
实施例28
化合物I-28的合成
[式64]
Figure 920836DEST_PATH_IMAGE112
步骤:化合物28a → 化合物27b → 化合物28c →化合物(I-28)
白色粉末状化合物I-28是由化合物28a(952mg,1.0mmol)和化合物28b(548mg,1.0mmol)经如上所述的类似方法得到的。
收率125mg,(16%)。
1H-NMR (D2O) δ: 0.98 (3H, t, J = 7.3 Hz), 1.83-1.92 (2H, m), 2.21 (2H, d, J = 16.8 Hz), 2.44-2.58 (3H, m), 2.71-2.80 (2H, m), 3.10 (3H, s), 3.49 (1H, d, J = 16.8 Hz), 3.93-4.10 (4H, m), 4.24 (1H, t, J = 7.4 Hz), 4.53 (1H, t, J = 6.2 Hz), 4.62 (1H, d, J = 14.2 Hz), 5.37 (1H, d, J = 5.0 Hz), 5.89 (1H, d, J = 5.0 Hz), 7.00 (1H, s), 7.09 (1H, s), 7.77 (1H, s)。
MS (m+1) = 745.34。
元素分析:C31H35N8O10S2Na・6.2H2O
计算值:C,42.38;H,5.44;N,12.76;S,7.30;Na,2.62 (%)
实验值:C,42.32;H,5.22;N,12.74;S,7.26;Na,2.78 (%)。
实施例29
化合物I-29的合成
[式65]
Figure 869201DEST_PATH_IMAGE113
步骤(1):化合物29a + 化合物29b → 化合物29c
向化合物29b(1.37g,3.0mmol)的N,N-二甲基甲酰胺(14ml)溶液中加入1-羟基苯并三唑(486mg,3.6mmol)、WSCD-HCl (633mg,3.3mmol)、化合物29a(1.41g,6.6mmol)和二异丙基乙胺(1.26mL,7.2mmol),然后在70℃搅拌过夜。通过蒸发除去N,N-二甲基甲酰胺,然后向残余物中加入1N的氢氧化钠水溶液并用乙酸乙酯萃取。将有机层用水和盐水洗涤,并用无水硫酸镁干燥。通过过滤除去无机物,并真空浓缩滤液。得到的粗产物经硅胶色谱纯化,得到棕色粉末状化合物29c。
收率526mg,(30%)。
1H-NMR (CDCl3) δ: 1.69-2.21 (8H, m), 2.30 (3H, s), 3.16 (2H, br s), 3.83 (3H, s), 4.21 (1H, q, J = 7.1 Hz), 5.12 (2H, s), 6.40 (1H, s), 6.91 (2H, d, J = 8.7 Hz), 7.27-7.44 (12H, m), 7.85 (1H, s), 7.86 (1H, s), 12.02 (1H, d, J = 7.5 Hz)。
MS (m+1) = 580.41。
步骤(2):化合物29d + 化合物29c → 化合物(I-29)
将化合物29c(290mg,0.50mmol)的N,N-二甲基甲酰胺(1ml)溶液冷却至15℃,向其中加入化合物29d(398mg,0.50mmol)并在真空中脱气。向反应混合物中加入碘化钠(150mg,1.0mmol),将混合物在15℃搅拌2小时,然后在冰箱中放置过夜。向反应混合物中加入N,N-二甲基甲酰胺(3.0mL)并将混合物在0℃冷却,按顺序向其中加入碘化钾(581mg,3.5mmol)和乙酰氯(143μl,2.0mmol),并在0℃搅拌3小时。将反应混合物慢慢地倒入冰冷的5%的盐水中。过滤沉淀,用水洗涤,悬浮在水中,然后冻干,得到黄色固体状化合物29e。得到的化合物29e不经纯化用于下一步骤。
将得到的全部量的化合物29e溶于二氯甲烷(8mL)中并冷却至-40℃,然后按顺序加入苯甲醚(546μl,5.0mmol)和2mol/L的氯化铝/硝基甲烷溶液(2.5mL,5.0mmol),并将混合物在0℃搅拌30分钟。向反应溶液中加入二异丙醚和一滴水并搅拌以促进沉淀,并通过倾析除去上清液。向粘在烧瓶中的不溶物质中加入稀盐酸和乙腈,搅拌并完全溶解,向其中加入异丙醚,并且水层从上清液中分离出来。将有机相用水再次萃取,合并所有的水相,向其中加入HP20-SS树脂,然后减压浓缩含有乙腈的溶液。将得到的混合溶液经ODS柱色谱纯化。向含有目标化合物的级分中加入0.2mol/L的氢氧化钠水溶液以调节至pH=6.0,然后向其中加入一块干冰。真空浓缩得到的溶液,然后冻干,得到白色粉末状化合物I-29。
收率 61mg,(16%)
1H-NMR (D2O) δ: 1.50 (3H, s), 1.52 (3H, s), 2.21 (2H, d, J = 17.2 Hz), 2.45-2.58 (3H, m), 2.72-2.80 (2H, m), 3.10 (3H, s), 3.50 (1H, d, J = 16.6 Hz), 3.93-4.10 (4H, m), 4.24 (1H, t, J = 6.9 Hz), 4.63 (1H, d, J = 14.3 Hz), 5.37 (1H, d, J = 4.8 Hz), 5.89 (1H, d, J = 4.8 Hz), 6.98 (1H, s), 7.09 (1H, s), 7.78 (1H, s)。
元素分析:C31H35N8O11S2Na(H2O)6.2(NaCl)0.2
计算值:C,41.09;H,5.27;N,12.37;S,7.08;Cl,0.78;Na,3.04 (%)
实验值:C,41.04;H,5.29;N,12.56;S,7.00;Cl,0.72;Na,3.24 (%)。
实施例30
化合物(I-30)的合成
[式66]
Figure 774840DEST_PATH_IMAGE114
步骤:化合物30a + 化合物29c → 化合物(I-30)
浅黄色粉末状化合物I-30是由化合物30a(398mg,0.50mmol)和化合物29c(290mg,0.50mmol)经如上所述的类似方法制备得到的。
收率130mg,(31%)。
1H-NMR (D2O) δ: 2.08 (2H, d, J = 16.8 Hz), 2.37 (2H, d, J = 9.5 Hz), 2.60-2.81 (6H, m), 3.11 (3H, s), 3.51 (1H, d, J = 16.6 Hz), 3.90-4.16 (4H, m), 4.34 (1H, t, J = 6.9 Hz), 4.61 (1H, d, J = 13.7 Hz), 4.97 (1H, dd, J = 8.2, 5.0 Hz), 5.34 (1H, d, J = 5.0 Hz), 5.84 (1H, d, J = 5.0 Hz), 7.02 (1H, s), 7.42 (1H, s), 7.64 (1H, s)。
MS (m+1) = 791.36。
元素分析:C31H32N8O13S2Na2・(H2O)7.0・NaHCO3(0.9)
计算值:C,36.97;H,4.56;N,10.81;S,6.19;Na,6.43 (%)
实验值:C,36.79;H,4.73;N,11.38;S,6.32;Na,6.52 (%)。
实施例31
化合物(I-31)的合成
[式67]
Figure 870972DEST_PATH_IMAGE115
步骤(1):化合物31a + 化合物29b → 化合物31b
向化合物29b(915mg,2.0mmol)的N,N-二甲基甲酰胺(9ml)溶液中加入1-羟基苯并三唑(324mg,2.4mmol)、WSCD-HCl (422mg,2.2mmol)和化合物31a(502mg,4.4mmol),然后在70℃搅拌过夜。通过蒸发除去N,N-二甲基甲酰胺。向残余物中加入1N的氢氧化钠水溶液并用乙酸乙酯萃取。将有机相用水和盐水洗涤,并用无水硫酸镁干燥。通过过滤除去无机物,并真空浓缩滤液。得到的粗产物经硅胶色谱纯化,得到棕色粉末状化合物31b。
收率400mg,(36%)。
1H-NMR (CDCl3) δ: 1.75-1.79 (4H, m), 2.55 (4H, br s), 2.67 (2H, t, J = 6.6 Hz), 3.55 (2H, dd, J = 12.2, 6.6 Hz), 3.82 (3H, s), 5.11 (2H, s), 6.40 (1H, s), 6.91 (2H, d, J = 8.7 Hz), 7.27-7.44 (12H, m), 7.86 (2H, s), 11.43 (1H, br s)。
步骤(2):化合物30a + 化合物31b → 化合物31c → 化合物(I-31)
橙色粉末状化合物I-31是由化合物30a(710mg,0.75mmol)和化合物31b(415mg,0.75mmol)经如上所述的类似方法制备得到的。
收率70mg,(12%)。
1H-NMR (D2O) δ: 2.21 (4H, br s), 2.70-2.73 (2H, m), 3.03-3.08 (2H, m), 3.39-3.64 (6H, m), 3.84-4.01 (3H, m), 4.14 (1H, d, J = 14.5 Hz), 4.97 (1H, dd, J = 8.1, 4.9 Hz), 5.35 (1H, d, J = 4.9 Hz), 5.85 (1H, d, J = 4.9 Hz), 7.02 (1H, s), 7.41 (1H, s), 7.63 (1H, s)。
MS (m+1) = 765.35。
元素分析:C29H30N8O13S2Na2・(H2O)8.3
计算值:C,36.35;H,4.90;N,11.69;S,6.69 (%)
实验值:C,36.29;H,4.65;N,11.75;S,6.50 (%)。
实施例32
化合物I-32的合成
[式68]
Figure 254680DEST_PATH_IMAGE116
步骤(1):化合物32a + 化合物29b → 化合物32b
向化合物29b(1.83g,4.0mmol)的N,N-二甲基甲酰胺(18ml)溶液中加入1-羟基苯并三唑(649mg,4.8mmol)、WSCD-HCl(843mg,4.4mmol)和化合物32a(1.23g,8.8mmol),并将混合物在70℃搅拌过夜。通过蒸发除去N,N-二甲基甲酰胺,然后向残余物中加入1N的氢氧化钠水溶液并用乙酸乙酯萃取。将有机相用水和盐水洗涤,并用无水硫酸镁干燥。通过过滤除去无机物,并真空浓缩滤液。得到的粗产物经硅胶色谱纯化,得到棕色粉末状化合物32b。
收率218mg,(9%)。
1H-NMR (CDCl3) δ: 1.45 (6H, t, J = 7.6 Hz), 2.89 (6H, t, J = 7.6 Hz), 3.21 (2H, d, J = 5.9 Hz), 3.83 (3H, s), 5.13 (2H, s), 6.41 (1H, s), 6.91 (2H, d, J = 8.7 Hz), 7.27-7.44 (12H, m), 7.85 (1H, s), 7.86 (1H, s), 11.53 (1H, br s)。
MS (m+1) = 580.41。
步骤(2):化合物29d + 化合物32b → 化合物32c → 化合物(I-32)
将化合物32b(261mg,0.45mmol)的N,N-二甲基甲酰胺(1ml)溶液冷却至15℃,并向其中加入化合物29d(358mg,0.45mmol)并在减压下脱气。向反应混合物中加入溴化钠(93mg,0.90mmol),并将混合物在15℃搅拌2小时,然后在冰箱中放置过夜。向反应混合物中加入N,N-二甲基甲酰胺(3.0mL),并将混合物冷却到0℃,按顺序向其中加入碘化钾(523mg,3.15mmol)和乙酰氯(128μl,1.8mmol),并将混合物在0℃搅拌3小时。将反应混合物慢慢的倒入预先冰冷却的5%的盐水中。过滤沉淀的固体,用水洗涤,悬浮在水中,然后冻干,得到黄色固体状化合物32c。将得到的化合物32c不经纯化用于下一反应。
将得到的全部量的化合物32c溶于二氯甲烷(8mL)中,并将该溶液冷却至-40℃,按顺序向其中加入苯甲醚(492μl,4.5mmol)和2 mol/L-氯化铝/硝基甲烷溶液(2.25mL,4.5mmol),并将混合物在0℃搅拌30分钟。向反应溶液中加入二异丙醚和一滴水,并将混合物搅拌以促进沉淀,并通过倾析除去上清液。向粘在烧瓶中的不溶物质中加入稀盐酸和乙腈,并将混合物搅拌并完全溶解,然后向其中加入异丙醚,然后从上清液中分离出水层。将有机相用水再次萃取,合并所有的水相,向其中加入HP20-SS树脂,然后减压浓缩含有乙腈的溶液。得到的混合溶液经ODS柱色谱纯化。向含有目标化合物的级分中加入0.2mol/L的氢氧化钠水溶液以调节pH=6.0,然后向其中加入一块干冰。真空浓缩得到的溶液,然后冻干,得到白色粉末状化合物I-32。
收率134mg,(38%)。
1H-NMR (D2O) δ: 1.50 (3H, s), 1.52 (3H, s), 1.93 (6H, t, J = 7.2 Hz), 3.40-3.53 (9H, m), 3.87 (1H, s), 3.92 (1H, d, J = 4.1 Hz), 4.60 (1H, d, J = 13.7 Hz), 5.36 (1H, d, J = 5.0 Hz), 5.88 (1H, d, J = 5.0 Hz), 6.98 (1H, s), 7.45 (1H, s), 7.75 (1H, s)。
MS (m+1) = 761.33。
元素分析:C31H35N8O11S2Na(H2O)5.2(NaHCO3)0.4
计算值:C,41.44;H,5.07;N,12.31;S,7.05;Na,3.54 (%)
实验值:C,41.40;H,5.10;N,12.55;S,7.00;Na,3.68 (%)。
实施例33
化合物(I-33)的合成
[式69]
Figure 385447DEST_PATH_IMAGE117
步骤:化合物30a + 化合物32b → 化合物33a → 化合物(I-33)
白色粉末状化合物I-33是由化合物30a(142mg,0.15mmol)和化合物32b (87mg,0.15mmol)经如上所述的类似方法制备得到的。
收率60mg,(48%)。
1H-NMR (D2O) δ: 1.94 (6H, t, J = 7.6 Hz), 2.71 (1H, d, J = 3.5 Hz), 2.73 (1H, s), 3.38-3.57 (9H, m), 3.84-3.93 (2H, m), 4.59 (1H, d, J = 14.0 Hz), 4.96 (1H, dd, J = 8.2, 4.9 Hz), 5.32 (1H, d, J = 5.0 Hz), 5.83 (1H, d, J = 5.0 Hz), 7.01 (1H, s), 7.41 (1H, s), 7.68 (1H, s)。
MS (m+1) = 791.28。
元素分析:C31H32N8O13S2Na2(H2O)7.0(NaHCO3)0.8
计算值:C,37.15;H,4.59;N,10.90;S,6.24;Na,6.26 (%)
实验值:C,37.04;H,4.60;N,11.26;S,6.54;Na,6.23 (%)。
本发明包括下式(II-A)、(II-B)、(II-C)、(II-D)、(II-E)、(II-F)、(II-G)、(II-H)、(II-I)、(II-J)、(II-K)、(II-L)和(II-M)的化合物:
[式70]
Figure 960523DEST_PATH_IMAGE118
Figure 543951DEST_PATH_IMAGE119
Figure 731349DEST_PATH_IMAGE120
Figure 716623DEST_PATH_IMAGE121
其中X、K和-E-D-选自X1至X3、K1至K29,并且ED1至ED92分别选自下表1至9:
Figure 964065DEST_PATH_IMAGE122
Figure 34789DEST_PATH_IMAGE123
Figure 25879DEST_PATH_IMAGE124
Figure 865659DEST_PATH_IMAGE125
Figure 74978DEST_PATH_IMAGE127
Figure 869759DEST_PATH_IMAGE128
Figure 564045DEST_PATH_IMAGE129
Figure 153289DEST_PATH_IMAGE130
(X,K,ED)=
(X1, K1, ED1), (X1, K1, ED2), (X1, K1, ED3), (X1, K1, ED4), (X1, K1, ED5), (X1, K1, ED6), (X1, K1, ED7), (X1, K1, ED8), (X1, K1, ED9), (X1, K1, ED10), (X1, K1, ED11), (X1, K1, ED12), (X1, K1, ED13), (X1, K1, ED14), (X1, K1, ED15), (X1, K1, ED16), (X1, K1, ED17), (X1, K1, ED18), (X1, K1, ED19), (X1, K1, ED20), (X1, K1, ED21), (X1, K1, ED22), (X1, K1, ED23), (X1, K1, ED24), (X1, K1, ED25), (X1, K1, ED26), (X1, K1, ED27), (X1, K1, ED28), (X1, K1, ED29), (X1, K1, ED30), (X1, K1, ED31), (X1, K1, ED32), (X1, K1, ED33), (X1, K1, ED34), (X1, K1, ED35), (X1, K1, ED36), (X1, K1, ED37), (X1, K1, ED38), (X1, K1, ED39), (X1, K1, ED40), (X1, K1, ED41), (X1, K1, ED42), (X1, K1, ED43), (X1, K1, ED44), (X1, K1, ED45), (X1, K1, ED46), (X1, K1, ED47), (X1, K1, ED48), (X1, K1, ED49), (X1, K1, ED50), (X1, K1, ED51), (X1, K1, ED52), (X1, K1, ED53), (X1, K1, ED54), (X1, K1, ED55), (X1, K1, ED56), (X1, K1, ED57), (X1, K1, ED58), (X1, K1, ED59), (X1, K1, ED60), (X1, K1, ED61), (X1, K1, ED62), (X1, K1, ED63), 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K26, ED40), (X3, K26, ED41), (X3, K26, ED42), (X3, K26, ED43), (X3, K26, ED44), (X3, K26, ED45), (X3, K26, ED46), (X3, K26, ED47), (X3, K26, ED48), (X3, K26, ED49), (X3, K26, ED50), (X3, K26, ED51), (X3, K26, ED52), (X3, K26, ED53), (X3, K26, ED54), (X3, K26, ED55), (X3, K26, ED56), (X3, K26, ED57), (X3, K26, ED58), (X3, K26, ED59), (X3, K26, ED60), (X3, K26, ED61), (X3, K26, ED62), (X3, K26, ED63), (X3, K26, ED64), (X3, K26, ED65), (X3, K26, ED66), (X3, K26, ED67), (X3, K26, ED68), (X3, K26, ED69), (X3, K26, ED70), (X3, K26, ED71), (X3, K26, ED72), (X3, K26, ED73), (X3, K26, ED74), (X3, K26, ED75), (X3, K26, ED76), (X3, K26, ED77), (X3, K26, ED78), (X3, K26, ED79), (X3, K26, ED80), (X3, K26, ED81), (X3, K26, ED82), (X3, K26, ED83), (X3, K26, ED84), (X3, K26, ED85), (X3, K26, ED86), (X3, K26, ED87), (X3, K26, ED88), (X3, K26, ED89), (X3, K26, ED90), (X3, K26, ED91), (X3, K26, ED92), (X3, K27, ED1), (X3, K27, ED2), (X3, K27, ED3), (X3, K27, ED4), (X3, K27, ED5), (X3, K27, ED6), (X3, K27, ED7), (X3, K27, ED8), (X3, K27, ED9), (X3, K27, ED10), (X3, K27, ED11), (X3, K27, ED12), (X3, K27, ED13), (X3, K27, ED14), (X3, K27, ED15), (X3, K27, ED16), (X3, K27, ED17), (X3, K27, ED18), (X3, K27, ED19), (X3, K27, ED20), (X3, K27, ED21), (X3, K27, ED22), (X3, K27, ED23), (X3, K27, ED24), (X3, K27, ED25), (X3, K27, ED26), (X3, K27, ED27), (X3, K27, ED28), (X3, K27, ED29), (X3, K27, ED30), (X3, K27, ED31), (X3, K27, ED32), (X3, K27, ED33), (X3, K27, ED34), (X3, K27, ED35), (X3, K27, ED36), (X3, K27, ED37), (X3, K27, ED38), (X3, K27, ED39), (X3, K27, ED40), (X3, K27, ED41), (X3, K27, ED42), (X3, K27, ED43), (X3, K27, ED44), (X3, K27, ED45), (X3, K27, ED46), (X3, K27, ED47), (X3, K27, ED48), (X3, K27, ED49), (X3, K27, ED50), (X3, K27, ED51), (X3, K27, ED52), (X3, K27, ED53), (X3, K27, ED54), (X3, K27, ED55), (X3, K27, ED56), (X3, K27, ED57), (X3, K27, ED58), (X3, K27, ED59), (X3, K27, ED60), (X3, K27, ED61), (X3, K27, ED62), (X3, K27, ED63), (X3, K27, ED64), (X3, K27, ED65), (X3, K27, ED66), (X3, K27, ED67), (X3, K27, ED68), (X3, K27, ED69), (X3, K27, ED70), (X3, K27, ED71), (X3, K27, ED72), (X3, K27, ED73), (X3, K27, ED74), (X3, K27, ED75), (X3, K27, ED76), (X3, K27, ED77), (X3, K27, ED78), (X3, K27, ED79), (X3, K27, ED80), (X3, K27, ED81), (X3, K27, ED82), (X3, K27, ED83), (X3, K27, ED84), (X3, K27, ED85), (X3, K27, ED86), (X3, K27, ED87), (X3, K27, ED88), (X3, K27, ED89), (X3, K27, ED90), (X3, K27, ED91), (X3, K27, ED92), (X3, K28, ED1), (X3, K28, ED2), (X3, K28, ED3), (X3, K28, ED4), (X3, K28, ED5), (X3, K28, ED6), (X3, K28, ED7), (X3, K28, ED8), (X3, K28, ED9), (X3, K28, ED10), (X3, K28, ED11), (X3, K28, ED12), (X3, K28, ED13), (X3, K28, ED14), (X3, K28, ED15), (X3, K28, ED16), (X3, K28, ED17), (X3, K28, ED18), (X3, K28, ED19), (X3, K28, ED20), (X3, K28, ED21), (X3, K28, ED22), (X3, K28, ED23), (X3, K28, ED24), (X3, K28, ED25), (X3, K28, ED26), (X3, K28, ED27), (X3, K28, ED28), (X3, K28, ED29), (X3, K28, ED30), (X3, K28, ED31), (X3, K28, ED32), (X3, K28, ED33), (X3, K28, ED34), (X3, K28, ED35), (X3, K28, ED36), (X3, K28, ED37), (X3, K28, ED38), (X3, K28, ED39), (X3, K28, ED40), (X3, K28, ED41), (X3, K28, ED42), (X3, K28, ED43), (X3, K28, ED44), (X3, K28, ED45), (X3, K28, ED46), (X3, K28, ED47), (X3, K28, ED48), (X3, K28, ED49), (X3, K28, ED50), (X3, K28, ED51), (X3, K28, ED52), (X3, K28, ED53), (X3, K28, ED54), (X3, K28, ED55), (X3, K28, ED56), (X3, K28, ED57), (X3, K28, ED58), (X3, K28, ED59), (X3, K28, ED60), (X3, K28, ED61), (X3, K28, ED62), (X3, K28, ED63), (X3, K28, ED64), (X3, K28, ED65), (X3, K28, ED66), (X3, K28, ED67), (X3, K28, ED68), (X3, K28, ED69), (X3, K28, ED70), (X3, K28, ED71), (X3, K28, ED72), (X3, K28, ED73), (X3, K28, ED74), (X3, K28, ED75), (X3, K28, ED76), (X3, K28, ED77), (X3, K28, ED78), (X3, K28, ED79), (X3, K28, ED80), (X3, K28, ED81), (X3, K28, ED82), (X3, K28, ED83), (X3, K28, ED84), (X3, K28, ED85), (X3, K28, ED86), (X3, K28, ED87), (X3, K28, ED88), (X3, K28, ED89), (X3, K28, ED90), (X3, K28, ED91), (X3, K28, ED92), (X3, K29, ED1), (X3, K29, ED2), (X3, K29, ED3), (X3, K29, ED4), (X3, K29, ED5), (X3, K29, ED6), (X3, K29, ED7), (X3, K29, ED8), (X3, K29, ED9), (X3, K29, ED10), (X3, K29, ED11), (X3, K29, ED12), (X3, K29, ED13), (X3, K29, ED14), (X3, K29, ED15), (X3, K29, ED16), (X3, K29, ED17), (X3, K29, ED18), (X3, K29, ED19), (X3, K29, ED20), (X3, K29, ED21), (X3, K29, ED22), (X3, K29, ED23), (X3, K29, ED24), (X3, K29, ED25), (X3, K29, ED26), (X3, K29, ED27), (X3, K29, ED28), (X3, K29, ED29), (X3, K29, ED30), (X3, K29, ED31), (X3, K29, ED32), (X3, K29, ED33), (X3, K29, ED34), (X3, K29, ED35), (X3, K29, ED36), (X3, K29, ED37), (X3, K29, ED38), (X3, K29, ED39), (X3, K29, ED40), (X3, K29, ED41), (X3, K29, ED42), (X3, K29, ED43), (X3, K29, ED44), (X3, K29, ED45), (X3, K29, ED46), (X3, K29, ED47), (X3, K29, ED48), (X3, K29, ED49), (X3, K29, ED50), (X3, K29, ED51), (X3, K29, ED52), (X3, K29, ED53), (X3, K29, ED54), (X3, K29, ED55), (X3, K29, ED56), (X3, K29, ED57), (X3, K29, ED58), (X3, K29, ED59), (X3, K29, ED60), (X3, K29, ED61), (X3, K29, ED62), (X3, K29, ED63), (X3, K29, ED64), (X3, K29, ED65), (X3, K29, ED66), (X3, K29, ED67), (X3, K29, ED68), (X3, K29, ED69), (X3, K29, ED70), (X3, K29, ED71), (X3, K29, ED72), (X3, K29, ED73), (X3, K29, ED74), (X3, K29, ED75), (X3, K29, ED76), (X3, K29, ED77), (X3, K29, ED78), (X3, K29, ED79), (X3, K29, ED80), (X3, K29, ED81), (X3, K29, ED82), (X3, K29, ED83), (X3, K29, ED84), (X3, K29, ED85), (X3, K29, ED86), (X3, K29, ED87), (X3, K29, ED88), (X3, K29, ED89), (X3, K29, ED90), (X3, K29, ED91), (X3, K29, ED92),
(X3, K30, ED1), (X3, K30, ED2), (X3, K30, ED3), (X3, K30, ED4), (X3, K30, ED5), (X3, K30, ED6), (X3, K30, ED7), (X3, K30, ED8), (X3, K30, ED9), (X3, K30, ED10), (X3, K30, ED11), (X3, K30, ED12), (X3, K30, ED13), (X3, K30, ED14), (X3, K30, ED15), (X3, K30, ED16), (X3, K30, ED17), (X3, K30, ED18), (X3, K30, ED19), (X3, K30, ED20), (X3, K30, ED21), (X3, K30, ED22), (X3, K30, ED23), (X3, K30, ED24), (X3, K30, ED25), (X3, K30, ED26), (X3, K30, ED27), (X3, K30, ED28), (X3, K30, ED29), (X3, K30, ED30), (X3, K30, ED31), (X3, K30, ED32), (X3, K30, ED33), (X3, K30, ED34), (X3, K30, ED35), (X3, K30, ED36), (X3, K30, ED37), (X3, K30, ED38), (X3, K30, ED39), (X3, K30, ED40), (X3, K30, ED41), (X3, K30, ED42), (X3, K30, ED43), (X3, K30, ED44), (X3, K30, ED45), (X3, K30, ED46), (X3, K30, ED47), (X3, K30, ED48), (X3, K30, ED49), (X3, K30, ED50), (X3, K30, ED51), (X3, K30, ED52), (X3, K30, ED53), (X3, K30, ED54), (X3, K30, ED55), (X3, K30, ED56), (X3, K30, ED57), (X3, K30, ED58), (X3, K30, ED59), (X3, K30, ED60), (X3, K30, ED61), (X3, K30, ED62), (X3, K30, ED63), (X3, K30, ED64), (X3, K30, ED65), (X3, K30, ED66), (X3, K30, ED67), (X3, K30, ED68), (X3, K30, ED69), (X3, K30, ED70), (X3, K30, ED71), (X3, K30, ED72), (X3, K30, ED73), (X3, K30, ED74), (X3, K30, ED75), (X3, K30, ED76), (X3, K30, ED77), (X3, K30, ED78), (X3, K30, ED79), (X3, K30, ED80), (X3, K30, ED81), (X3, K30, ED82), (X3, K30, ED83), (X3, K30, ED84), (X3, K30, ED85), (X3, K30, ED86), (X3, K30, ED87), (X3, K30, ED88), (X3, K30, ED89), (X3, K30, ED90), (X3, K30, ED91), (X3, K30, ED92), (X3, K31, ED1), (X3, K31, ED2), (X3, K31, ED3), (X3, K31, ED4), (X3, K31, ED5), (X3, K31, ED6), (X3, K31, ED7), (X3, K31, ED8), (X3, K31, ED9), (X3, K31, ED10), (X3, K31, ED11), (X3, K31, ED12), (X3, K31, ED13), (X3, K31, ED14), (X3, K31, ED15), (X3, K31, ED16), (X3, K31, ED17), (X3, K31, ED18), (X3, K31, ED19), (X3, K31, ED20), (X3, K31, ED21), (X3, K31, ED22), (X3, K31, ED23), (X3, K31, ED24), (X3, K31, ED25), (X3, K31, ED26), (X3, K31, ED27), (X3, K31, ED28), (X3, K31, ED29), (X3, K31, ED30), (X3, K31, ED31), (X3, K31, ED32), (X3, K31, ED33), (X3, K31, ED34), (X3, K31, ED35), (X3, K31, ED36), (X3, K31, ED37), (X3, K31, ED38), (X3, K31, ED39), (X3, K31, ED40), (X3, K31, ED41), (X3, K31, ED42), (X3, K31, ED43), (X3, K31, ED44), (X3, K31, ED45), (X3, K31, ED46), (X3, K31, ED47), (X3, K31, ED48), (X3, K31, ED49), (X3, K31, ED50), (X3, K31, ED51), (X3, K31, ED52), (X3, K31, ED53), (X3, K31, ED54), (X3, K31, ED55), (X3, K31, ED56), (X3, K31, ED57), (X3, K31, ED58), (X3, K31, ED59), (X3, K31, ED60), (X3, K31, ED61), (X3, K31, ED62), (X3, K31, ED63), (X3, K31, ED64), (X3, K31, ED65), (X3, K31, ED66), (X3, K31, ED67), (X3, K31, ED68), (X3, K31, ED69), (X3, K31, ED70), (X3, K31, ED71), (X3, K31, ED72), (X3, K31, ED73), (X3, K31, ED74), (X3, K31, ED75), (X3, K31, ED76), (X3, K31, ED77), (X3, K31, ED78), (X3, K31, ED79), (X3, K31, ED80), (X3, K31, ED81), (X3, K31, ED82), (X3, K31, ED83), (X3, K31, ED84), (X3, K31, ED85), (X3, K31, ED86), (X3, K31, ED87), (X3, K31, ED88), (X3, K31, ED89), (X3, K31, ED90), (X3, K31, ED91), (X3, K31, ED92)。
测试实施例1
已经对本发明化合物(I)的体外抗菌活性进行了研究。
(测试方法)
(细菌(Microbe)/菌株的种类(Strain species)第1~4号):
最小抑菌浓度(MIC,微克/ml)的测量是按照日本化疗协会(Japan Society for Chemotherapy)的标准方法进行的,接种的菌量为1000cfu/点,使用敏感性碟状培养基作为测试培养基,并采用琼脂平板培养来进行所述测量。
(细菌/菌株的种类第5号):
最小抑菌浓度(MIC,微克/ml)的测量是按照CLSI(Clinical and Laboratory Standards Institute)进行的,接种的菌量为10000cfu/点,并使用Mueller-Hinton琼脂培养基作为测试培养基,并采用琼脂平板培养来进行所述测量。
测试结果显示在表10和11中。在这些表中,抑菌活性的数值单位为微克/ml(μg/ml)。
Figure 136289DEST_PATH_IMAGE131
Figure 531498DEST_PATH_IMAGE132
上表中的菌种、其产生的酶(β-内酰胺酶)以及菌株类型的描述显示在下表12中。
Figure 516509DEST_PATH_IMAGE133
测试实施例2
对本发明化合物(I)的体内抗菌活性进行了研究。
(测试方法)
将小鼠(ICR系,雄性,五周龄)腹腔内接种绿脓杆菌SR27001(多药耐药绿脓杆菌;产IMP-1菌株)以引发感染。一个半小时后,静脉内给药小鼠两次,然后基于七天后的存活率计算出ED50值。
测试结果:本发明化合物(I)在体内显效。
从以上的结果可见,本发明的化合物显示出广的抗菌谱,特别是对革兰氏阴性菌的强的抗菌谱,和/或对多药耐药菌的效力,并对产β-内酰胺酶的革兰氏阴性菌显示出高的稳定性。与市售的具有类似结构的耐β-内酰胺酶的头孢菌素类抗生素盐酸头孢吡肟水合物(CFPM)相比,本发明化合物显示出具有更强的抗菌活性。因此表明本发明化合物可用作药品。
制剂实施例1
将本发明化合物的粉末充填以制备用于注射的制剂。
[工业实用性]
本发明化合物具有广的抗菌谱,并且可有效作为对产β-内酰胺酶的革兰氏阴性菌具有高的稳定性的抗菌药物。此外,本发明化合物生物利用度好、水溶性高,因此特别适合制成可注射制剂。

Claims (25)

1.下式的化合物:
[式1]
Figure 325665DEST_PATH_IMAGE001
或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,
其中,
X为–N=、-CH=、-C(-R5)=、-C(-Br)=或-C(-Cl)=;
R5为低级烷基或卤代(低级)烷基;
W为-CH2-、-S-或-O-;
当W为-CH2-时,U是-CH2-、-S-或-O-,或者当W为-S-或-O-时,U为-CH2-;
R1和R2各自独立地为氢原子、卤素、羟基、羧基、任选取代的低级烷基、任选取代的碳环基或任选取代的杂环基;或者
R1和R2与相邻原子一起可以形成任选取代的碳环基或任选取代的杂环基;
Q为单键、任选取代的碳环基或任选取代的杂环基;
环A为具有1-3个氮原子的六元芳香杂环基;
R3为氢原子、-OCH3或–NH-CH(=O);
k为从0到2的整数;
m为从0到2的整数;
每个R4独立地为氢原子、卤素、羟基、-CN、-C(=O)-R6、-C(=O)-OH或-OR6
R6为低级烷基或卤代(低级)烷基;
关于D和E,
a)D为单键、-N(R8)-或-R7-N(R8)-,其中R7为任选取代的低级亚烷基,R8为氢或低级烷基,并且E为任选取代的选自下式(1)~(40)的环状基团;或者
b)D为下式:
[式2]
Figure 429756DEST_PATH_IMAGE002
其中q为0或1,并且
E为取代基E的下式中式(10)或式(41)的基团:
[式3]
Figure 209493DEST_PATH_IMAGE003
Figure 542385DEST_PATH_IMAGE004
Figure 179220DEST_PATH_IMAGE006
Figure 633204DEST_PATH_IMAGE007
[式4]
Figure 832104DEST_PATH_IMAGE008
Figure 438666DEST_PATH_IMAGE009
Figure 432030DEST_PATH_IMAGE010
Figure 186359DEST_PATH_IMAGE011
Figure 110322DEST_PATH_IMAGE012
Figure 571390DEST_PATH_IMAGE013
其中p为从1到3的整数;n为1或2;并且Rx为任选取代的低级烷基。
2.根据权利要求1所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中D为单键、-NH-或-R7-NH-,R7为低级亚烷基,并且E选自式(1)~(40)。
3.根据权利要求2所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中D为-NH-、-CH2-NH-或-CH2-CH2-NH-。
4.根据权利要求3所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中E为选自式(5)、(6)、(10)、(11)、(26)、(29)~(34)、(36)和(37)的基团。
5.根据权利要求3所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中E为式(26)或(31)的基团。
6.根据权利要求2所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中D为单键。
7.根据权利要求6所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中E为选自式(1)~(4)、(7)、(12)~(25)、(27)和(28)的基团。
8.根据权利要求6所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中E为选自式(1)~(3)、(7)和(12)的基团。
9.根据权利要求1所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中D为下式:
[式5]
Figure 1234DEST_PATH_IMAGE014
其中q如权利要求1中的定义。
10.根据权利要求1~9任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中U为-S-。
11.根据权利要求1~10任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中W为-CH2-。
12.根据权利要求1~11任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中R3为氢原子或-OCH3
13.根据权利要求1~12任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中X为-N=、-CH=或–C(-Cl)=。
14.根据权利要求1~13任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中下式:
[式6]
Figure 242860DEST_PATH_IMAGE015
选自下式:
[式7]
Figure 704934DEST_PATH_IMAGE016
Figure 348405DEST_PATH_IMAGE017
Figure 683571DEST_PATH_IMAGE018
Figure 350176DEST_PATH_IMAGE019
Figure 428991DEST_PATH_IMAGE020
15.根据权利要求1~13任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中下式:
[式8]
Figure 926968DEST_PATH_IMAGE021
选自下式:
[式9]
Figure 885566DEST_PATH_IMAGE022
Figure 836204DEST_PATH_IMAGE023
16.根据权利要求1~15任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中Q为单键或任选取代的亚苯基。
17.根据权利要求16所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中R1为任选取代的低级烷基并且R2为氢原子。
18.根据权利要求16所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中R1为氢原子并且R2为任选取代的低级烷基。
19.根据权利要求16所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中R1和R2各自独立地为低级烷基。
20.根据权利要求17所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物,其中m为0。
21.药物组合物,其包含根据权利要求1~20任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物。
22.根据权利要求21所述的药物组合物,其具有抗菌活性。
23.用于治疗感染性疾病的方法,其特征在于给予根据权利要求1~20任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物。
24.用于治疗感染性疾病的根据权利要求1~20任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物。
25.根据权利要求1~20任一项所述的化合物或其酯、其在7位侧链中的环上的氨基处被保护的化合物、其药学上可接受的盐或其溶剂化物在制备用于治疗感染性疾病的治疗剂中的应用。
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