CN103917539B - 2-氧代-噁唑烷-3,5-二基抗生素衍生物 - Google Patents
2-氧代-噁唑烷-3,5-二基抗生素衍生物 Download PDFInfo
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- CN103917539B CN103917539B CN201280054955.4A CN201280054955A CN103917539B CN 103917539 B CN103917539 B CN 103917539B CN 201280054955 A CN201280054955 A CN 201280054955A CN 103917539 B CN103917539 B CN 103917539B
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- dihydro
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- MHNHYTDAOYJUEZ-UHFFFAOYSA-N triphenylphosphane Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 MHNHYTDAOYJUEZ-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 239000000304 virulence factor Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
Abstract
本发明是关于式I的抗细菌化合物其中R1a代表H或羧基且R1b代表H,或R1a及R1b一起代表基团*‑C(O)‑NH‑S‑#或基团*‑C(OH)=N‑S‑#,其中“*”代表R1a的附接点且“#”代表R1b的附接点;R2代表H、(C1‑C3)烷基、羟基‑(C1‑C3)烷基、苄基或(C3‑C5)环烷基;R3代表H或卤素;U代表N或CR4;其中R4是H或(C1‑C3)烷氧基;A代表CH,B代表NH且m代表1或2且n代表1或2;或A代表N,B不存在,m代表2且n代表2;Y代表CH或N;且Q代表O或S;及该等化合物的盐。
Description
技术领域
本发明是关于2-氧代-噁唑烷-3,5-二基抗生素衍生物、含有该化合物的医药抗细菌组合物及该等化合物在制造用于治疗感染(例如细菌感染)的医药中的用途。该等化合物是有效抵抗各种人类及兽类病原体(尤其包括革兰氏阳性(Gram-positive)及革兰氏阴性(Gram-negative)需氧及厌氧细菌及分枝杆菌)的有用抗微生物剂。
背景技术
抗生素的广泛使用已对微生物施加选择性进化压力,从而产生基于遗传的抗性机制。现代医学及社会-经济行为因产生病原体微生物在(例如)人工关节中缓慢生长的情形及因支持(例如)免疫受损患者中的长期贮存宿主而加剧抗性出现的问题。
在医院环境中,主要感染源金黄色葡萄球菌(Staphylococcus aureus)、肺炎链球菌(Streptococcus pneumoniae)、肠球菌(Enterococcus spp.)及绿脓杆菌(Pseudomonasaeruginosa)的不断增加的菌株正变得对多种药物具有抗性且因此难以(若并非不可能)治疗:
-金黄色葡萄球菌对β-内酰胺、喹诺酮具有抗性且现在甚至对万古霉素(vancomycin)亦具有抗性;
-肺炎链球菌正变得对青霉素(penicillin)或喹诺酮抗生素具有抗性且甚至对新颖巨环内酯亦具有抗性;
-肠球菌(Enteroccocci)是喹诺酮及有万古霉素抗性且β-内酰胺抗生素对抵抗该等菌株无效;
-肠杆菌(Enterobacteriacea)是头孢菌素(cephalosporin)及有喹诺酮抗性;
-绿脓杆菌是β-内酰胺及有喹诺酮抗性。
此外,多药物抗性革兰氏阴性菌株(例如肠细菌及绿脓杆菌)的发病率正逐渐增加,且已在治疗中用当前使用的抗生素选择的新出现的生物体(例如不动杆菌(Acinetobacter spp.)或难养芽孢梭菌(Clostridium difficile))正变为医院环境中的真正问题。因此,医学上非常需要可抵抗该等多药物抗性细菌的新颖抗细菌剂。
另外,引起持续性感染的微生物正逐渐被视为严重慢性疾病(例如消化性溃疡或心脏病)的致病因子或辅因子。
WO2006/024171及US2007/0060558阐述式(A1)的抗细菌化合物
其中
n及n'各自独立地代表0、1、2或3;
R1a及R1b可(尤其)各自独立地代表卤素、(C1-C6)烷基或(C1-C6)烷氧基;
R2可尤其代表H且基团-(Y1)p-(U)p-(Y2)p″-可尤其代表2-乙基氨基、2-丙基氨基或3-丙基氨基,或R2亦可与Y1、U或Y2形成环状结构;
R6及R7可(尤其可能)一起形成环状结构。
此外,WO2008/126034阐述式(A2)的抗细菌化合物
其中
R1代表氢、烷氧基、卤素或氰基;
U、V、W及X中的一者或二者代表N且其余各自代表CH,或在X情形下代表CRa,Ra代表H或卤素;
R2、R3、R4及R5中的每一者可尤其代表H;
R6代表H或(C1-C4)烷基;
A、B、m、n、D及E可尤其具有以下代表性含义:
·A代表N,B代表N,D代表键,E代表CH2或*-COCH2-(其中星号指示该键附接至B),且m及n各自代表1;或
·A代表N,B代表C(OH),D代表键,E代表CH2,且m及n各自代表1;或
·A代表N,B代表CH,D代表NRb,E代表CH2,Rb代表H或(C1-C4)烷基,且m及n各自代表1;或
·A代表N,B代表CH,D代表NH,E代表CH2,m代表整数2,且n代表0;或
·A代表N,B代表CH,D代表NRc,E代表CH2,CO或CH2CH2,Rc代表H或(C1-C4)烷基,m代表1,且n代表0;或
·A代表N,B代表CH,D代表*-CH(Rd)-N(Re)-(其中星号指示该键附接至B),E代表CH2或CO,Rd代表H,Re代表H或(C1-C4)烷基,m代表1,且n代表0;或
·A代表N,B代表CH,D代表*-CONH-(其中星号指示该键附接至B),E代表CH2,m代表1,且n代表0;或
·A代表N,B代表C(OH),D代表*-CH2-NH-(其中星号指示该键附接至B),E代表CH2,m代表1,且n代表0;或
·A代表N,B代表CH,D代表*-CO-NH-(其中星号指示该键附接至B),E代表CH2,且m及n各自代表0;或
·A代表N,B代表CH,D代表*-CH2-N(Rf)-(其中星号指示该键附接至B),E代表CH2、CH2CH2或CO,Rf代表H或(C1-C4)烷基,且m及n各自代表0;或
·A代表N,B代表CH,D代表NRg,E代表CH2、CH2CH2、CO或*-COCH2-(其中星号指示该键附接至B),Rg代表H、(C1-C4)烷基或(C2-C4)烷基(其经羟基单取代或二取代),且m及n各自代表0;
G可尤其代表基团
其中Rh代表H或氟,M代表CH或N且Q'代表O或S。
发明内容
本发明提供其它抗细菌化合物,其包含2-氧代-噁唑烷-3,5-二基组元,即本文所述式I化合物。
下文阐述本发明的各个实施例:
1)本发明涉及式I化合物
其中
R1a代表H或羧基且R1b代表H,或R1a及R1b一起代表基团*-C(O)-NH-S-#或基团*-C(OH)=N-S-#,其中“*”代表R1a的附接点且“#”代表R1b的附接点;
R2代表H、(C1-C3)烷基、羟基-(C1-C3)烷基、苄基或(C3-C5)环烷基;
R3代表H或卤素(尤其氟);
U代表N或CR4,其中R4是H或(C1-C3)烷氧基;
A代表CH,B代表NH,m代表1或2且n代表1或2;或A代表N,B不存在(即A直接键结至CH2基团),m代表2且n代表2;
Y代表CH或N;且
Q代表O或S。
2)本发明尤其是关于实施例1)的式I化合物,其亦是式IE1化合物
其中噁唑烷酮部分的绝对构型如式IE1中所绘示[即噁唑烷酮部分的绝对构型是(R)]。
3)本发明还尤其是关于实施例1)的式I化合物,其亦是式IE2化合物
其中噁唑烷酮部分的绝对构型如式IE2中所绘示[即噁唑烷酮部分的绝对构型是(S)]。
4)本发明具体而言是关于实施例1)的式I化合物,其亦是式IP化合物
其中
R1a代表H或羧基;
R1b代表H;
R2代表H、(C1-C3)烷基、羟基-(C1-C3)烷基、苄基或(C3-C5)环烷基;
R3代表H或卤素(尤其氟);
U代表N或CR4;其中R4是H或(C1-C3)烷氧基;
A代表CH,B代表NH且m代表1且n代表1或m代表2且n代表2;或A代表N,B不存在(即A直接键结至CH2基团),m代表2且n代表2;
Y代表CH或N;且
Q代表O或S。
5)本发明的另一实施例是关于实施例4)的式IP化合物,其亦是式IPE1化合物
其中噁唑烷酮部分的绝对构型如式IE1中所绘示[即噁唑烷酮部分的绝对构型是(R)]。
6)本发明的另一实施例是关于实施例4)的式IP化合物,其亦是式IPE2化合物
其中噁唑烷酮部分的绝对构型如式IPE2中所绘示[即噁唑烷酮部分的绝对构型是(S)]。
以下段落提供本发明化合物中各化学部分的定义,且除非另有明确陈述的定义提供更宽或更窄的定义,否则意在整个说明书及权利要求范围中统一应用。
单独或组合使用的术语“烷基”是指含有1至4个碳原子的直链或具支链烷基。术语“(C1-Cx)烷基”(x是整数)是指含有1至x个碳原子的直链或具支链烷基。举例而言,(C1-C3)烷基含有1至3个碳原子。烷基的代表性实例包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基及叔丁基。优选是甲基及乙基。
术语“(Cx-Cy)羟基烷基”(x及y各自是整数)是指羟基烷基,其中该烷基含有x至y个碳原子。(C1-C3)羟基烷基的代表性实例包括(但不限于)羟基甲基、2-羟基-乙基、1-羟基-乙基及3-羟基-丙基。优选(C1-C3)羟基烷基是2-羟基-乙基及3-羟基-丙基。(C2-C3)羟基烷基的代表性实例包括(但不限于)2-羟基-乙基、1-羟基-乙基、2-羟基-丙基及3-羟基-丙基。优选(C2-C3)羟基烷基是2-羟基-乙基及3-羟基-丙基。
术语“环烷基”是指具有3至6个碳环原子的饱和单环基团,例如环丙基、环丁基、环戊基、环己基。术语“(C3-Cx)环烷基”(x是介于4与6之间的整数)是指含有3至x个碳原子的饱和单环基团。举例而言,(C3-C5)环烷基含有3至5个碳原子。如本文所定义的任何环烷基皆可经一个、两个卤素取代基(尤其氟)取代。术语“环烷基”优选是指环丙基。
术语“烷氧基”是指含有1至4个碳原子的直链或具支链烷氧基。术语“(Cx-Cy)烷氧基”(x及y各自是整数)是指如上文所述的含有x至y个碳原子的烷氧基。举例而言,(C1-C3)烷氧基含有1至3个碳原子。烷氧基的代表性实例包括甲氧基、乙氧基、正丙氧基及异丙氧基。优选是甲氧基及乙氧基。更优选是甲氧基。对于取代基R4,优选是甲氧基。
术语“卤素”是指氟、氯、溴或碘,且优选是指氟或氯。
术语“羧基”是指基团-COOH。
7)本发明的又一实施例是关于实施例1)至6)中任一实施例的式I化合物,其中R1a代表羧基且R1b代表H,或R1a及R1b一起代表基团*-C(O)-NH-S-#或基团*-C(OH)=N-S-#,其中“*”代表R1a的附接点且“#”代表R1b的附接点。
8)根据实施例7)的一变化形式,实施例7)的式I化合物将是R1a代表羧基且R1b代表H。
9)根据实施例7)的另一变化形式,实施例7)的式I化合物将是R1a及R1b一起代表基团*-C(O)-NH-S-#或基团*-C(OH)=N-S-#,其中“*”代表R1a的附接点且“#”代表R1b的附接点。
10)本发明的又一实施例是关于实施例1)至9)中任一实施例的式I化合物,其中R2代表H、(C1-C3)烷基、羟基-(C2-C3)烷基、苄基或(C3-C5)环烷基。
11)根据实施例10)的一变化形式,实施例10)的式I化合物将是R2代表(C1-C3)烷基或(C3-C5)环烷基(尤其环丙基)。
12)根据实施例10)的另一变化形式,实施例10)的式I化合物将是R2代表苄基。
13)根据实施例10)的另一变化形式,实施例10)的式I化合物将是R2代表环丙基。
14)本发明的又一实施例是关于实施例1)至13)中任一实施例的式I化合物,其中R3代表卤素(尤其氟)。
15)本发明的又一实施例是关于实施例1)至14)的式I化合物,其中U代表N。
16)本发明的又一实施例是关于实施例1)至14)的式I化合物,其中U代表CR4,其中R4是H或(C1-C3)烷氧基(尤其H)。
17)本发明的又一实施例是关于实施例1)至3)的式I化合物,或是关于如实施例1)至3)中的任一实施例以及实施例7)至16)中的任一实施例所定义的式I化合物,其中基团
选自以下基团:
及
其中星号表示将所述基团与附接至噁唑烷酮部分的CH2基团连接的键。
18)根据实施例17)的特定变化形式,实施例17)的式I化合物将是基团
是基团
其中星号表示将该基团与附接至噁唑烷酮部分的CH2基团连接的键。
19)本发明的又一实施例是关于实施例4)至6)中任一实施例的式I化合物,或是关于如实施例4)至6)中的任一实施例以及实施例7)至16)中的任一实施例所定义的式I化合物,其中基团
选自以下基团:
其中星号表示将所述基团与附接至噁唑烷酮部分的CH2基团连接的键。
20)本发明的又一实施例是关于如实施例1)至3)中任一实施例所定义的式I化合物,或是关于如实施例1)至3)中的任一实施例以及实施例7)至16)中的任一实施例所定义的式I化合物,其中A代表CH,B代表NH,m代表1或2且n代表1或2。
21)根据实施例20)的一变化形式,实施例20)的式I化合物将是A代表CH,B代表NH,m代表1且n代表1。
22)根据实施例20)的另一变化形式,实施例20)的式I化合物将是A代表CH,B代表NH,m代表1且n代表2。
23)根据实施例20)的另一变化形式,实施例20)的式I化合物将是A代表CH,B代表NH,m代表2且n代表2。
24)本发明的又一实施例是关于实施例4)至6)中任一实施例的式I化合物,或实施例4)至6)中的任一实施例以及实施例8)及11)至16)中的任一实施例的式I化合物,其中A代表CH,B代表NH且m及n中的每一者代表1。
25)本发明的又一实施例是关于实施例4)至6)中任一实施例的式I化合物,或实施例4)至6)中的任一实施例以及实施例8)及11)至16)中的任一实施例的式I化合物,其中A代表N,B不存在且m及n中的每一者代表2。
26)本发明的又一实施例是关于实施例4)至6)中任一实施例的式I化合物,或实施例4)至6)中的任一实施例以及实施例8)及11)至16)中的任一实施例的式I化合物,其中A代表CH,B是NH且m及n中的每一者代表2。
27)本发明的又一实施例是关于实施例1)至26)中任一实施例的式I化合物,其中Y代表CH或N且Q代表O,或Y代表CH且Q代表S。
28)本发明的又一实施例是关于实施例1)至26)中任一实施例的式I化合物,其中Y代表N且Q代表O,或Y代表CH且Q代表S。
29)本发明的特定实施例是关于实施例1)至3)中任一实施例的式I化合物,其中:
●R1a代表羧基且R1b代表H,或R1a及R1b一起代表基团*-C(O)-NH-S-#或基团*-C(OH)=N-S-#,其中“*”代表R1a的附接点且“#”代表R1b的附接点;
●R2代表环丙基;
●R3代表氟;
●U代表N;
●A代表CH,B代表NH,m代表1或2且n代表1或2;
●Y代表N;且
●Q代表O。
30)根据本发明的主要变化形式,如实施例1)中所定义的式I化合物亦可是式I2化合物
其中
R1a代表H或羧基且R1b代表H;
R2代表H、(C1-C3)烷基、羟基-(C1-C3)烷基、苄基或(C3-C5)环烷基;
R3代表H或卤素(尤其氟);
U代表N或CR4,其中R4是H或(C1-C3)烷氧基;
A代表CH,B代表NH,m代表1或2且n代表1或2;或A代表N,B不存在(即A直接键结至CH2基团),m代表2且n代表2;
Y代表CH或N;且
Q代表O或S。
31)本发明的特定实施例是关于实施例30)的式I化合物,其中:
●R1a代表羧基且R1b代表H;
●R2代表环丙基;
●R3代表氟;
●U代表N;
●A代表CH,B代表NH,m代表1或2且n代表1或2;
●Y代表N;且
●Q代表O。
32)根据本发明的另一主要变化形式,如实施例1)中所定义的式I化合物亦可是式I3或I3'化合物
其中
R2代表H、(C1-C3)烷基、羟基-(C1-C3)烷基、苄基或(C3-C5)环烷基;
R3代表H或卤素(尤其氟);
U代表N或CR4,其中R4是H或(C1-C3)烷氧基;
A代表CH,B代表NH,m代表1或2且n代表1或2;或A代表N,B不存在(即A直接键结至CH2基团),m代表2且n代表2;
Y代表CH或N;且
Q代表O或S。
33)本发明的特定实施例是关于实施例32)的式I化合物,其中:
●R2代表环丙基;
●R3代表氟;
●U代表N;
●A代表CH,B代表NH,m代表1或2且n代表1或2;
●Y代表N;且
●Q代表O。
34)本发明的又一实施例是关于实施例1)或4)的式I化合物,其选自由以下组成的群:
●1-环丙基-6-氟-4-氧代-7-{4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-喹啉-3-甲酸;
●1-环丙基-6-氟-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
●1-环丙基-6-氟-4-氧代-7-{4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-喹啉-3-甲酸;
●1-环丙基-6-氟-4-氧代-7-{4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸;
●6-((R)-5-{[1-(8-环丙基-3-氟-5-氧代-5,8-二氢-[1,8]萘啶-2-基)-氮杂环丁-3-基氨基]-甲基}-2-氧代-噁唑烷-3-基)-4H-苯并[1,4]噻嗪-3-酮;
●1-环丙基-6-氟-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
●1-环丙基-8-甲氧基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-喹啉-3-甲酸;
●1-环丙基-8-甲氧基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-喹啉-3-甲酸;
●1-乙基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
●1-环丙基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
●1-甲基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
●6-氟-1-甲基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
●1-苄基-6-氟-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
●1-环丙基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
●6-氟-1-(2-羟基-乙基)-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
●1-环丙基-6-氟-4-氧代-7-{4-[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸;
●1-环丙基-6-氟-4-氧代-7-(4-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-哌啶-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;及
●1-环丙基-6-氟-4-氧代-7-{4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸。
35)本发明的又一实施例是关于实施例1)的式I化合物,其选自由以下组成的群:
●1-环丙基-6-氟-4-氧代-7-{4-[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸;
●1-环丙基-6-氟-4-氧代-7-(4-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-哌啶-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
●1-环丙基-6-氟-4-氧代-7-(3-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-吡咯烷-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
●1-环丙基-6-氟-4-氧代-7-[(S)-3-({[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-甲基)-吡咯烷-1-基]-1,4-二氢-[1,8]萘啶-3-甲酸;
●9-环丙基-6-氟-3-羟基-7-(4-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-哌啶-1-基)-9H-1-硫杂-2,8,9-三氮杂-环戊[b]萘-4-酮;
●9-环丙基-6-氟-3-羟基-7-(3-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-9H-1-硫杂-2,8,9-三氮杂-环戊[b]萘-4-酮;及
●9-环丙基-6-氟-3-羟基-7-{4-[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-9H-1-硫杂-2,8,9-三氮杂-环戊[b]萘-4-酮。
36)本发明另外是关于选自由实施例34)及35)中所列示化合物组成的群的式I化合物的群,该化合物的群另外对应于实施例2)至33)中的一者,以及该等化合物的盐(具体而言医药上可接受的盐)。
37)本发明另外是关于选自由实施例34)及35)中所列示化合物组成的群的任一个别式I化合物,且是关于该个别化合物的盐(具体而言医药上可接受的盐)。
倘若使用化合物、盐、医药组合物、疾病或诸如此类的复数形式,则此亦指单一化合物、盐、疾病或诸如此类。
若适宜且方便,任一次提及式I、IE1、IE2、IP、IPE1、IPE2、I2、I3及I3'化合物时应理解为亦提及该等化合物的盐、尤其医药上可接受的盐。
术语“医药上可接受的盐”是指无毒无机或有机酸加成盐及/或碱加成盐。可参照“Salt selection for basic drugs”,Int.J.Pharm.(1986),33,201-217。
此外,本文所用术语“室温”是指25℃的温度。
除非使用时涉及温度,否则置于数值“X”之前的术语“约”在本申请案中是指自X-10%X延伸至X+10%X的区间,且优选是指自X-5%X延伸至X+5%X的区间。在温度的特定情形下,置于温度“Y”的前的术语“约”在本申请案中是指自温度Y-10℃延伸至Y+10℃的区间,且优选是指自Y-5℃延伸至Y+5℃的区间。
每当用词语“介于…的间”阐述数字范围时,应理解所示范围的端点明确包括在该范围中。举例而言:若将温度范围阐述为介于40℃与80℃之间,则此意指端点40℃及80℃包括在该范围中;或若将变量定义为介于1与4之间的整数,则此意指变量为整数1、2、3或4。
本发明亦包括经同位素标记、尤其经2H(氘)标记的如实施例1)至36)中任一实施例所定义的式I化合物,该等化合物与式I化合物相同,只是一或多个原子已各自经具有相同原子序数但原子质量与通常在自然界中所发现的原子质量不同的原子替代。经同位素标记、尤其经2H(氘)标记的式I化合物及其盐在本发明范围内。用较重同位素2H(氘)取代氢可提高代谢稳定性,从而(例如)延长活体内半衰期或降低剂量要求;或可降低对细胞色素P450酶的抑制,从而(例如)改良安全性特征。在本发明的一实施例中,式I化合物未经同位素标记,或其仅经一或多个氘原子标记。在子实施例中,式I化合物完全未经同位素标记。经同位素标记的式I化合物可以与下文所述类似的方法来制备,但使用适宜试剂或起始材料的合适同位素变化形式。
式I化合物及其医药上可接受的盐可作为(例如)呈医药组合物形式的医药用于经肠(尤其例如经口)或非经肠投与(包括局部施加或吸入)。
在本发明的优选实施例中,所投与的式I化合物的量将介于1mg/天与1000mg/天之间,具体而言介于5mg/天与500mg/天之间,更具体而言介于25mg/天与400mg/天之间,尤其介于50mg/天与200mg/天之间。
本发明的另一态样是医药组合物,其包含式I化合物或其医药上可接受的盐及医药上可接受的赋形剂/载剂材料。
该等医药组合物的制备可以任一熟习此项技术者熟悉的方式(例如,参见MarkGibson编辑,Pharmaceutical Preformulation and Formulation,IHS Health Group,Englewood,CO,USA,2001;Remington,The Science and Practice of Pharmacy,第20版,Philadelphia College of Pharmacy and Science)藉由将所述式I化合物或其医药上可接受的盐视情况与其它具有治疗价值的物质的组合与治疗上兼容的适宜无毒惰性固体或液体载剂材料及(若需要)常用医药佐剂一起制成草本投与形式来实现。
本发明(即上文实施例1)至37)中的任一者)的式I化合物适合用作人类及兽类医学中的化学治疗活性化合物,且适合用作用于保存无机及有机材料(具体而言,所有类型的有机材料,例如聚合物、润滑剂、涂料、纤维、皮革、纸及木材)的物质。
实施例1)至37)中任一实施例的式I化合物可尤其有效地抵抗细菌及细菌样生物体。因此,其在人类及兽类医学中尤其适于由该等病原体引起的局部及全身感染以及与细菌感染相关的病症的预防及化学治疗,该等病症包含与以下的感染相关的肺炎、中耳炎、鼻窦炎、支气管炎、扁桃体炎及乳突炎:肺炎链球菌、流感嗜血菌(Haemophilus influenzae)、黏膜炎莫拉氏菌(Moraxella catarrhalis)、金黄色葡萄球菌、粪肠球菌(Enterococcusfaecalis)、屎肠球菌(E.faecium)、钻黄肠球菌(E.casseliflavus)、表皮葡萄球菌(S.epidermidis)、溶血性葡萄球菌(S.haemolyticus)或消化链球菌(Peptostreptococcusspp.);与以下的感染相关的咽炎、风湿热及肾丝球肾炎:酿脓链球菌(Streptococcuspyogenes)、C群及G群链球菌(Groups C and G streptococci)、白喉棒状杆菌(Corynebacterium diphtheriae)或溶血放线杆菌(Actinobacillus haemolyticum);与以下的感染有关的呼吸道感染:人肺炎霉浆菌(Mycoplasma pneumoniae)、退伍军人嗜肺病菌(Legionella pneumophila)、肺炎链球菌、流感嗜血菌或肺炎披衣菌(Chlamydiapneumoniae);由以下引起的血液及组织感染,包括心内膜炎及骨髓炎:金黄色葡萄球菌、溶血性葡萄球菌、粪肠球菌、屎肠球菌、耐久肠球菌(E.durans),包括对已知抗细菌剂(例如,但不限于β-内酰胺、万古霉素、氨基糖苷、喹诺酮、氯霉素(chloramphenicol)、四环素(tetracycline)及巨环内酯)具有抗性的菌株;与以下的感染有关的非复杂性皮肤及软组织感染及脓疮及产褥热:金黄色葡萄球菌、凝固酶阴性葡萄球菌(即表皮葡萄球菌、溶血性葡萄球菌等)、酿脓链球菌、无乳链球菌(Streptococcus agalactiae)、链球菌群C-F(微小菌落链球菌)、草绿色链球菌(viridans streptococci)、微细棒状杆菌(Corynebacteriumminutissimum)、梭菌(Clostridium spp.)或韩瑟勒巴通氏菌(Bartonella henselae);与以下的感染相关的非复杂性急性尿道感染:金黄色葡萄球菌、凝固酶阴性葡萄球菌或肠球菌;尿道炎及宫颈炎;与以下的感染相关的性病:砂眼披衣菌(Chlamydia trachomatis)、杜克雷嗜血杆菌(Haemophilus ducreyi)、梅毒螺旋体(Treponema pallidum)、尿素分解尿霉浆菌(Ureaplasma urealyticum)或淋病双球菌(Neiserria gonorrheae);与以下的感染相关的毒素疾病:金黄色葡萄球菌(食物中毒及毒性休克症候群)或A群、B群及C群链球菌;与以下的感染相关的溃疡:幽门螺旋杆菌(Helicobacter pylori);与以下的感染相关的全身性发热症候群:回归热螺旋体(Borrelia recurrentis);与伯氏疏螺旋体(Borreliaburgdorferi)感染相关的莱姆病(Lyme disease);与以下的感染相关的结膜炎、角膜炎及泪囊炎:砂眼披衣菌、淋病双球菌、金黄色葡萄球菌、肺炎链球菌、酿脓链球菌、流感嗜血菌或李氏菌(Listeria spp.);与以下的感染相关的播散性复合鸟分枝杆菌(disseminatedMycobacterium avium complex(MAC))疾病:鸟分枝杆菌(Mycobacterium avium)或细胞内分枝杆菌(Mycobacterium intracellulare);由以下引起的感染:结核分枝杆菌(Mycobacterium tuberculosis)、麻风分枝杆菌(M.leprae)、副结核分枝杆菌(M.paratuberculosis)、堪萨斯分枝杆菌(M.kansasii)或龟鳖分枝杆菌(M.chelonei);与空肠曲杆菌(Campylobacter jejuni)感染相关的胃肠炎;与隐孢子虫(Cryptosporidiumspp.)感染相关的肠内原生动物;与草绿色链球菌感染相关的齿源性感染;与百日咳博德氏杆菌(Bordetella pertussis)感染相关的持续性咳嗽;与以下的感染相关的气性坏疽:产气荚膜芽孢梭菌(Clostridium perfringens)或非病原性肠杆菌(Bacteroides spp.);及与以下的感染相关的动脉粥样硬化或心血管疾病:幽门螺旋杆菌或肺炎披衣菌。
实施例1)至37)中任一实施例的式I化合物或其医药上可接受的盐可用于制备预防或治疗细菌感染的医药且适用于该预防或治疗。
因此,实施例1)至37)中任一实施例的式I化合物或其医药上可接受的盐可用于制备预防或治疗选自由以下组成的群的细菌感染的医药且适用于该预防或治疗:呼吸道感染、中耳炎、脑膜炎、皮肤及软组织感染(复杂性或非复杂性)、肺炎(包括医院获得性肺炎)、菌血症、心内膜炎、腹内感染、胃肠感染、难养芽孢梭菌感染、尿道感染、性传播感染、异物感染、骨髓炎、莱姆病、局部感染、眼感染、结核病及热带疾病(例如疟疾),且尤其用于预防或治疗选自由以下组成的群的细菌感染:呼吸道感染、中耳炎、脑膜炎、皮肤及软组织感染(复杂性或非复杂性)、肺炎(包括医院获得性肺炎)及菌血症。
实施例1)至37)中任一实施例的式I化合物可另外可用于制备治疗由以下介导的感染的医药且适用于该治疗:革兰氏阴性细菌,例如大肠杆菌(E.coli)、克留氏肺炎杆菌(Klebsiella pneumoniae)及其它肠杆菌、不动杆菌(包括鲍氏不动杆菌(Acinetobacterbaumanii))、绿脓杆菌(Pseudomonas aeruginiosa)、嗜麦芽窄食单胞菌(Stenotrophomonas maltophilia)、脑膜炎双球菌(Neisseria meningitidis)及非病原性肠杆菌。
实施例1)至37)中任一实施例的式I化合物可另外可用于制备治疗由以下介导的感染的医药且适用于该治疗:革兰氏阳性细菌,例如蜡状杆菌(Bacillus cereus)、炭疽杆菌(Bacillus anthracis)、难养芽孢梭菌、棒状杆菌(Corynebacterium spp.)及座疮丙酸杆菌(Propionibacterium acnes)。
实施例1)至37)中任一实施例的式I化合物可另外可用于制备治疗由以下介导的原生动物感染的医药且适用于该治疗:三日疟原虫(Plasmodium malaria)、恶性疟原虫(Plasmodium falciparum)、弓虫(Toxoplasma gondii)、肺胞囊虫(Pneumocystiscarinii)、布鲁氏锥虫(Trypanosoma brucei)及利什曼原虫(Leishmania spp)。
所示病原体列表应仅视为实例且决不具有限制性。
因此,本发明的一态样是关于实施例1)至37)中任一实施例的式I化合物或其医药上可接受的盐的用途,其用于制造预防或治疗细菌感染的医药。本发明的另一态样是关于实施例1)至37)中任一实施例的式I化合物或其医药上可接受的盐的用途,其用于预防或治疗细菌感染(具体而言用于预防或治疗由金黄色葡萄球菌或鲍氏不动杆菌引起的细菌感染,及尤其由喹诺酮抗性金黄色葡萄球菌或鲍氏不动杆菌引起的细菌感染)。
本发明的另一态样是关于预防或治疗患者的如上文所详述的感染(且具体而言预防或治疗由金黄色葡萄球菌或鲍氏不动杆菌引起的细菌感染,及尤其由喹诺酮抗性金黄色葡萄球菌或鲍氏不动杆菌引起的细菌感染)的方法,其包含向该患者投与医药活性量的实施例1)至37)中的一实施例的式I化合物或其医药上可接受的盐。
如同在人类中一般,亦可使用式I化合物(或其医药上可接受的盐)治疗其它物种(例如猪、反刍动物、马、狗、猫及家禽)的细菌感染。
因此,本发明是关于如实施例1)中所定义、或考虑到其各别依赖性进一步受实施例2)至37)中任一实施例的特性限制的式I化合物,且是关于其医药上可接受的盐。本发明另外是关于该等化合物作为医药的用途,其尤其用于预防或治疗细菌感染,具体而言用于预防或治疗由金黄色葡萄球菌或鲍氏不动杆菌引起、且尤其由喹诺酮抗性金黄色葡萄球菌或鲍氏不动杆菌引起的细菌感染。因此,以下与实施例1)的式(I)化合物相关的实施例是可能的且意欲呈个别化形式且以个别化形式具体揭示于此:
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在以上列表中,数字是指在上文中提供的实施例的编号,而“+”是指来自另一实施例的依赖性。不同个别化实施例藉由逗号隔开。换言的,例如,“4+3+1”是指依赖于实施例3)且依赖于实施例1)的实施例4),即实施例“4+3+1”对应于进一步受实施例3)及4)的特征限制的实施例1)。类似地,“28+18+17+1”是指依赖于(经必要修正)实施例17)及18)且依赖于实施例1)的实施例28),即实施例“28+18+17+1”对应于进一步受实施例28)的特征限制且进一步受实施例17)及18)的特征限制的实施例1)。
此外,本发明针对式I化合物(针对该等化合物本身、其盐、含有该等化合物或其盐的组合物、该等化合物或其盐的用途等)所述的任何特性皆适用于(经必要修正)式IE1、式IE2、式IP、式IPE1、式IPE2、式I2、式I3及式I3'化合物。
式I化合物可根据本发明使用下文所述程序来制备。
式I化合物的制备
一般制备方法:
式I化合物的制备:
式I化合物可藉由下文所给出的方法、藉由实例中所给出的方法或藉由类似方法来制造。最佳反应条件可随所用特定反应物或溶剂而变,但该等条件可由熟习此项技术者藉由常规最佳化程序来确定。
下文章节a)及b)阐述制备式I化合物的一般方法。若无另外说明,通用基团R1a、R1b、R2、R3、R4、A、B、Q、U及Y及整数m与n是如针对式I所定义。在下文中通篇反复使用的一般合成方法参照且阐述于上文标题为“一般反应技术”的章节中。所用其它缩写定义于实验章节中。在一些情况下,通用基团B可能与下文程序及方案中阐释的装配不兼容,且因此将需要使用保护基团。保护基团的使用为业内所熟知(例如,参见“Protective Groups inOrganic Synthesis”,T.W.Greene,P.G.M.Wuts,Wiley-Interscience,1999)。
式I化合物可藉由以下方法a)或b)来获得:
a)在诸如TEA或DIPEA等有机碱存在下使式II化合物
其中A、B、Y、Q、m及n具有与式I中相同的含义,与式III化合物反应
其中R1a及R1b具有与式I中相同的含义,或R1a代表基团COORa,其中Ra代表烷基、苄基、烯丙基或基团B(OAc)2,R1b代表H且X代表卤素(例如Br、Cl或I)。在Ra代表烷基、苄基或烯丙基的情形中,基团Ra可藉由分别用诸如NaOH等有机碱处理、经诸如Pd/C等贵金属催化剂氢化或藉由在亚磷酸三乙酯及2-甲基己酸钠存在下用Pd(OAc)2处理来移除。在Ra代表B(OAc)2的特定情形中,在反应后用诸如HCl等无机酸水溶液处理,之后进行纯化。
b)使用一般反应技术1在诸如TEA或DIPEA等有机碱存在下使式IV化合物
其中Z代表卤素(例如碘)或磺酸根(例如MsO、TsO或TfO)。
用于制备式I化合物的中间体的制备:
式II及V化合物:
式V化合物可如文献程序(WO2008/126034或WO2010/041194)中所述或以类似方式来制备。
式II化合物可根据WO2008/126034(m=n=1)或藉由下文方案1及2中所述一般途径中的一者来制备。
在方案1中,Z代表碘或磺酸根(例如OMs或OTs)且PG1代表胺保护基团(例如Cbz或Boc)。
可使用一般反应技术1在诸如TEA等碱存在下使式V化合物(方案1)与式I-1的胺(市售)反应,之后使用一般反应技术2移除胺保护基团。或者,可使用一般反应技术3或4及5将式V化合物转化为式I-2的相应胺,且使用一般反应技术6与式I-3的酮(市售)反应,之后使用一般反应技术2移除胺保护基团。
在方案2中,Xa代表卤素(例如氯或溴),PG1代表胺保护基团(例如Alloc或Boc),且m、n、A、B、Y及Q具有与式I中相同的含义。
式II化合物可藉由使式II-1化合物与式II-2化合物反应来获得(阐述于WO2010/041194中)。在Y=N时,此反应可在NaH存在下进行;在Y=CH时,其可在针对金属催化的2-噁唑烷酮或酰胺的N-芳基化所述的条件下进行,具体而言藉由使用CuI及1,1,1-叁(羟基甲基)乙烷在Cs2CO3存在下进行(Chen等人,Org.Lett.(2006),8,5609),或使用Pd(OAc)2及DPEphos在K3PO4存在下进行。
在Y=N且Q=O的特定情形中,式II化合物可另外如下文方案3中所述来制备。
在方案3中,Xa代表卤素(例如氯或溴),PG1代表胺保护基团(例如Alloc或Boc)且m、n、A及B具有与式I中相同的含义。
可在碱(例如K2CO3、Pd(OAc)2及DPEphos)存在下使式II-1的噁唑烷酮(方案3)与式III-1的硝基吡啶衍生物(如WO2007/118130中所述来制备)反应。可用氯化铵及铁粉处理所得式III-2的噁唑烷酮,之后使用一般反应技术2移除氮保护基团,从而获得式II化合物(其中Y=N且Q=O)。
式III化合物:
式III化合物(其中R1a代表羧基且R1b代表H)是自市场购得或可藉由在浓HCl水溶液存在下水解其相应已知烷基酯(例如III,其中U=N,R2=环丙基且R3=H:EP607825)来制备。式III化合物(其中R1a及R1b中的每一者代表H)可藉由相应式III化合物(其中R1a代表羧基)在热条件(介于150℃与250℃之间)下去羧来制备。式III化合物(其中R1a及R1b一起代表基团*-C(O)-NH-S-#或基团*-C(OH)=N-S-#,其中“*”代表R1a的附接点且“#”代表R1b的附接点)可根据J.Heterocycl.Chem.(1990),27(5),1191-1195或以类似方式来制备。
式IV化合物:
式IV化合物是自市场购得或可如EP235762、DE2362553、DE2840910、EP241206或Chemical&Pharmaceutical Bulletin(1988),36(3),1223-8中所述来制备。
式II-1化合物:
式II-1化合物可如下文方案4中所述来制备。
在方案4中,PG1代表胺保护基团(例如Alloc或Boc)且m、n、A及B具有与式I中相同的含义。
可在MgSO4存在下使式IV-1或IV-3的市售哌啶衍生物(方案4)与式IV-2的市售环氧化物反应。可使所得式IV-4的氨基醇衍生物与K2CO3反应,从而获得式II-1的噁唑烷酮衍生物。
一般反应技术:
一般反应技术1(用甲磺酸酯或碘化物将胺烷基化):
在介于0℃与+80℃之间,在诸如K2CO3等无机碱或诸如TEA或DIPEA等有机碱存在下,在诸如THF、DMF或DMSO等溶剂中使胺衍生物与所需碘化物衍生物或活化为磺酸酯(OMs、ONf、ONs、OBs、OTf、OTs)的醇衍生物反应。其它细节可参见Comprehensive OrganicTransformations.A guide to Functional Group Preparations;第2版,R.C.Larock,Wiley-VC;New York,Chichester,Weinheim,Brisbane,Singapore,Toronto,(1999)Section Amines,第779页。
一般反应技术2(移除氨基保护基团):
Cbz保护基团是藉由经贵金属催化剂(例如Pd/C或Pd(OH)2/C)氢解来移除。Boc基团是在酸性条件下(例如,存于诸如MeOH或二恶烷等有机溶剂中的HCl,或纯净TFA或稀释于诸如DCM等溶剂中的TFA)移除。在介于0℃与50℃之间,在诸如THF等溶剂中,在四(三苯基膦)钯(0)存在下,在烯丙基正离子清除剂(例如吗啉、双甲酮(dimedone)或三丁基氢化锡)存在下移除Alloc基团。移除胺保护基团的其它一般方法已阐述于Protecting Groups inOrganic Synthesis,第3版(1999),494-653;T.W.Greene,P.G.M.Wuts;(出版商:JohnWiley and Sons公司,New York,N.Y.)中。
一般反应技术3(迭氮化物的形成):
在介于20℃与100℃之间,在诸如DIPEA或TEA等有机碱或诸如Na2CO3等无机碱存在下,在诸如DMSO或DMF等溶剂中,使活化醇(活化为磺酸酯或碘化物衍生物)与迭氮化钠反应。或者,亦可藉由在Mitsunobu条件下,在介于-20℃与+60℃之间,在PPh3及DEAD或DIAD存在下,在诸如THF、DMF、DCM或DME等溶剂中活化醇来获得迭氮化物,如Synthesis(1981),1-28中所综述。或者,在介于-20℃与+60℃之间,在诸如TEA或DBU等碱存在下,在诸如THF等溶剂中,使醇与DPPA直接反应,如J.Org.Chem.(1993),58,5886-5888中所述。
一般反应技术4(酞酰亚胺的形成):
在介于20℃与100℃之间,在诸如DMSO或DMF等溶剂中使活化醇(活化为磺酸酯或碘化物衍生物)与酞酰亚胺钾反应。
一般反应技术5(胺的形成):
经贵金属催化剂(例如Pd/C)在诸如MeOH或EA等溶剂中氢化迭氮化物。倘若分子含有不饱和双键或三键,则可在水存在下使用PPh3进行还原,如J.Med.Chem.(1993),36,2558-68中所述。此外,在介于50℃与120℃之间,在诸如MeOH或EtOH等溶剂中用肼衍生物(例如水合肼、甲基肼)或胺(例如N1,N1-二甲基丙基-1,3-二胺)处理酞酰亚胺衍生物。其它一般方法已阐述于Protecting Groups in Organic Synthesis,第3版(1999),564-566;T.W.Greene,P.G.M.Wuts(出版商:John Wiley and Sons公司,New York)中。
一般反应技术6(还原胺化):
胺与醛或酮之间的反应是在容许经由物理或化学方式(例如,蒸馏溶剂-水共沸物或存在干燥剂(例如分子筛、MgSO4或Na2SO4))移除所形成水的溶剂系统中进行。该溶剂通常为甲苯、Hex、THF、DCM或DCE或诸如DCE/MeOH等溶剂混合物。可藉由痕量酸(通常为AcOH)来催化反应。中间体亚胺是用适宜还原剂(例如,NaBH4、NaBH3CN或NaBH(OAc)3)或经由经贵金属催化剂(例如Pd/C)氢化来还原。反应是在介于-10℃与110℃之间、优选介于0℃与60℃之间实施。反应亦可以一锅式方法来实施。其亦可在甲吡啶-硼烷复合物存在下在质子溶剂(例如MeOH或水)中进行(Tetrahedron(2004),60, 7899-7906)。
本发明的特定实施例阐述于以下实例中,这样的实例用于更详细地阐释本发明而非以任何方式限制本发明的范围。
实例
缩写(此处及上文说明中所用):
Ac 乙酰基
Alloc 烯丙氧基羰基
aq. 水性
Boc 叔丁氧基羰基
Bs 4-溴苯磺酰基(对溴苯磺酸酯基(brosylate))
Bu 丁基
Cbz 苄氧基羰基
CC 经硅胶柱层析
Cipro 环丙沙星(ciprofloxacin)
DAD 二极管阵列检测
DBU 1,8-二氮杂二环[5.4.0]十一-7-烯
DCE 1,2-二氯乙烷
DCM 二氯甲烷
DEAD 偶氮二甲酸二乙酯
dil. 经稀释
DPEphos 双(2-二苯基膦基苯基)醚
DIAD 偶氮二甲酸二异丙酯
DIPEA N,N-二异丙基乙胺
DME 1.2-二甲氧基乙烷
DMF N,N-二甲基甲酰胺
DMSO 二甲亚砜
DPPA 二苯基磷酰基迭氮化物
EA 乙酸乙酯
ELSD 蒸发光散射检测器
ESI 电喷雾离子化
eq. 当量
Et 乙基
Hept 庚烷
Hex 己烷
HPLC 高压液相层析
LC 液相层析
Me 甲基
MS 质谱法
Ms 甲烷磺酰基(甲磺酰基)
Nf 九氟丁烷磺酰基
Ns 4-硝基苯磺酰基(硝基磺酸酯)
org. 有机
Pd/C 碳载钯
Pd(OH)2/C 碳载二氢氧化钯
Ph 苯基
PPh3 三苯基膦
Pyr 吡啶
rac 外消旋
rt 室温
sat. 饱和
TBME 叔丁基甲基醚
tBu 叔丁基
TEA 三乙胺
Tf 三氟甲烷磺酰基(三氟甲磺酰基)
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层层析
Ts 对甲苯磺酰基
wt% 重量百分比
所有温度皆表示为℃。所有温度皆表示为℃。除非另外指明,否则反应是在rt下进行。
分析型TLC表征是使用0.2mm板来实施:Merck,硅胶60F254。溶析是使用EA、Hept、DCM、MeOH或其混合物来实施。检测是使用UV或使用随后加热的KMnO4(3g)、K2CO3(20g)、5%NaOH(3mL)及H2O(300mL)的溶液来进行。
CC是使用Brunschwig60A硅胶(0.032-0.63mm)来实施;洗脱是使用EA、Hept、DCM、MeOH或其混合物来实施。在化合物含有酸官能基的情形中,将1%AcOH添加至洗脱剂中。
藉由1H-NMR(300MHz)(Varian Oxford)或藉由1H-NMR(400MHz)(BrukerAdvance400)来表征化合物。化学位移δ是相对于所用溶剂以ppm来表示;多重性:s=单峰,d=双重峰,t=三重峰,q=四重峰,p=五重峰,hex=六重峰,hep=七重峰,m=多重峰,br.=宽峰,耦合常数是以Hz来表示。或者,化合物是藉由以下来表征:LC-MS(Sciex API2000,具有Agilent1100二元泵以及DAD及ELSD;或Agilent四极MS6140,具有Agilent1200二元泵、DAD及ELSD);TLC(TLC板,来自Merck,硅胶60F254);或熔点。藉由在硅胶60A上层析来纯化化合物。用于CC的NH4OH是25%aq.。
LC-MS数据已使用以下三种各别方法来实施:
方法1(MS1):
●泵:Waters Acquity二元泵,溶剂管理器;MS:Waters SQ检测器;DAD:AcquityUPLC PDA检测器;ELSD:Acquity UPLC ELSD。
●柱:Acquity UPLC CSH C181.7μm,2.1×50mm,来自Waters,在Acquity UPLC柱管理器中在60℃下恒温。
●洗脱剂:A:H2O+0.05%甲酸;B:MeCN+0.045%甲酸。梯度:经3.0min自2%B→98%。流速:0.6mL/min。
●检测:UV214nm,ELSD及MS;滞留时间tR是以min来表方法2(MS2):
●Thermo MSQ Plus,具有Dionex GHP3200二元泵、DAD及ELSD。
●洗脱剂:A:H2O+0.04%TFA;B:MeCN;梯度:经3.0min自2%B→98%。流速:0.6mL/min
●柱:ZorbaxSB-Aq,3.7μm,4.6×50mm/USXA001358
方法3(MS3):
●与MS2相同的方法,但
●柱:Waters Atlantis T3,5μm,4.6×30mm/01273031412503。
针对所测试每一化合物的相应[M+H+]峰给出的小数字数取决于实际上使用的LC-MS装置的精确度。
HPLC是在固定相上实施,例如快速分离Zorbax SB C18(1.8μm)柱或快速分离Zorbax Eclipse Plus C18(1.8μm)柱。典型HPLC条件是洗脱剂A(水:MeCN95:5,含有0.1%甲酸,在5mmol/L甲酸铵存在或不存在下)及洗脱剂B(MeCN:水95:5,含有0.1%甲酸,在5mmol/L甲酸铵存在或不存在下)的梯度,流速为0.8至5mL/min。
实例1:1-环丙基-6-氟-4-氧代-7-{4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-喹啉-3-甲酸:
将1-环丙基-6-氟-1,4-二氢-7-(1-哌嗪基)-4-氧代-3-喹啉甲酸(市售;331mg)、6-((S)-5-碘甲基-2-氧代噁唑烷-3-基)-4H-苯并[1,4]噻嗪-3-酮(根据WO2008/126034制备;395mg)及DIPEA(0.5ml)存于DMSO(6ml)中的混合物在80℃下加热24h。使反应混合物达到rt,倾倒在0.1N HCl(50ml)上并过滤。藉由CC(DCM/MeOH19:1至9:1至4:1,之后DCM/MeOH19:1+1%AcOH)纯化所得固体,从而在减压下浓缩且在MeOH/EA中搅拌后获得灰棕色固体。
1H NMR(DMSO-d6)δ:11.40(s,1H);10.55(s,1H);8.68(s,1H);7.95-7.80(m,1H);7.59-7.45(m,1H);7.36-7.25(m,2H);7.15-7.06(m,1H);4.99-4.79(m,1H);4.18-4.01(m,1H);3.81-3.62(m,2H);3.41(s,2H);3.34-3.18(m,4H);
2.83-2.62(m,6H);1.37-1.21(m,2H);1.13-0.97(m,2H)。MS(ESI,m/z):对于C29H28N5O6FS,594.4[M+H+];tR=0.65min(MS2)。
实例2:1-环丙基-6-氟-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
将7-氯-1-环丙基-6-氟-4-氧代-1,4-二氢-[1,8]萘啶-3-甲酸(市售;141mg)、6-[(5R)-5-[(3-氮杂环丁基氨基)甲基]-2-氧代-3-噁唑烷基]-2H-1,4-苯并噻嗪-3(4H)-酮(根据WO2008/126034制备;167mg)及TEA(0.15ml)存于MeCN(4ml)中的混合物在75℃下加热2h。使反应混合物达到rt,用水稀释,过滤且用MeOH及EA洗涤固体,从而获得灰棕色固体。
1H NMR(DMSO-d6)δ:10.54(s,1H);8.54(s,1H);7.94(d,J=11.5Hz,1H);7.32-7.26(m,2H);7.11(dd,J=2.3Hz,J=8.6Hz,1H);4.79-4.62(m,1H);4.59-4.36(m,2H);4.17-3.92(m,3H);3.89-3.70(m,2H);3.70-3.56(m,1H);3.41(s,2H);2.95-2.75(m,3H);1.21-0.98(m,4H)。MS(ESI,m/z):对于C27H25N6O6FS,582.2[M+H+];tR=0.64min(MS2)。
实例3:1-环丙基-6-氟-4-氧代-7-{4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-喹啉-3-甲酸:
与实例1类似,自1-环丙基-6-氟-1,4-二氢-7-(1-哌嗪基)-4-氧代-3-喹啉甲酸(市售;166mg)及6-[(5R)-5-[[(甲基磺酰基)氧基]甲基]-2-氧代-3-噁唑烷基]-2H-吡啶并[3,2-b]-1,4-噻嗪-3(4H)-酮(以类似于WO2010/041194中所述其(S)镜像异构物的方式制备;180mg)开始,在CC(DCM/MeOH9:1)及自EtOH结晶后获得呈灰棕色固体的标题化合物。
1H NMR(DMSO-d6)δ:11.40(s,1H),10.84(s,1H);8.65(s,1H);7.89(d,J=13.3Hz,1H);7.81-7.74(m,1H);7.70-7.64(m,1H),7.55(d,J=7.4Hz,1H);4.97-4.81(m,1H);4.26-4.13(m,1H);3.89-3.74(m,2H);3.51(s,2H);3.36-3.22(m,4H);2.82-2.65(m,6H);1.37-1.22(m,2H);1.22-1.11(m,2H)。MS(ESI,m/z):对于C28H27N6O6FS,595.18[M+H+];tR=1.13min(MS1)。
实例4:1-环丙基-6-氟-4-氧代-7-{4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸:
4.1.4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-甲酸叔丁基酯:
将6-((S)-5-碘甲基-2-氧代噁唑烷-3-基)-4H-苯并[1,4]噻嗪-3-酮(根据WO2008/126034制备;1.0g)及Boc-哌嗪(1.43g)存于DMF(10ml)中的溶液在rt下搅拌过夜且在60℃下搅拌2h。使反应混合物达到rt,用水稀释且用EA(2×)萃取。用水及盐水洗涤经合并有机层,经MgSO4干燥,过滤并在减压下蒸发,从而在TBME中搅拌残余物后获得无色固体。
1H NMR(CDCl3)δ:8.15(s,1H);7.41(d,J=2.3Hz,1H);7.29(d,J=8.5Hz,1H);6.95(dd,J=2.3Hz,J=8.6Hz,1H);4.88-4.67(m,1H);4.05(t,J=8.7Hz,1H);3.79(dd,J=7.0Hz,J=8.8Hz,1H);3.47-3.36(m,4H);3.41(s,2H);2.80-2.67(m,2H);2.64-2.43(m,4H);1.46(s,9H)。MS(ESI,m/z):449.1[M+H+]。
4.2.6-((R)-2-氧代-5-哌嗪-1-基甲基-噁唑烷-3-基)-4H-苯并[1,4]噻嗪-3-酮:
用三乙基硅烷(0.28ml)及TFA(3.12ml)处理中间体4.1(730mg)存于DCM(10ml)中的溶液。在rt下搅拌30min后,在减压下蒸发溶液且在DCM中吸收残余物并用稀NH4OH溶液洗涤。用DCM/MeOH(9:1)萃取水性层且经MgSO4干燥经合并有机层,过滤并在减压下蒸发,从而获得无色发泡体。
1H NMR(DMSO-d6)δ:10.52(s,1H);7.35-7.24(m,2H);7.11(dd,J=2.2Hz,J=8.6Hz,1H);4.88-4.72(m,1H);4.05(t,J=8.8Hz,1H);3.68(dd,J=7.1Hz,J=8.5Hz,1H);3.42(s,2H);2.72-2.61(m,4H);2.61-2.56(m,2H);2.43-2.31(m,4H)。MS(ESI,m/z):对于C16H20N4O3S,349.0[M+H+]。
4.3.1-环丙基-6-氟-4-氧代-7-{4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例2类似,自中间体4.2(174mg)及7-氯-1-环丙基-6-氟-4-氧代-1,4-二氢-[1,8]萘啶-3-甲酸(市售;141mg)开始,获得呈无色发泡体的标题化合物。
1H NMR(DMSO-d6)δ:11.40(s,1H),10.54(s,1H);8.60(s,1H);8.06(d,J=13.5Hz,1H);7.33(d,J=2.2Hz,1H);7.30(d,J=8.6Hz,1H);7.11(dd,J=2.3Hz,J=8.7Hz,1H);4.95-4.78(m,1H);4.14-4.02(m,1H);3.92-3.80(m,4H);3.78-3.62(m,2H);3.42(s,2H);2.79-2.60(m,6H);1.25-1.11(m,2H);1.11-1.02(m,2H)。MS(ESI,m/z):对于C28H27N6O6FS,595.18[M+H+];tR=1.12min(MS1)。
实例5:6-((R)-5-{[1-(8-环丙基-3-氟-5-氧代-5,8-二氢-[1,8]萘啶-2-基)-氮杂环丁-3-基氨基]-甲基}-2-氧代-噁唑烷-3-基)-4H-苯并[1,4]噻嗪-3-酮:
5.1.7-氯-1-环丙基-6-氟-1H-[1,8]萘啶-4-酮:
将7-氯-1-环丙基-6-氟-4-氧代-1,4-二氢-[1,8]萘啶-3-甲酸(2.0g)逐份添加至陶氏热媒(Dowtherm)的沸腾溶液(50ml,在250℃下加热)中,且在此温度下进一步搅拌1h。使反应混合物达到rt并用1N NaOH(100ml)稀释且用EA萃取。弃去有机相。用3N HCl酸化水性相且用醚/EA萃取。过滤水性层且用醚/EA萃取滤液。用水及盐水洗涤经合并有机层,经MgSO4干燥,过滤并在减压下蒸发,从而提供固体,将其在Hept/EA中搅拌并过滤。在减压下浓缩滤液且藉由CC(EA至EA/MeOH9:1)纯化,从而获得灰棕色固体。
1H NMR(CDCl3)δ:8.36(d,J=7.5Hz,1H);7.73(d,J=8.0Hz,1H);6.25(d,J=8.0Hz,1H);3.62-3.51(m,1H);1.33-1.20(m,2H);1.03-0.93(m,2H)。MS(ESI,m/z):对于C11H8N2OClF,239.16[M+H+];tR=0.67min(MS3)。
5.2.6-((R)-5-{[1-(8-环丙基-3-氟-5-氧代-5,8-二氢-[1,8]萘啶-2-基)-氮杂环丁-3-基氨基]-甲基}-2-氧代-噁唑烷-3-基)-4H-苯并[1,4]噻嗪-3-酮:
与实例2类似,自中间体5.1(30mg)及6-[(5R)-5-[(3-氮杂环丁基氨基)甲基]-2-氧代-3-噁唑烷基]-2H-1,4-苯并噻嗪-3(4H)-酮(根据WO2008/126034制备;42mg)开始,获得呈灰棕色固体的标题化合物。
1H NMR(DMSO-d6)δ:10.54(s,1H);7.77(d,J=3.9Hz,1H);7.74(d,J=7.8Hz,1H);7.36-7.25(m,3H);7.14-7.07(m,1H);4.76-4.63(m,1H);4.44-4.30(m,1H);4.09-3.89(m,3H);3.85-3.69(m,2H);3.47-3.42(m,1H);3.41(s,2H);2.90-2.76(m,4H);1.07-0.85(m,4H)。MS(ESI,m/z):对于C26H25N6O4FS,537.17[M+H+];tR=0.95min(MS1)。
实例6:1-环丙基-6-氟-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例2类似,自7-氯-1-环丙基-6-氟-4-氧代-1,4-二氢-[1,8]萘啶-3-甲酸(70mg)及6-[(5R)-5-[(3-氮杂环丁基氨基)甲基]-2-氧代-3-噁唑烷基]-2H-1,4-苯并噁嗪-3(4H)-酮(根据WO2008/126034制备;89mg)开始,获得呈灰棕色固体的标题化合物。
1H NMR(DMSO-d6)δ:11.40(s,1H);11.16(s,1H);8.54(s,1H);7.94(d,J=11.5Hz,1H);7.59(d,J=8.7Hz,1H);7.40(d,J=8.7Hz,1H);4.78-4.62(m,1H);4.59(s,2H);4.54-4.38(m,2H);4.21-3.95(m,3H);3.91-3.74(m,2H);3.71-3.56(m,1H);2.91-2.81(m,2H);1.21-0.99(m,4H)。MS(ESI,m/z):对于C26H24N7O7F,566.18[M+H+];tR=1.00min(MS1)。
实例7:1-环丙基-8-甲氧基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-喹啉-3-甲酸:
标题化合物是以与实例2类似的方式自含有硼酸(1:1)及含有乙酸(1:2)的1-环丙基-7-氟-1,4-二氢-8-甲氧基-4-氧代-3-喹啉甲酸酐(101mg;根据WO2010/056633制备)及6-[(5R)-5-[(3-氮杂环丁基氨基)-甲基]-2-氧代-3-噁唑烷基]-2H-1,4-苯并噻嗪-3(4H)-酮(根据WO2008/126034制备;167mg)开始来制备。在反应结束时,在减压下浓缩反应混合物且在MeOH中吸收残余物,且用存于MeOH(3ml)中的1N HCl处理15min。用水(2ml)稀释反应混合物且过滤出固体。在减压下浓缩有机相且藉由CC(DCM/MeOH9:1,之后DCM/MeOH9:1+1%AcOH)纯化,从而在蒸发且将残余物与MeOH/TBME一起搅拌后获得灰棕色固体。
1H NMR(DMSO-d6)δ:11.40(s,1H),10.56(s,1H);8.59(s,1H);7.99-7.83(m,1H);7.33(d,J=2.3Hz,1H);7.29(d,J=8.6Hz,1H);7.10(dd,J=2.3Hz,J=8.6Hz,1H);6.84-6.68(m,1H);4.78-4.61(m,1H);4.33-4.18(m,2H);4.11-3.98(m,2H);3.83-3.67(m,4H);3.55(s,3H);3.41(s,2H);2.85(d,J=5.2Hz,2H);1.80(br.s,1H);1.13-0.99(m,2H);0.99-0.86(m,2H)。MS(ESI,m/z):对于C29H29N5O7S,592.19[M+H+];tR=1.01min(MS1)。
实例8:1-环丙基-8-甲氧基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-喹啉-3-甲酸:
与实例2类似,自含有硼酸(1:1)及含有乙酸(1:2)的1-环丙基-7-氟-1,4-二氢-8-甲氧基-4-氧代-3-喹啉甲酸酐(101mg;根据WO2010/056633制备)及6-[(5R)-5-[(3-氮杂环丁基氨基)甲基]-2-氧代-3-噁唑烷基]-2H-1,4-苯并恶嗪-3(4H)-酮(根据WO2008/126034制备;89mg)开始,获得呈灰棕色固体的标题化合物。
1H NMR(DMSO-d6)δ:11.40(s,1H),11.16(s,1H);8.61(s,1H);7.98-7.86(m,1H);7.62-7.55(m,1H);7.41(d,J=8.7Hz,1H);6.86-6.69(m,1H);4.78-4.63(m,1H);4.59(s,2H);4.34-4.18(m,2H);4.18-4.03(m,2H);3.91-3.80(m,1H);3.80-3.65(m,3H);3.55(s,3H);2.85(d,J=4.9Hz,2H);1.86(s,1H);1.15-1.01(m,2H);1.01-0.90(m,2H)。MS(ESI,m/z):对于C28H28N6O8,577.21[M+H+];tR=0.94min(MS1)。
实例9:1-乙基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例2类似,自7-氯-1-乙基-1,4-二氢-4-氧代-1,8-萘啶-3-甲酸(根据US3149104制备;63mg)及6-[(5R)-5-[(3-氮杂环丁基氨基)甲基]-2-氧代-3-噁唑烷基]-2H-1,4-苯并恶嗪-3(4H)-酮(根据WO2008/126034制备;89mg)开始,获得呈灰棕色固体的标题化合物。
1H NMR(DMSO-d6)δ:11.40(s,1H);11.22(s,1H);8.93(s,1H),8.31(d,J=8.9Hz,1H);7.62-7.56(m,1H);7.46-7.39(m,1H);6.75(d,J=8.9Hz,1H);4.60(s,2H);4.53-4.36(m,4H);4.32-4.15(m,4H);3.83(dd,J=6.9Hz,J=10.5Hz,1H);3.48-3.24(m,4H);1.38(t,J=7.0Hz,3H)。MS(ESI,m/z):对于C25H25N7O7,536.19[M+H+];tR=0.92min(MS1)。实例10:1-环丙基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
10.1.7-氯-1-环丙基-4-氧代-1,4-二氢-[1,8]萘啶-3-甲酸:
将7-氯-1-环丙基-1,4-二氢-4-氧代-1,8-萘啶-3-甲酸乙基酯(根据EP607825制备;500mg)存于6N HCl(6ml)中的悬浮液在100℃下搅拌30min。使反应混合物达到rt并藉由过滤收集所得晶体且依序用水及MeOH洗涤,从而获得灰棕色固体。
1H NMR(DMSO-d6)δ:11.40(s,1H),8.81(s,1H);8.70(d,J=8.4Hz,1H);7.78(d,J=8.4Hz,1H);3.85-3.74(m,1H);1.27-1.07(m,4H)。MS(ESI,m/z):对于C12H9N2O3Cl,265.1[M+H+];tR=0.7min(MS3)。
10.2.1-环丙基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例2类似,自中间体10.1(66mg)及6-[(5R)-5-[(3-氮杂环丁基氨基)甲基]-2-氧代-3-噁唑烷基]-2H-1,4-苯并噻嗪-3(4H)-酮(根据WO2008/126034制备;84mg)开始,获得呈灰棕色固体的标题化合物。
1H NMR(DMSO-d6)δ:11.40(s,1H),10.54(s,1H);8.53(s,1H);8.22(d,J=8.9Hz,1H);7.33(d,J=2.3Hz,1H);7.32-7.26(m,1H);7.10(dd,J=2.3Hz,J=8.5Hz,1H);6.65(d,J=8.9Hz,1H);4.77-4.63(m,1H);4.37-4.27(m,2H);4.05(t,J=8.7Hz,1H);3.93-3.72(m,4H);3.70-3.58(m,1H);3.42(s,2H);2.91-2.80(m,2H);1.18-0.93(m,4H)。MS(ESI,m/z):对于C27H26N6O6S,563.17[M+H+];tR=1.01min(MS1)。
实例11:1-甲基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例2类似,自7-氯-1,4-二氢-1-甲基-4-氧代-1,8-萘啶-3-甲酸(60mg;根据JP01165584制备)及6-[(5R)-5-[(3-氮杂环丁基氨基)甲基]-2-氧代-3-噁唑烷基]-2H-1,4-苯并恶嗪-3(4H)-酮(根据WO2008/126034制备;89mg)开始,获得呈灰棕色固体的标题化合物。
1H NMR(DMSO-d6)δ:11.40(s,1H),11.23(s,1H);8.92(s,1H);8.32(d,J=8.9Hz,1H);7.62-7.56(m,1H);7.44(d,J=8.8Hz,1H);6.76(d,J=8.9Hz,1H);5.09-5.97(m,1H);4.61(s,2H);4.52-4.39(m,1H);4.38-4.21(m,4H);3.91(s,3H);3.88-3.78(m,1H);3.55-3.33(m,4H)。MS(ESI,m/z):对于C24H23N7O7,522.16[M+H+];tR=0.47min(MS3)。
实例12:6-氟-1-甲基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例2类似,自7-氯-6-氟-1,4-二氢-1-甲基-4-氧代-1,8-萘啶-3-甲酸(64mg;根据WO2011/037433制备)及6-[(5R)-5-[(3-氮杂环丁基氨基)甲基]-2-氧代-3-噁唑烷基]-2H-1,4-苯并恶嗪-3(4H)-酮(根据WO2008/126034制备;89mg)开始,获得呈灰棕色固体的标题化合物。
1H NMR(DMSO-d6)δ:11.40(s,1H),11.16(s,1H);8.87(s,1H);7.93(d,J=11.5Hz,1H);7.62-7.55(m,1H);7.40(d,J=8.7Hz,1H);4.78-4.61(m,1H);4.58(s,2H);4.55-4.34(m,2H);4.19-3.92(m,3H);3.87(s,3H);3.86-3.74(m,2H),2.93-2.77(m,2H)。MS(ESI,m/z):对于C24H22N7O7F,540.16[M+H+];tR=0.91min(MS1)。
实例13:1-苄基-6-氟-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例2类似,自1-苄基-7-氯-6-氟-4-氧代-1,4-二氢-[1,8]萘啶-3-甲酸(83mg;自市场购得或藉由在6M HCl存在下水解根据CN101792443获得的相应酯来制备)及6-[(5R)-5-[(3-氮杂环丁基氨基)甲基]-2-氧代-3-噁唑烷基]-2H-1,4-苯并恶嗪-3(4H)-酮(根据WO2008/126034制备;89mg)开始,获得呈灰棕色固体的标题化合物。
1H NMR(DMSO-d6)δ:11.40(s,1H),11.16(s,1H);8.87(s,1H);7.93=11.5Hz,1H);7.63-7.56(m,1H);7.40(d,J=8.7Hz,1H);7.41-7.20(m,5H);5.62(s,2H);4.78-4.61(m,1H);4.59(s,2H);4.55-4.31(m,2H);4.20-4.08(m,1H);
4.07-3.91(m,2H);3.90-3.70(m,2H);2.91-2.76(m,2H)。MS(ESI,m/z):对于C30H26N7O7F,616.20[M+H+];tR=1.19min(MS1)。
实例14:1-环丙基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例2类似,自中间体10.1(66mg)及6-[(5R)-5-[(3-氮杂环丁基氨基)甲基]-2-氧代-3-噁唑烷基]-2H-1,4-苯并恶嗪-3(4H)-酮(根据WO2008/126034制备;89mg)开始,获得呈灰棕色固体的标题化合物。
1H NMR(DMSO-d6)δ:11.40(s,1H),11.15(s,1H);8.53(s,1H);8.21(d,J=8.9Hz,1H);7.62-7.55(m,1H);7.40(d,J=8.7Hz,1H);6.64(d,J=8.9Hz,1H);4.78-4.62(m,1H);4.59(s,2H);4.37-4.25(m,2H);4.20-4.07(m,1H);3.93-3.72(m,4H);3.71-3.58(m,1H);2.91-2.81(m,2H);1.21-1.08(m,2H);1.08-0.97(m,2H)。MS(ESI,m/z):对于C26H25N7O7F,548.19[M+H+];tR=0.93min(MS1)。
实例15:6-氟-1-(2-羟基-乙基)-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
15.1.(Z)-2-(2,6-二氯-5-氟烟碱酰基)-3-((2-羟基乙基)氨基)丙烯酸乙基酯:
用乙醇胺(0.18mL)处理2,6-二氯-α-(乙氧基亚甲基)-5-氟-β-氧代-3-吡啶丙酸乙基酯(1.00g;根据EP132845制备)的溶液。在数分钟后,反应混合物变黏稠且用Hept/醚(1:1;10mL)稀释。在rt下进一步搅拌1.5h后,在减压下蒸发溶剂且将粗制黄色油直接用于下一步骤中。
1H NMR(DMSO-d6)δ:8.22(s,1H);8.02(d,J=7.9Hz,1H);3.90(q,J=7.1Hz,2H);3.61-3.45(m,4H);3.34(t,J=5.7Hz,1H);0.94(t,J=7.1Hz,3H)。MS(ESI,m/z):
350.94[M+H+](MS3)。
15.2.7-氯-6-氟-1-(2-羟基乙基)-4-氧代-1,4-二氢-1,8-萘啶-3-甲酸乙基酯:
在0℃下用LiHMDS(3.11ml)处理中间体15.1(1.04g)存于THF(15mL)中的溶液。将反应混合物在rt下进一步搅拌1h,过滤且用THF洗涤固体。藉由CC(DCM/MeOH9:1至4:1)纯化所得固体,从而获得黄色固体。
1H NMR(DMSO-d6)δ:8.73(s,1H);8.45(d,J=7.9Hz,1H);4.98-4.90(m,1H);4.44(t,J=5.1Hz,2H);4.23(q,J=7.1Hz,2H);3.78-3.67(m,2H);1.27(t,J=7.1Hz,3H)。MS(ESI,m/z):314.94[M+H+](MS3)。
15.3.7-氯-6-氟-1-(2-羟基-乙基)-4-氧代-1,4-二氢-[1,8]萘啶-3-甲酸:
将中间体15.2(330mg)存于6M HCl(40ml)中的悬浮液在100℃下搅拌1h。使反应混合物达到rt且藉由过滤收集所得固体,从而获得灰棕色固体。
1H NMR(DMSO-d6)δ:11.40(s,1H);9.05(s,1H);8.70(d,J=7.7Hz,1H);4.66-4.55(m,2H);3.76(t,J=5.2Hz,2H)。MS(ESI,m/z):286.91[M+H+](MS3)。
15.4.6-氟-1-(2-羟基-乙基)-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例2类似,自中间体15.3(72mg)及6-[(5R)-5-[(3-氮杂环丁基氨基)甲基]-2-氧代-3-噁唑烷基]-2H-1,4-苯并恶嗪-3(4H)-酮(根据WO2008/126034制备;89mg)开始,获得呈灰棕色固体的标题化合物。
1H NMR(DMSO-d6)δ:11.40(s,1H),11.15(s,1H);8.72(s,1H);7.96(d,J=11.6Hz,1H);7.63-7.53(m,1H);7.40(d,J=8.7Hz,1H);4.97-4.83(m,1H);4.78-4.61(m,1H);4.59(s,2H);4.54-4.29(m,4H);4.20-3.90(m,3H);3.89-3.65(m,4H);2.93-2.73(m,2H)。MS(ESI,m/z):对于C25H24N7O8F,570.18[M+H+];tR=0.87min(MS1)。
实例16:1-环丙基-6-氟-4-氧代-7-{4-[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸:
以与实例4类似的方式获得呈灰棕色固体的标题化合物,但在第一步骤中使用6-((R)-5-碘甲基-2-氧代噁唑烷-3-基)-4H-苯并[1,4]噻嗪-3-酮(根据WO2008/126034制备)。与实例4相比,对于中间体及最终化合物,制备产率在相同范围内且收集到相同光谱数据(MS、NMR)。
实例17:1-环丙基-6-氟-4-氧代-7-(4-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-哌啶-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
17.1.(4-((R)-3-苄氧基羰基氨基-2-羟基-丙基氨基)-哌啶-1-甲酸叔丁基酯:
用MgSO4(12.3g)处理[(2S)-环氧乙烷基甲基]-氨基甲酸苄基酯(15.6g;根据WO2004/002973制备)及4-(N-Boc-氨基)哌啶(15.1g)存于MeOH(100mL)中的溶液,且将白色悬浮液在rt下搅拌6h。蒸发混合物,悬浮于DCM中且在水(1l)与DCM(1l)之间分配。分离各层且用DCM再次萃取水性层。蒸发经合并有机层且藉由CC(EE至EE/MeOH9:1)纯化,从而获得黄色油。
MS(ESI,m/z):对于C21H33N3O5,408.12[M+H+];tR=0.66min(MS2)。
17.2.4-[((R)-2-氧代-噁唑烷-5-基甲基)-氨基]-哌啶-1-甲酸叔丁基酯:
用K2CO3(1.24g)处理中间体17.1(3.2g)存于MeOH(36ml)中的溶液且在60℃下搅拌3.5h。在真空中浓缩反应混合物且在EA/水中吸收残余物。用EA将水性层萃取2×。用盐水洗涤经合并有机层,经MgSO4干燥,过滤,蒸发且藉由CC(EA/MeOH9:1)纯化,从而获得黄色油。
MS(ESI,m/z):对于C14H25N3O4,300.06[M+H+];tR=0.49min(MS2)。
17.3.4-{[(R)-3-(5-乙氧基羰基甲氧基-6-硝基-吡啶-2-基)-2-氧代-噁唑烷-5-基甲基]-氨基}-哌啶-1-甲酸叔丁基酯:
向50ml烧瓶中装填(6-溴-2-硝基吡啶-3-基氧基)乙酸乙基酯(1.1g;如WO2007/118130中所述来制备)、中间体17.2(1.2g)且稀释于二恶烷(18ml)中。添加Pd(OAc)2(41.2mg)、DPEphos(198mg)及K2CO3粉(621mg)且用氩使悬浮液脱气。在密封烧瓶中将混合物在85℃下加热2h。使反应混合物冷却至rt且在EA与水之间分配。用盐水洗涤有机层,经MgSO4干燥,在减压下浓缩且藉由CC(EA至EA/MeOH9:1)纯化,从而获得灰白色发泡体。
MS(ESI,m/z):对于C23H33N5O9,524.14[M+H+];tR=0.72min(MS2)。
17.4.4-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-哌啶-1-甲酸叔丁基酯:
将铁粉(720mg)添加至氯化铵(1.15g)存于H2O/MeOH(1:1;18ml)中的溶液中。将悬浮液加热至40℃且用中间体17.3(1.5g)存于MeOH(28.7ml)中的溶液逐滴处理。将反应物在70℃下进一步搅拌5h。经硅藻土垫过滤反应混合物且用MeOH洗涤。用AcOH(9ml)酸化滤液且将黄色溶液在85℃下搅拌过夜。在减压下浓缩溶剂且将悬浮液与H2O一起研磨,冷却至0℃并过滤。然后用水及醚洗涤滤饼,从而获得灰白色固体。
MS(ESI,m/z):对于C21H29N5O6,448.04[M+H+];tR=0.61min(MS2)。
17.5.6-[(R)-2-氧代-5-(哌啶-4-基氨基甲基)-噁唑烷-3-基]-4H-吡啶并[3,2-b][1,4]噁嗪-3-酮盐酸盐:
将中间体17.4(900mg)存于二恶烷/MeOH(1:1;20ml)中的悬浮液在rt下用存于二恶烷(5.2ml)中的4M HCl处理且进一步搅拌6h。用醚稀释反应混合物且藉由过滤收集灰棕色晶体,用醚及MeOH洗涤,从而获得灰白色晶体。
MS(ESI,m/z):对于C15H22N5O4,348.07[M+H+];tR=0.38min(MS2)。
17.6.1-环丙基-6-氟-4-氧代-7-(4-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-哌啶-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例2类似,自中间体17.5(166mg)及7-氯-1-环丙基-6-氟-4-氧代-1,4-二氢-[1,8]萘啶-3-甲酸(市售;100mg)开始,获得呈灰白色固体的标题化合物。
1H NMR(DMSO-d6)δ:11.17(s,1H),8.59(s,1H),8.04(d,J=13.6Hz,1H),7.58(d,J=8.7Hz,1H),7.40(d,J=8.7Hz,1H),4.27(br.,1H),4.59(s,2H),4.42(m,2H),4.14(m,1H),3.85(m,1H),3.68(m,1H),3.28(m,2H),2.93(m,3H),2.00(m,3H),1.40(m,2H),1.12(m,4H)。MS(ESI,m/z):对于C28H28N7O7F,594.09[M+H+];tR=0.64min(MS2)。
实例18:1-环丙基-6-氟-4-氧代-7-{4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸:
18.1.4-((S)-3-苄氧基羰基氨基-2-羟基-丙基)-哌嗪-1-甲酸叔丁基酯:
化合物是以与实例17中的步骤17.1类似的方式自1-Boc-哌嗪(20.41g)及[(2S)-环氧乙烷基甲基]-氨基甲酸苄基酯(22.75g)开始来制备。获得淡黄色油(16.0g;37%产率)。
MS(ESI,m/z):对于C20H31N3O5,394.12[M+H+];tR=0.67min(MS2)。
18.2.4-((S)-2-氧代-噁唑烷-5-基甲基)-哌嗪-1-甲酸叔丁基酯:
化合物是以与实例17的步骤17.2类似的方式自中间体18.1(16.0g)开始来制备。获得无色固体(5.11g;44%产率)。
MS(ESI,m/z):对于C13H23N3O4,259.22[M-CO];tR=0.68min(MS2)。
18.3.4-[(R)-3-(5-乙氧基羰基甲氧基-6-硝基-吡啶-2-基)-2-氧代-噁唑烷-5-基甲基]-哌嗪-1-甲酸叔丁基酯:
化合物是以与实例17的步骤17.3类似的方式自中间体18.2(6.44g)及(6-溴-2-硝基吡啶-3-基氧基)乙酸乙基酯(6.22g;如WO2007/118130中所述来制备)开始来制备。获得灰棕色发泡体(9.71g;93.5%产率)。
MS(ESI,m/z):对于C22H31N5O9,510.15[M+H+];tR=0.70min(MS2)。
18.4.4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-甲酸叔丁基酯:
化合物是以与实例17的步骤17.4类似的方式自中间体18.3(9.71g)开始来制备。获得灰棕色固体(6.27g;75.9%产率)。
MS(ESI,m/z):对于C20H27N5O6。434.03[M+H+];tR=0.59min(MS2)。
18.5.6-((R)-2-氧代-5-哌嗪-1-基甲基-噁唑烷-3-基)-4H-吡啶并[3,2-b][1,4]噁嗪-3-酮:
化合物是以与实例17的步骤17.5类似的方式自中间体18.4(579mg)开始来制备。获得黄色固体(130mg,29%产率)。
MS(ESI,m/z):对于C15H19N5O4,334.04[M+H+];tR=0.45min(MS2)。
18.6.1-环丙基-6-氟-4-氧代-7-{4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例2类似,自中间体18.5(117mg)及7-氯-1-环丙基-6-氟-4-氧代-1,4-二氢-[1,8]萘啶-3-甲酸(市售;90mg)开始,获得呈灰白色固体的标题化合物(80mg;43.3%产率)。
1H NMR(DMSO-d6)δ:11.17(s,1H),8.59(s,1H),8.06(d,J=13.8Hz,1H),7.59(d,J=8.8Hz,1H),7.41(d,J=8.8Hz,1H),4.87(m,1H),4.59(s,2H),4.20(m,1H),3.82(m,5H),3.69(m,1H),2.70(m,6H),1.13(m,4H)。MS(ESI,m/z):对于C27H26N7O7F,580.07[M+H+];tR=0.62min(MS2)。
实例19:1-环丙基-6-氟-4-氧代-7-{4-[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸:
19.1.6-((S)-2-氧代-5-哌嗪-1-基甲基-噁唑烷-3-基)-4H-吡啶并[3,2-b][1,4]噁嗪-3-酮:
化合物是以与实例18的步骤18.1至18.5类似的方式自[(2R)-环氧乙烷基甲基]-氨基甲酸苄基酯开始来制备。5个步骤的各自产率如下:59%(淡黄色油;环氧开环)、28%(无色固体;噁唑烷酮形成)、23%(褐色油;芳基化)、59%(灰棕色固体;噁嗪酮形成)及99%(灰棕色固体;HCl处理)。
MS(ESI,m/z):对于C15H19N5O4,334.04[M+H+];tR=0.45min(MS2)。
19.2.1-环丙基-6-氟-4-氧代-7-{4-[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例18的步骤18.6类似,自中间体19.1(101mg)及7-氯-1-环丙基-6-氟-4-氧代-1,4-二氢-[1,8]萘啶-3-甲酸(市售;77mg)开始,获得呈灰棕色固体的标题化合物(130mg;82%产率)。
1H NMR(DMSO-d6)δ:11.17(s,1H);8.59(s,1H);8.06(d,J=13.8Hz,1H);7.59(d,J=8.8Hz,1H);7.41(d,J=8.8Hz,1H);4.87(m,1H);4.59(s,2H);4.20(m,1H);3.82(m,5H);3.69(m,1H);2.70(m,6H);1.13(m,4H)。MS(ESI,m/z):对于C27H26N7O7F,580.07[M+H+];tR=0.62min(MS2)。
实例20:1-环丙基-6-氟-4-氧代-7-(4-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-哌啶-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
20.1.6-[(S)-2-氧代-5-(哌啶-4-基氨基甲基)-噁唑烷-3-基]-4H-吡啶并[3,2-b][1,4]噁嗪-3-酮二盐酸盐:
化合物是以与实例17的步骤17.1至17.5类似的方式自[(2S)-环氧乙烷基甲基]-氨基甲酸苄基酯开始来制备。5个步骤的各自产率如下:71%(无色油;环氧开环)、96%(淡黄色油;氨基甲酸酯形成)、93%(黄色发泡体;芳基化)、81%(灰棕色固体;环化)及81%(黄色发泡体;HCl处理)。
MS(ESI,m/z):对于C15H19N5O4,348.27[M+H+];tR=0.61min(MS2)。
20.2.1-环丙基-6-氟-4-氧代-7-(4-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-哌啶-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例17的步骤17.6类似,自中间体20.1(1.76g)及7-氯-1-环丙基-6-氟-4-氧代-1,4-二氢-[1,8]萘啶-3-甲酸(市售;1.13g)开始,获得呈灰棕色固体的标题化合物(1.05g;44%产率)。
1H NMR(DMSO-d6)δ:11.17(s,1H),8.59(s,1H),8.04(d,J=13.6Hz,1H),7.58(d,J=8.7Hz,1H),7.40(d,J=8.7Hz,1H),4.27(br.,1H),4.59(s,2H),4.42(m,2H),4.14(m,1H),3.85(m,1H),3.68(m,1H),3.28(m,2H),2.93(m,3H),2.00(m,3H),1.40(m,2H),1.12(m,4H)。MS(ESI,m/z):对于C28H28N7O7F,594.09[M+H+];tR=0.63min(MS2)。
实例21:1-环丙基-6-氟-4-氧代-7-((RS)-3-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-吡咯烷-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
21.1.(RS)-3-((S)-3-苄氧基羰基氨基-2-羟基-丙基氨基)-吡咯烷-1-甲酸叔丁基酯:
标题化合物是以与实例17的步骤17.1类似的方式自[(2R)-环氧乙烷基甲基]-氨基甲酸苄基酯(8.23g;根据WO2004/002973制备)及存于MeCN(300mL)中的外消旋-3-氨基-1-Boc-吡咯烷(7.40g;市售)开始来制备,从而获得无色油(10.7g;68%产率)。
MS(ESI,m/z):对于C20H31N3O5,394.19[M+H+];tR=0.64min(MS2)。
21.2.(RS)-3-[((S)-2-氧代-噁唑烷-5-基甲基)-氨基]-吡咯烷-1-甲酸叔丁基酯:
将中间体21.1(10.7g)存于THF(175mL)中的溶液在0℃下用KOtBu(3.05g)处理且在rt下进一步搅拌1h。在真空中浓缩反应混合物且在EA/水中吸收残余物。用EA将水性层萃取两次。用盐水洗涤经合并有机层,经MgSO4干燥,过滤,蒸发且藉由CC(EA/MeOH19:1至9:1+1%NH4OH)纯化,从而获得无色玻璃(6.90g;89%产率)。
MS(ESI,m/z):对于C13H23N3O4,331.20[M+H+];tR=0.50min(MS2)。
21.3.(RS)-3-{[(S)-3-(5-乙氧基羰基甲氧基-6-硝基-吡啶-2-基)-2-氧代-噁唑烷-5-基甲基]-氨基}-吡咯烷-1-甲酸叔丁基酯:
标题化合物是以与实例17的步骤17.1类似的方式自(6-溴-2-硝基吡啶-3-基氧基)乙酸乙基酯(6.84g;如WO2007/118130中所述来制备)及中间体21.2(6.4g)开始来制备,从而获得淡黄色发泡体(11.34g;99%产率)。
MS(ESI,m/z):对于C22H31N5O9,454.08[M+H+];tR=0.70min(MS2)。
21.4.(RS)-3-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-吡咯烷-1-甲酸叔丁基酯:
与实例17的步骤17.4类似,标题化合物是自中间体21.3(11.34g)制备,从而获得淡黄色发泡体(7.13g;74%产率)。
MS(ESI,m/z):对于C20H27N5O6,434.16[M+H+];tR=0.57min(MS2)。
21.5.6-((S)-2-氧代-5-(((RS)-吡咯烷-3-基氨基)甲基)噁唑烷-3-基)-2H-吡啶并[3,2-b][1,4]噁嗪-3(4H)-酮二盐酸盐:
与实例17的步骤17.5类似,标题化合物是自中间体21.4(7.0g)制备,从而获得淡黄色固体(6.7g,100%产率)。
MS(ESI,m/z):对于C15H21N5O4Cl2,334.22[M+H+];tR=0.40min(MS2)。
21.6.1-环丙基-6-氟-4-氧代-7-((RS)-3-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-吡咯烷-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例2类似,自中间体21.5(406mg)及7-氯-1-环丙基-6-氟-4-氧代-1,4-二氢-[1,8]萘啶-3-甲酸(市售;283mg)开始,获得呈灰棕色固体的标题化合物(非镜像异构物的混合物;398mg;68%产率)。
MS(ESI,m/z):对于C27H26N7O7F,580.07[M+H+];tR=0.62min(MS2)。
实例22:1-环丙基-6-氟-4-氧代-7-[(S)-3-({[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-甲基)-吡咯烷-1-基]-1,4-二氢-[1,8]萘啶-3-甲酸:
22.1.(S)-3-[((S)-3-苄氧基羰基氨基-2-羟基-丙基氨基)-甲基]-吡咯烷-1-甲酸叔丁基酯:
标题化合物是以与实例17的步骤17.1类似的方式自[(2R)-环氧乙烷基甲基]-氨基甲酸苄基酯(5.17g;根据WO2004/002973制备)及存于MeCN(120mL)中的(S)-3-氨基甲基吡咯烷-1-甲酸叔丁基酯(5.00g;市售)开始来制备,从而获得无色油(6.4g;63%产率)。
MS(ESI,m/z):对于C21H33N3O5,408.21[M+H+];tR=0.66min(MS2)。
22.2.(S)-3-{[((S)-2-氧代-噁唑烷-5-基甲基)-氨基]-甲基}-吡咯烷-1-甲酸叔丁基酯:
将中间体22.1(6.4g)存于THF(100mL)中的溶液在0℃下用KOtBu(1.76g)处理且在rt下进一步搅拌1h。在真空中浓缩反应混合物且在EA/水中吸收残余物。用EA将水性层萃取两次。用盐水洗涤经合并有机层,经MgSO4干燥,过滤,蒸发且藉由CC(EA/MeOH19:1至9:1+1%NH4OH)纯化,从而获得无色油(4.34g;92%产率)。
MS(ESI,m/z):对于C14H25N3O4,300.17[M+H+];tR=0.50min(MS2)。
22.3.(S)-3-({[(S)-3-(5-乙氧基羰基甲氧基-6-硝基-吡啶-2-基)-2-氧代-噁唑烷-5-基甲基]-氨基}-甲基)-吡咯烷-1-甲酸叔丁基酯:
标题化合物是以与实例17的步骤17.3类似的方式自(6-溴-2-硝基吡啶-3-基氧基)乙酸乙基酯(4.01g;根据WO2007/118130来制备)及中间体22.2(3.94g)开始来制备,从而获得淡黄色发泡体(7.01g;100%产率)。
MS(ESI,m/z):对于C23H33N5O9,524.22[M+H+];tR=0.71min(MS2)。
22.4.(S)-3-({[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-甲基)-吡咯烷-1-甲酸叔丁基酯:
与实例17的步骤17.4类似,标题化合物是自中间体22.3(7.01g)制备,从而获得淡黄色发泡体(4.1g;68%产率)。
MS(ESI,m/z):对于C21H29N5O6,448.18[M+H+];tR=0.61min(MS2)。
22.5.6-((S)-2-氧代-5-{[((R)-1-吡咯烷-3-基甲基)-氨基]-甲基}-噁唑烷-3-基)-4H-吡啶并[3,2-b][1,4]噁嗪-3-酮二盐酸盐:
与实例17的步骤17.5类似,标题化合物是自中间体22.4(4.0g)制备,从而获得无色固体(3.87g;100%产率)。
MS(ESI,m/z):对于C16H23N5O4Cl2,348.26[M+H+];tR=0.40min(MS2)。
22.6.1-环丙基-6-氟-4-氧代-7-[(S)-3-({[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-甲基)-吡咯烷-1-基]-1,4-二氢-[1,8]萘啶-3-甲酸:
与实例2类似,自中间体22.5(420mg)及7-氯-1-环丙基-6-氟-4-氧代-1,4-二氢-[1,8]萘啶-3-甲酸(市售;283mg)开始,获得呈灰棕色固体的标题化合物(440mg;74%产率)。
1H NMR(DMSO-d6)δ:11.15(s,1H),8.52(s,1H),7.91(d,J=12.7Hz,1H),7.57(d,J=8.7Hz,1H),7.39(d,J=8.7Hz,1H),4.77(br.,1H),4.59(s,2H),4.14(m,1H),3.77(m,6H),2.95(m,2H),2.94(m,2H),2.73(m,2H),2.05(s,1H),1.85(m,1H),1.09(m,4H)。MS(ESI,m/z):对于C28H28N7O7F,594.06[M+H+];tR=0.64min(MS2)。
实例23:9-环丙基-6-氟-3-羟基-7-(4-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-哌啶-1-基)-9H-1-硫杂-2,8,9-三氮杂-环戊[b]萘-4-酮:
与实例2类似,自中间体20.1(151mg)及7-氯-9-环丙基-6-氟-异噻唑并[5,4-b][1,8]萘啶-3,4(2H,9H)-二酮(93mg;根据Chu等人,J.Heterocycl.Chem.(1990),27(5),1191-1195来制备)开始,获得呈灰棕色固体的标题化合物(110mg;59%产率)。
1H NMR(DMSO-d6)δ:11.16(s,1H),7.89(d,J=12.7Hz,1H),7.58(d,J=8.7Hz,1H),7.40(d,J=8.7Hz,1H),4.68(m,1H),4.58(s,2H),4.33(m,2H),4.11(m,1H),3.86(m,1H),3.27(m,5H),2.88(d,J=5.2Hz,2H),2.76(m,1H),1.95(m,2H),1.36(m,2H),1.17(m,4H)。MS(ESI,m/z):对于C28H27N8O6FS,622.98[M+H+];tR=0.61min(MS2)。
实例24:9-环丙基-6-氟-3-羟基-7-(3-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-9H-1-硫杂-2,8,9-三氮杂-环戊[b]萘-4-酮:
与实例2类似,自6-[(5S)-5-[(3-氮杂环丁基氨基)甲基]-2-氧代-3-噁唑烷基]-2H-1,4-苯并噁嗪-3(4H)-酮(以与WO2008/126034类似的方式制备;128mg)及7-氯-9-环丙基-6-氟-异噻唑并[5,4-b][1,8]萘啶-3,4(2H,9H)-二酮(93mg;根据Chu等人,J.Heterocycl.Chem.(1990),27(5),1191-1195来制备)开始,获得呈灰棕色固体的标题化合物(100mg;56%产率)。
1H NMR(DMSO-d6)δ:7.83(d,J=11.7Hz,1H),7.59(d,J=8.6Hz,1H),7.40(d,J=8.6Hz,1H),4.71(m,1H),4.59(s,2H),4.41(m,2H),4.14(m,1H),4.01(m,2H),3.84(m,2H),3.32(m,8H),2.87(m,2H),1.16(m,4H)。MS(ESI,m/z):对于C26H23N8O6FS,594.88[M+H+];tR=0.58min(MS2)。
实例25:9-环丙基-6-氟-3-羟基-7-{4-[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-9H-1-硫杂-2,8,9-三氮杂-环戊[b]萘-4-酮:
与实例2类似,自6-((S)-2-氧代-5-哌嗪-1-基甲基-噁唑烷-3-基)-4H-吡啶并[3,2-b][1,4]噁嗪-3-酮(中间体19.1;133mg)及7-氯-9-环丙基-6-氟-异噻唑并[5,4-b][1,8]萘啶-3,4(2H,9H)-二酮(93mg;根据Chu等人,J.Heterocycl.Chem.(1990),27(5),1191-1195来制备)开始,获得呈灰棕色固体的标题化合物(90mg;49%产率)。
1H NMR(DMSO-d6)δ:11.23(s,1H),8.03(d,J=13.2Hz,1H),7.57(m,1H),7.43(m,1H),4.61(s,2H),4.55(m,2H),4.29(m,1H),3.54(m,10H),1.21(m,4H)。MS(ESI,m/z):对于C27H25N8O6FS,608.97[M+H+];tR=0.59min(MS2)。
本发明化合物的药理性质
活体外分析
细菌生长最小抑制浓度:
实验方法:
最小抑制浓度(MIC;mg/l)是在阳离子调节的Mueller–Hinton Broth中藉由微量稀释方法遵循“Methods for Dilution Antimicrobial Susceptibility Tests forBacteria that Grow Aerobically”,已批准标准,第7版,Clinical and LaboratoryStandards Institute(CLSI)Document M7-A7,Wayne,PA,USA,2006中给出的说明来确定。
所有实例化合物皆是针对若干种革兰氏阳性及革兰氏阴性细菌来测试。典型抗细菌测试结果展示于下表中(MIC,mg/l)。金黄色葡萄球菌A798及鲍氏不动杆菌T6474是多抗性菌株,尤其是喹诺酮抗性菌株。
Claims (14)
1.一种式I化合物,
其中
R1a代表H或羧基且R1b代表H,或R1a及R1b一起代表基团*-C(O)-NH-S-#或基团*-C(OH)=N-S-#,其中“*”代表R1a的连接点且“#”代表R1b的连接点;
R2代表H、C1-C3烷基、羟基-C1-C3烷基、苄基或C3-C5环烷基;
R3代表H或卤素;
U代表N或CR4;其中R4是H或C1-C3烷氧基;
A代表CH,B代表NH,m代表1或2且n代表1或2;或A代表N,
B不存在,m代表2且n代表2;
Y代表CH或N;且
Q代表O或S;
或该化合物的盐。
2.如权利要求1所述的式I化合物,其中:
R1a代表H或羧基;
R1b代表H;
R2代表H、C1-C3烷基、羟基-C1-C3烷基、苄基或C3-C5环烷基;
R3代表H或卤素;
U代表N或CR4;其中R4是H或C1-C3烷氧基;
A代表CH,B代表NH且m代表1且n代表1或m代表2且n代表2;
或A代表N,B不存在,m代表2且n代表2;
Y代表CH或N;且
Q代表O或S;
或该化合物的盐。
3.如权利要求1或2所述的式I化合物,其中R1a代表羧基;
或该化合物的盐。
4.如权利要求1或2所述的式I化合物,其中R2代表C1-C3烷基或C3-C5环烷基;
或该化合物的盐。
5.如权利要求4所述的式I化合物,其中R2代表环丙基;
或该化合物的盐。
6.如权利要求1或2所述的式I化合物,其中R3代表卤素;
或该化合物的盐。
7.如权利要求1或2所述的式I化合物,其中U代表N;
或该化合物的盐。
8.如权利要求1或2所述的式I化合物,其中U代表CR4,其中R4是H
或C1-C3烷氧基;
或该化合物的盐。
9.如权利要求1或2所述的式I化合物,其中基团
选自以下基团:
其中星号表示将该基团与连接至噁唑烷酮部分的CH2基团连接的键;
或该化合物的盐。
10.如权利要求1或2所述的式I化合物,其中Y代表CH或N且Q代表O,或Y代表CH且Q代表S;
或该化合物的盐。
11.如权利要求1所述的式I化合物,其中:
R1a代表羧基且R1b代表H,或R1a及R1b一起代表基团*-C(O)-NH-S-#或基团*-C(OH)=N-S-#,其中“*”代表R1a的连接点且“#”代表R1b的连接点;
R2代表环丙基;
R3代表氟;
U代表N;
A代表CH,B代表NH,m代表1或2且n代表1或2;
Y代表N;且
Q代表O;
或该化合物的盐。
12.如权利要求1所述的式I化合物,其选自以下化合物:
1-环丙基-6-氟-4-氧代-7-{4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-喹啉-3-甲酸;
1-环丙基-6-氟-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
1-环丙基-6-氟-4-氧代-7-{4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-喹啉-3-甲酸;
1-环丙基-6-氟-4-氧代-7-{4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸;
6-((R)-5-{[1-(8-环丙基-3-氟-5-氧代-5,8-二氢-[1,8]萘啶-2-基)-氮杂环丁-3-基氨基]-甲基}-2-氧代-噁唑烷-3-基)-4H-苯并[1,4]噻嗪-3-酮;
1-环丙基-6-氟-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
1-环丙基-8-甲氧基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-喹啉-3-甲酸;
1-环丙基-8-甲氧基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-喹啉-3-甲酸;
1-乙基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
1-环丙基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
1-甲基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
6-氟-1-甲基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
1-苄基-6-氟-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
1-环丙基-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
6-氟-1-(2-羟基-乙基)-4-氧代-7-(3-{[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
1-环丙基-6-氟-4-氧代-7-{4-[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-苯并[1,4]噻嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸;
1-环丙基-6-氟-4-氧代-7-(4-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-哌啶-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
1-环丙基-6-氟-4-氧代-7-{4-[(R)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸;
1-环丙基-6-氟-4-氧代-7-{4-[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-1,4-二氢-[1,8]萘啶-3-甲酸;
1-环丙基-6-氟-4-氧代-7-(4-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-哌啶-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
1-环丙基-6-氟-4-氧代-7-(3-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-吡咯烷-1-基)-1,4-二氢-[1,8]萘啶-3-甲酸;
1-环丙基-6-氟-4-氧代-7-[(S)-3-({[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-甲基)-吡咯烷-1-基]-1,4-二氢-[1,8]萘啶-3-甲酸;
9-环丙基-6-氟-3-羟基-7-(4-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-哌啶-1-基)-9H-1-硫杂-2,8,9-三氮杂-环戊[b]萘-4-酮;
9-环丙基-6-氟-3-羟基-7-(3-{[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-氨基}-氮杂环丁-1-基)-9H-1-硫杂-2,8,9-三氮杂-环戊[b]萘-4-酮;及
9-环丙基-6-氟-3-羟基-7-{4-[(S)-2-氧代-3-(3-氧代-3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪-6-基)-噁唑烷-5-基甲基]-哌嗪-1-基}-9H-1-硫杂-2,8,9-三氮杂-环戊[b]萘-4-酮;
或该化合物的盐。
13.一种医药组合物,其含有作为有效成份的如权利要求1至12中任一项所述的式I化合物或其医药上可接受的盐及至少一种医药上可接受的赋形剂。
14.如权利要求1至12中任一项所述的式I化合物或其医药上可接受的盐在制备用于预防或治疗细菌感染的药物中的用途。
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PCT/IB2012/056236 WO2013068948A1 (en) | 2011-11-08 | 2012-11-07 | 2-oxo-oxazolidin-3,5-diyl antibiotic derivatives |
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