CN112513049B - 杂环化合物及它们在预防或治疗细菌感染中的用途 - Google Patents
杂环化合物及它们在预防或治疗细菌感染中的用途 Download PDFInfo
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- CN112513049B CN112513049B CN201980051369.6A CN201980051369A CN112513049B CN 112513049 B CN112513049 B CN 112513049B CN 201980051369 A CN201980051369 A CN 201980051369A CN 112513049 B CN112513049 B CN 112513049B
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- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
本发明涉及式(I)的化合物,及它们用于治疗或预防细菌感染的用途,或作为抗菌剂和/或β‑内酰胺酶抑制剂的用途。
Description
技术领域
本发明涉及杂环化合物、它们的制备方法、包含这些化合物的药物组合物,以及任选地与其他抗菌剂和/或β-内酰胺化合物组合用于预防或治疗细菌感染的用途。本发明还涉及这些化合物作为β-内酰胺酶抑制剂和/或作为抗菌剂的用途。
背景技术
据记载,抗菌耐药性的持续演变会导致已知的抗菌化合物对细菌菌株无效。
因此,需要提供能够克服细菌抗生素耐性的有效化合物和组合物。
发明内容
本发明的目的在于提供能够用作抗菌剂和/或β-内酰胺酶抑制剂的杂环化合物。
本发明的目的还在于提供能够用于预防或治疗细菌感染的杂环化合物。
本发明的另一个目的在于提供能够克服细菌抗生素耐性的杂环化合物。
本发明的目的还在于提供用于预防或治疗细菌感染并且能够克服细菌抗生素耐性的包含这类杂环化合物,任选地与一种或多种其它抗菌剂组合的药物组合物。
其他目的将会在本发明的整体描述中显现出来。
因此,本发明提供了式(I)的化合物以及它们的外消旋体、对映异构体、非对映异构体、几何异构体或药学上可接受的盐,
其中,
R1选自由以下各项组成的组中:H、(CH2)mCN、(CH2)mC(=O)NR2R3、(CH2)mC(=O)NR4NR2R3、(CH2)mC(=O)NR2OR3、(CH2)nOR2、(CH2)nNR2R3、(CH2)nNR4C(=NR4)N(R4)2、(CH2)mC(=NOZ4)NZ1Z2或(CH2)n-包含1个或4个独立地选自由N、O或S组成的组中的杂原子的(5至6元)杂芳基;
m是介于0至6之间的整数;
n是介于1至6之间的整数;
R2和R3相同或不同,选自由H、直链或支链的(C1-C6)烷基、(C3-C11)环烷基、(C6-C10)芳基、包含1个或2个独立地选自由N、O或S组成的组中的杂原子的(4至6元)杂环基、包含1至4个独立地选自由N、O或S组成的组中的杂原子的(5至10元)杂芳基、C(=O)(C1-C6)烷基、C(=O)包含1个或2个独立地选自由N、O或S组成的组中的杂原子的(4至6元)杂环基组成的组中,或与该R2和R3所连接的氮原子一起形成包含1个或2个独立地选自由N、O或S组成的组中的杂原子的(4至6元)杂环基;其中,所述烷基、环烷基、芳基、杂环基和杂芳基任选地被一个或多个R5取代;
R4各自相同或不同,独立地选自由H和任选地被一个或多个R5取代的直链或支链的(C1-C6)烷基组成的组中;
R5各自相同或不同,选自由OH、O(C1-C6)烷基、NH2、NH(C1-C6)烷基、N[(C1-C6)烷基]2、C(=O)NH2、C(=O)NH(C1-C6)烷基、C(=O)N[(C1-C6)烷基]2组成的组中;
Y1选自由SO3H、CHFC(=O)Y2和CF2C(=O)Y2、SO3(C1-C6)烷基-C(=O)O(C1-C6)烷基组成的组中;
Y2选自由OH、直链或支链的O(C1-C6)烷基、O(C3-C11)环烷基、O-包含1个或2个独立地选自由N、O和S组成的组中的杂原子的(4至6元)杂环基、NY3Y4组成的组中;其中,所述烷基、环烷基和杂环基任选地被一个或多个Y5取代;
Y3和Y4各自相同或不同,选自由直链或支链的(C1-C6)烷基,直链或支链的O(C1-C6)烷基,(C3-C11)环烷基,包含1个或2个独立地选自由N、O或S组成的组中的杂原子的(4至6元)杂环基组成的组中,或与该Y3和Y4所连接的氮原子一起形成包含1个或2个独立地选自由N、O或S组成的组中的杂原子的(4至6元)杂环基;其中,所述烷基、环烷基和杂环基任选地被一个或多个Y5取代;
Y5各自相同或不同,选自由以下各项组成的组中:直链或支链的(C1-C6)烷基、(C3-C6)环烷基、直链或支链的O(C1-C6)烷基、直链或支链的O(C1-C6)烷基-O(C1-C6)烷基、直链或支链的(C1-C6)烷基-O(C1-C6)烷基,和O(C3-C6)环烷基;
X1=X2选自由N=CX4、CX3=N、CX3=CX4、CX3=CA1和CA1=CX4组成的组中;
A1选自由以下各项组成的组中:H、卤素、直链或支链的(C1-C6)烷基、(CH2)m-C(=O)NA2A3、(CH2)n-NA2A3、(CH2)m-苯基、(CH2)m-(包含1至4个独立地选自由N、O、S组成的组中的杂原子的5至6元杂芳基),其中,所述烷基任选地被一个或多个OH、CN和/或卤素取代,并且所述苯基和杂芳基任选地被一个或多个卤素、直链或支链的(C1-C6)烷基、直链或支链的(C1-C6)烷氧基、CF3取代;
A2和A3各自相同或不同,选自由H、直链或支链的(C1-C6)烷基、直链或支链的O-(C1-C6)烷基组成的组中;
X3和X4各自相同或不同,选自由以下各项组成的组中:(CH2)m-C(=O)NX6X7、(CH2)m-C(=O)NX6OX7、(CH2)m-C(=O)NX6NX7X8、(CH2)m-C(=NOX6)X7、(CH2)m-C(=NX6)NHX7、(CH2)n-NX6X7、(CH2)n-NX6C(=O)X7、(CH2)n-NX6C(=O)NX7X8、(CH2)n-NX6S(=O)2NX7X8、(CH2)n-NX6S(=O)2X7、(CH2)n-NHC(=NX6)NHX7、(CH2)n-NHC(=NX6)X7、(CH2)n-OX5、(CH2)m-S(=O)2NX6X7、(CH2)m-(C3-C6)环烷基、(CH2)m-苯基、(CH2)m-(包含1至4个独立地选自由N、O、S组成的组中的杂原子的5至6元杂芳基)、(CH2)m-(包含1至2个独立地选自由N、O、S组成的组中的杂原子的4至6元杂环基),其中,所述环烷基任选地被卤素取代,并且所述苯基和杂芳基至少被一个或多个Z3取代,并且所述杂环基任选地被Z3取代;
X5各自相同或不同,选自由以下各项组成的组中:直链或支链的(C1-C6)烷基、直链或支链的(C2-C6)烷基-NZ1Z2、直链或支链的(C2-C6)烷基-NH-C(=NZ1)NHZ2、直链或支链的(C2-C6)烷基-NH-C(=NZ1)H、直链或支链的(C2-C6)烷基-NZ1C(=O)Z2、直链或支链的(C2-C6)烷基-OZ1、直链或支链的(C1-C6)烷基-C(=NZ1)NHZ2、直链或支链的(C1-C6)烷基-CONZ1Z2、直链或支链的(C1-C6)烷基-COOZ1、(CH2)m-芳基、(CH2)m-(包含1至2个独立地选自由N、O、S组成的组中的杂原子的4至6元杂环基)、(CH2)m-(包含1至4个独立地选自由N、O、S组成的组中的杂原子的5至6元杂芳基),其中,所述芳基、杂环基和杂芳基任选地被一个或多个卤素或Z5取代;
X6、X7和X8各自相同或不同,选自由H、直链或支链的(C1-C6)烷基、(C6-C10)芳基、(C7-C11)芳烷基、直链或支链的(C1-C6)烷基-Z3、(C6-C10)芳基-Z3、(C7-C11)芳烷基-Z3、(CH2)m-(包含1至4个独立地选自由N、O、S组成的组中的杂原子的5至6元杂芳基)、(CH2)m-(包含1至2个独立地选自由N、O、S组成的组中的杂原子的4至6元杂环基)组成的组中,或与该X6、X7和X8所连接的氮原子一起形成包含1至2个独立地选自由N、O,或S组成的组中的杂原子的4至6元杂环基,其中,所述杂芳基和杂环基任选地被Z3取代;
Z1和Z2各自相同或不同,选自由H、直链或支链的(C1-C6)烷基组成的组中;其中,所述烷基任选地被一个或多个卤素或Z5取代;
Z3各自相同或不同,选自由以下各项组成的组中:(CH2)m-(C6-C10)芳基-Z4、(CH2)m-(包含1至4个独立地选自由N、O、S组成的组中的杂原子的5至6元杂芳基)-Z4、(CH2)m-(包含1个或2个独立地选自由N、O,或S组成的组中的杂原子的4至6元杂环基)-Z4、(CH2)n-OZ1、OZ5、(CH2)m-NZ1Z2、(CH2)m-C(=O)NZ1Z2、(CH2)m-NZ1C(=O)Z2、(CH2)m-NHC(=NH)Z1、(CH2)m-NHC(=NH)NHZ1;
Z4各自相同或不同,选自由H、直链或支链的(C1-C6)烷基组成的组中,其中,所述烷基任选地被一个或多个卤素或Z5取代;
Z5各自相同或不同,选自由H、(CH2)p-OH、(CH2)p-NH2、(CH2)p-CONH2、(CH2)p-NHC(=NH)NH2组成的组中,
p是选自2、3、4、5或6中的整数;
杂环中存在的任何硫原子能够被氧化形成S=O基团或S(O)2基团;
杂环中存在的任何氮原子或其中的氮原子被三取代而形成叔氨基的基团中存在的任何氮原子能够进一步被甲基季铵化;
例外是,如果X3或X4中的一个表示(CH2)m-C(=O)NX6X7、(CH2)m-C(=O)NX6OX7,或(CH2)n-NX6X7,则X6或X7中的至少一个不同于H、(C1-C6)烷基、(C6-C10)芳基、(C7-C11)芳烷基或(C1-C6)烷基-吡啶基。
优选地,
R1选自由以下各项组成的组中:H、(CH2)mCN、(CH2)mC(=O)NR2R3、(CH2)mC(=O)NR4NR2R3、(CH2)mC(=O)NR2OR3、(CH2)nOR2、(CH2)nNR2R3、(CH2)nNR4C(=NR4)N(R4)2、(CH2)n-(包含1个或4个独立地选自由N、O或S组成的组中的杂原子的5至6元杂芳基),和/或
Y1选自由SO3H、CHFC(=O)Y2和CF2C(=O)Y2组成的组中。
本发明还涉及式(I*)的化合物:
其中,R1、X1、X2和Y1如式(I)的化合物所定义。
优选地,在式(I)的化合物中,本发明涉及式(IA)或式(IA*)的化合物:
其中,R1、X4和Y1如上述式(I)的化合物所定义。
优选地,在式(I)的化合物中,本发明涉及式(IB)或式(IB*)的化合物:
其中,R1、X3、A1和Y1如上述式(I)的化合物所定义。
优选地,在式(I)的化合物中,本发明涉及式(IC)或式(IC*)的化合物:
其中,R1、X4、A1和Y1如上述式(I)的化合物所定义。
优选地,在式(I)的化合物中,本发明涉及式(ID)或式(ID*)的化合物:
其中,R1、X4、X3和Y1如上述式(I)的化合物所定义。
优选地,在式(I)的化合物中,本发明涉及式(IE)或式(IE*)的化合物:
其中,R1、X3和Y1如上述式(I)的化合物所定义。
优选地,在本发明的式(I)、(I*)、(IA)、(IA*)、(IB)、(IB*)、(IC)、(IC*)、(ID)、(ID*)、(IE)、(IE*)的化合物中,
R1选自由以下各项组成的组中:H、CN、C(=O)NR2R3、C(=O)NHNHR2、C(=O)NHOR2、CH2OR2、CH2NHR2、CH2NR4C(=NR4)N(R4)2、C(=NOZ4)NZ1Z2、CH2-(包含1个或4个独立地选自由N、O或S组成的组中的杂原子的5至6元杂芳基);
R2和R3各自相同或不同,选自由以下各项组成的组中::H;直链或支链的(C1-C6)烷基;包含1个或2个独立地选自由N、O或S组成的组中的杂原子的(4至6元)杂环基;C(=O)(包含1个或2个独立地选自由N、O或S组成的组中的杂原子的4至6元杂环基);
R4各自相同或不同,独立地选自由H、直链或支链的(C1-C6)烷基组成的组中,其中,所述烷基任选地被一个或多个R5取代;
R5各自相同或不同,选自由以下各项组成的组中:OH、O(直链或支链的C1-C6)烷基、NH2、NH(直链或支链的C1-C6)烷基、N[(直链或支链的C1-C6)烷基]2、C(=O)NH2、C(=O)NH(直链或支链的C1-C6)烷基、C(=O)N[直链或支链的(C1-C6)烷基]2;
Y2选自由以下各项组成的组中:OH、直链或支链的O(C1-C6)烷基、O-包含1个或2个独立地选自由N、O和S组成的组中的杂原子的(4-6元杂环基);其中,所述烷基、杂环基任选地被一个或多个Y5取代;
Y5各自相同或不同,选自由以下各项组成的组中:直链或支链的(C1-C6)烷基、(C3-C6)环烷基、直链或支链的O(C1-C6)烷基、直链或支链的O(C1-C6)烷基-O(C1-C6)烷基、直链或支链的(C1-C6)烷基-O(C1-C6)烷基,和O(C3-C6)环烷基;
X1=X2选自由N=CX4、CX3=CX4、CX3=CA1和CA1=CX4组成的组中。
优选地,R1选自由以下各项组成的组中:H、CN、C(=O)NR2R3、C(=O)NHNHR2、C(=O)NHOR2、CH2OR2、CH2NHR2、CH2NR4C(=NR4)N(R4)2、CH2-包含1个或4个独立地选自由N、O或S组成的组中的杂原子的(5至6元杂芳基)。
在一个优选的实施方式中,本发明涉及式(IA)或式(IA*)的化合物:
其中,
R1为H;
X4为(CH2)m-C(O)-NH-(C1-C3)烷基-NH2、(CH2)n-NH-C(=NH)-NH2或(CH2)m-C(O)-NH-(C1-C3)烷基-NH-C(=NH)-NH2;
Y1如上述式(I)的化合物所定义。
优选地,在该实施方式中,Y1为SO3H、CF2COOH。
在一个实施方式中,Y2表示O-CY6Y7Y8,其中,Y6、Y7和Y8相同或不同,表示(C1-C3)-烷基、(C3-C6)-环烷基、包含1至2个选自N-Y10、O或S中的杂原子的(C4-C8)-杂环烷基、CH2-O-(C1-C3)-烷基、或CH2-O-(CH2)2-O-(C1-C3)-烷基,其中,所述烷基、环烷基和杂环烷基任选地被一个或多个Y9取代;或者
Y6和Y7可以共同与它们所连接的碳原子一起形成(C3-C6)-环烷基或包含1至2个选自N-Y10、O或S中的杂原子的(C4-C8)-杂环烷基,其中,所述环烷基和杂环烷基任选地被一个或多个Y9取代;
Y10表示(C1-C6)-烷基、(C3-C6)-环烷基、C(=O)(C1-C6)-烷基或C(=O)(C3-C6)-环烷基;
Y9表示(C1-C6)-烷基、(C3-C6)-环烷基、O(C1-C6)-烷基或O(C3-C6)-环烷基;
在一个实施方式中,在本发明的化合物中,Y2选自
除非另有说明,如本文所用的术语“烷基”是指在链中具有1至6个碳原子的直链或支链的脂族烃基。优选的烷基在链中具有1个或2个碳原子。烷基的具体示例包括但不限于甲基、乙基、正丙基、异丙基。优选地,所述烷基为甲基或乙基。
术语“环烷基”是指3至11个碳原子,优选3至4个碳原子的饱和单环或双环非芳族烃环,该环烷基可包含一个或多个不饱和度。单环环烷基的具体示例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基。优选地,所述环烷基为环丙基或环丁基。
芳基涉及包含6至10个碳原子的芳族单环或芳族双环。芳基的示例是苯基、萘基,优选苯基。
如本文所用的且在没有具体提及的相反定义的情况下,术语“杂环基”在单独或与其它基团结合时,是指含有4至6个原子的单环饱和的或部分不饱和的非芳族环,其中环的至少一个原子,优选1个或2个原子为杂原子,例如N、O、S、S(O)或S(O)2。优选地,所述杂环是含有4至6个原子的单环饱和的或部分不饱和的非芳族环,其中环的至少一个原子,优选1个或2个原子是杂原子,例如N、O、S、S(O)或S(O)2。杂环基的碳原子也可被氧化形成C(O)基团。合适的杂环也公开于Handbook of Chemistry and Physics,76th Edition,CRC Press,Inc.,1995-1996,第2-25至2-26页中。示例性的杂环基包括但不限于氮杂环丁烷基、氧杂环丁烷基、噁唑基、噁唑烷基、噁二唑基、吡咯基、吡咯烷基、吡啶基、二氢吡啶基、四氢吡啶基、哌啶基、吗啉基、吡唑基、嘧啶基、吡嗪基、四唑基、咪唑基、噻吩基、噻唑基、呋喃基、噻二唑基、异噻唑基、三唑基、四唑基、吡唑基、异噁唑基、2-吡咯烷酮基、咪唑-2,4-二酮、1,2,4-噁二唑-5-酮、1,5-二氢吡咯基-2-酮、吡嗪酮、哒嗪酮、吡啶酮、嘧啶酮、二噁烷基、吡咯烷基、咪唑烷基、吡喃基、四氢呋喃基、二氧戊环基、二氢吡喃基、四氢吡喃基。在没有具体提及的相反定义的情况下,杂环基可以是碳连接的或氮连接的。
如本文所用的且在没有具体提及的相反定义的情况下,杂芳基在单独或与另一基团结合时,是指包含5至6个原子的芳族单环杂环基环,其中环的至少一个原子,优选1至4个原子为杂原子,例如N、O、S、S(O)或S(O)2。在没有具体提及的相反定义的情况下,杂芳基可以是碳连接的或氮连接的。杂芳基的实例是呋喃基、咪唑基、异噻唑基、异噁唑基、噁唑基、吡嗪基、吡唑基、哒嗪基、嘧啶基、吡啶基、吡咯基、四唑基、噻二唑基、噻唑基、噻吩基、三唑基等。
此外,根据本发明的一些化合物可以含有碱性氨基,并因此可以与酸性基团-OSO3H、-OCFHCO2H或-OCF2CO2H形成内部两性离子盐(或两性离子),并且这种内部两性离子盐也包括在本发明中。
表述“任选取代的”是指“未取代的或被进一步定义的化学基团取代的”或“未取代的或取代有进一步定义的化学基团”。
本文使用的术语“外消旋体”是指等量的两种特定对映异构体。
本文使用的术语“对映异构体”是指两种特定立体异构体中的一种,这两种特定立体异构体彼此是不可重叠的镜像,但通过映射彼此相关。
根据本发明的化合物可包括一个或多个不对称碳原子,并因此可以以旋光异构体的形式以及该化合物的外消旋混合物或非外消旋混合物的形式存在。根据本发明的化合物可以以单一异构体使用或以立体化学异构形式的混合物使用。非对映异构体,即不可重叠的立体化学异构体可通过常规手段,诸如色谱法、蒸馏、结晶或升华来分离。旋光异构体(对映异构体)可以通过使用光学活性起始材料,通过根据常规方法拆分外消旋混合物来获得,例如通过用光学活性酸或碱处理而形成非对映异构体盐或通过使用手性色谱柱来获得。
如本文所用,表述“药学上可接受的盐”是指所公开的化合物的衍生物,其中,通过制成母体化合物的酸盐或碱盐来对母体化合物进行修饰。药学上可接受的盐的示例包括但不限于碱性残基(诸如胺)的无机酸盐或有机酸盐;酸性残基(诸如羧酸或氨基羟基-O-磺酸)的碱性盐或有机盐;等等。本发明的药学上可接受的盐可以通过常规化学方法由包含碱性部分或酸性部分的母体化合物来合成。此外,表述“药学上可接受的盐”是指本发明的化合物的相对无毒的、无机和有机酸加成盐或碱加成盐。这些盐可以在化合物的最终分离和纯化期间来原位制备。具体而言,酸加成盐可以通过将纯化形式的经纯化的化合物与有机酸或无机酸单独反应并通过分离由此形成的盐来制备。在酸加成盐的示例中有氢溴酸盐、盐酸盐、氢碘酸盐、氨基磺酸盐、硫酸盐、硫酸氢盐、磷酸盐、硝酸盐、乙酸盐、丙酸盐、琥珀酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、酒石酸盐、萘酸盐、甲磺酸盐、葡庚糖酸盐、葡萄糖酸盐、谷氨酸盐、乳糖酸盐、丙二酸盐、水杨酸盐、亚甲基双-b-羟基萘甲酸盐、龙胆酸、羟乙基磺酸盐、二对甲苯甲酰酒石酸盐、乙磺酸盐、苯磺酸盐、环己基氨基磺酸盐、奎尼月桂基磺酸盐(quinateslaurylsulfonate salts)等。碱加成盐的示例包括与有机碱的铵盐、金属盐,所述铵盐,诸如氨基丁三醇、葡甲胺、吡咯乙醇(epolamine)等;所述金属盐,诸如钠盐、锂盐、钾盐、钙盐、锌盐或镁盐等,所述有机碱诸如二环己基胺盐、N-甲基-D-葡糖胺。合适的盐的列表可见Remington's Pharmaceutical Sciences,17th ed.,Mack PublishingCompany,Easton,PA,1985,p.1418,P.H.Stahl,C.G.Wermuth,Handbook ofPharmaceutical salts-Properties,Selection and Use,Wiley-VCH,2002以及S.M.Berge等人,“Pharmaceutical Salts”J.Pharm.Sci,66:p.1-19(1977)。
根据本发明的化合物还包括同位素标记的化合物,其中,一个或多个原子被具有相同原子序数的原子取代,但原子质量或原子质量数不同于通常在自然界中的原子质量或原子质量数。适合于包括在上述化合物中的同位素的示例包括但不限于2H、3H、11C、13C、14C、18F、19F、13N、15N、33S、34S、35S、36S、17O或18O。同位素标记的化合物可用于药物和/或底物组织分布研究中。用较重的同位素(诸如氘(2H))取代可提供更高的代谢稳定性(例如增加体内半衰期或降低剂量要求)。同位素标记的化合物通过任何合适的方法或通过使用适当的同位素标记的试剂代替原本使用的非标记的试剂的方法来制备。
本发明提供了具有抗菌性质的化合物和/或用作β-内酰胺酶抑制剂的化合物。
本发明还提供了一种用于制备根据本发明的化合物的方法。
本发明的式(I)的化合物可通过以下反应路线1-9来制备。
反应路线1:合成的一般路线
反应路线2:引入R1,路线A
反应路线3:引入R1,路线B
反应路线4:噻唑X4官能化
反应路线5:异噻唑X3官能化
反应路线6:噻吩X3官能化
反应路线7:噻吩X4官能化
反应路线8:噻吩X3、X4和A1官能化
反应路线9:噻吩X3、X4和A1官能化
本发明还提供了根据本发明的化合物在控制细菌中的用途。然后,根据本发明的化合物通常与至少一种药学上可接受的赋形剂组合使用。
本文使用的术语“药学上可接受的”是指在合理的医学判断范围内,适合于与人和动物的组织接触,而没有过度毒性、刺激、过敏反应或其他问题或并发症,与合理的益处/风险比相称的那些化合物、材料、组合物和/或剂型。
本发明还提供了一种组合物,优选药物组合物,该组合物包含至少一种根据本发明的化合物与药学上可接受的赋形剂的混合物。因此,根据本发明的组合物可包含至少一种选自式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(IC)、式(IC*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物的化合物与药学上可接受的赋形剂的混合物。
根据本发明的组合物可以进一步包含至少一种或多种抗菌剂,优选地,这些抗菌剂中的至少一种为β-内酰胺。
术语“贝塔-内酰胺”或“β-内酰胺”是指包含β-内酰胺单元,即β-内酰胺化学基团或β-内酰胺部分的抗菌化合物。
所用术语“药学上可接受的载体”或“药学上可接受的赋形剂”是指不会在人或动物中引起例如过敏反应的二次反应的任何赋形剂、溶剂、分散介质、吸收阻滞剂、稀释剂或佐剂等,诸如防腐剂或抗氧化剂、填充剂、粘合剂、崩解剂、润湿剂、乳化剂、悬浮剂、溶剂、分散介质、包衣剂、抗菌剂、等渗剂和吸收延迟剂等。典型的但非限制性的赋形剂实例包括甘露醇、乳糖、硬脂酸镁、糖化钠、滑石、纤维素、交联羧甲基纤维素钠、葡萄糖、明胶、淀粉、乳糖、磷酸二钙、蔗糖、高岭土、碳酸镁、润湿剂、乳化剂、增溶剂、无菌水、生理盐水、pH缓冲剂、非离子表面活性剂、润滑剂、稳定剂、粘合剂和食用油(诸如花生油、芝麻油等)。此外,可包括本领域常用的各种赋形剂。药学上可接受的载体或赋形剂为本领域技术人员所熟知,并且包括Remington's Pharmaceutical Sciences(Mack Publishing Company,Easton,USA,1985),Merck Index(Merck&Company,Rahway,N.J.),Gilman等人(Eds.Thepharmacological basis of therapeutics,8th Ed.,Pergamon press,1990)中记载的那些。除了任何常规介质或佐剂与根据本发明的活性成分不兼容的情况之外,这些赋形剂在治疗组合物中的用途是可预期的。
如本文所用的表述“抗菌剂”是指能够抑制、减少或阻止细菌生长,抑制或降低细菌在对象中引起感染的能力,或抑制或降低细菌在环境中繁殖或保持感染的能力,或降低细菌的感染性或毒性的任何物质、化合物或它们的组合。
抗菌剂可选自以下家族中的一种或它们的混合物:氨基糖苷类、β-内酰胺类、甘氨酰环素类、四环素类、喹诺酮类、氟喹诺酮类、糖肽类、脂肽类、大环内酯类、酮内酯类、林可酰胺类、链阳性菌素、噁唑烷酮类和多粘菌素类。优选地,进一步的抗菌剂选自β-内酰胺家族,更优选选自青霉素、头孢菌素、青霉烯类、碳青霉烯类和单菌霉素中的一种或它们的混合物。
在青霉素中,抗菌剂优选选自由以下各项组成的组中的一种或它们的混合物:阿莫西林、氨苄西林、阿洛西林、美洛西林、阿帕西林、海他西林、巴氨西林、羧苄青霉素、磺苄西林、替莫西林、替卡西林、哌拉西林、美西林、匹美西林、甲氧西林、环己西林、塔兰西林[HG1]、阿扑西林、苯唑西林、氯唑西林、双氯西林、氟氯西林、奈夫西林和匹凡西林。
在头孢菌素中,抗菌剂优选选自由以下各项组成的组中的一种或它们的混合物:头孢曲嗪、头孢唑啉、头孢地尔、头孢西丁、头孢氨苄、头孢拉定、头孢唑肟、头孢乙腈、头孢拉宗、头孢丙烯、头孢吡普、头孢托罗酯、头孢洛林、头孢洛林酯(ceftaroline fosaminyl)、头孢洛宁、头孢米诺、头孢雷特、头孢替坦、头孢布烯、头孢卡品酯、头孢妥仑匹酯、头孢达肟、头孢沙定、头孢洛生嗪(ceftolozane)和S-649266、头孢噻吩、头孢噻啶、头孢克洛、头孢羟氨苄、头孢羟唑、头孢唑啉、头孢氨苄、头孢拉定、头孢唑肟、头孢乙腈、头孢替安、头孢噻肟、头孢磺啶、头孢哌酮、头孢甲肟、头孢美唑、头孢来星、头孢尼西、头孢地嗪、头孢匹罗、头孢他啶、头孢曲松、头孢匹胺、头孢拉宗、头孢唑兰、头孢吡肟、头孢噻利、头孢瑞南、头孢唑喃、头孢咪唑、头孢克定、头孢克肟、头孢布烯、头孢地尼、头孢泊肟酯(cefpodoximeaxetil,cefpodoxime proxetil)、头孢特仑酯、头孢他美酯、头孢卡品酯、头孢托仑酯、头孢呋辛、头孢呋辛酯、氯碳头孢和拉氧头孢。
在碳青霉烯类中,抗菌剂优选选自由亚胺培南、多尼培南、美罗培南、比阿培南、厄他培南和帕尼培南组成的组中的一种或它们的混合物。
在单菌霉素中,抗菌剂优选选自由氨曲南、替吉莫南、卡芦莫南、BAL30072、LYS228和诺卡菌素A组成的组中的一种或它们的混合物。
本发明还涉及一种组合物,该组合物包含至少一种根据本发明的式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(1C)、式(1C*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物和头孢他啶。
本发明还提供了一种套件,该套件包括:
根据本发明的药物组合物,和
包含一种或多种抗菌剂的至少一种其他组合物,优选地,这些抗菌剂中的至少一种是β-内酰胺。
这两种组合物各自可分别用一种特定的药学上可接受的载体来制备,然后可尤其是在临用时进行混合。
本发明还涉及一种套件,该套件包括:
包含至少一种根据本发明的式(I)或式(I*)的化合物的药物组合物;和
包含头孢他啶的药物组合物。
本发明还涉及选自根据本发明的式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(1C)、式(1C*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物中的化合物用作药物。
本发明还涉及选自根据本发明的式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(1C)、式(1C*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物中的化合物用于制备药物。
本发明还涉及选自根据本发明的式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(1C)、式(1C*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物中的化合物用作抗菌剂。
本发明还涉及选自根据本发明的式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(1C)、式(1C*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物中的化合物或根据本发明的药物组合物用于制备包含药物的抗菌剂的用途。
本发明还涉及选自根据本发明的式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(1C)、式(1C*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物中的化合物或根据本发明的药物组合物用于制备包含药物的β-内酰胺酶抑制剂的用途。
本发明还涉及选自根据本发明的式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(1C)、式(1C*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物中的化合物或根据本发明的药物组合物用于制备包含抗菌剂和β-内酰胺酶抑制剂的药物的用途。
本发明还涉及选自根据本发明的式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(1C)、式(1C*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物中的化合物或根据本发明的药物组合物或根据本发明的套件用于治疗或用于预防至少一种细菌感染的用途。
本发明还涉及选自根据本发明的式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(1C)、式(1C*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物中的化合物或根据本发明的药物组合物或根据本发明的套件用于制备用于治疗或预防至少一种细菌感染的药物的用途。
如本文所用的术语“预防(prevention)”、“预防(prevent)”和“预防(preventing)”用于指给药本发明的化合物或组合物以预防由细菌引起的感染或预防相关感染和/或疾病的发生。术语“预防(prevention)”、“预防(prevent)”和“预防(preventing)”还包括通过将根据本发明的化合物或组合物至易感染的患者或存在被细菌感染风险的患者以预防至少一种细菌感染。
如本文所用的术语“治疗(treatment)”、“治疗(treat)”和“治疗(treating)”尤其用于指将包含根据本发明的化合物或组合物的治疗物给药至受感染的患者。如本文所用的术语“治疗(treatment)”、“治疗(treat)”和“治疗(treating)”还指将根据本发明的化合物或组合物,任选地与一种或多种额外的抗菌剂的组合给药以:
减轻或消除细菌感染或与细菌感染相关的一种或多种症状,或
延缓细菌感染或与细菌感染相关的一种或多种症状的进展,或
减轻细菌感染或与细菌感染相关的一种或多种症状的严重性,或
抑制细菌感染的临床表现,或
抑制由细菌感染引起的不良症状的表现。
如本文所用的表述“感染”或“细菌感染”包括在对象体内或体表上存在细菌,如果抑制了该细菌的生长,则将会对该对象产生益处。因此,术语“感染”或“细菌感染”除了指存在细菌之外,还指不期望的正常菌群。术语“感染”包括由细菌引起的感染。这种细菌感染的示例为尿路感染(UTI)、肾脏感染(肾盂肾炎)、妇科和产科感染、呼吸道感染(RTI)、慢性支气管炎急性发作(AECB)、社区获得性肺炎(CAP)、医院获得性肺炎(HAP)、呼吸机相关性肺炎(VAP)、腹腔内肺炎(IAI)、急性中耳炎、急性鼻窦炎、败血症、导管相关性败血症、软下疳、衣原体、皮肤感染、菌血症。
如本文所使用的术语“生长”是指一种或多种微生物的生长,并且包括诸如细菌的微生物的繁殖或种群扩增。该术语还包括保持微生物的持续代谢过程,包括使微生物保持存活的过程。
根据本发明,细菌选自革兰氏阳性细菌或革兰氏阴性细菌,优选革兰氏阴性细菌。根据本发明,细菌还可以选自产生“贝塔-内酰胺酶”或“β-内酰胺酶”的细菌。这些细菌为本领域技术人员所熟知。如本文所用的术语“贝塔-内酰胺酶”或“β-内酰胺酶”是指能够分解β-内酰胺环的任何酶或蛋白质或任何其他物质。术语“贝塔-内酰胺酶”或“β-内酰胺酶”包括由细菌产生的并且具有使诸如抗菌剂的化合物中存在的β-内酰胺环部分或完全水解的能力的酶。
在革兰氏阳性细菌中,根据本发明的细菌优选选自葡萄球菌(Staphylococcus)、键球菌(Streptococcus)、葡萄球菌属(Staphylococcus species)(包括金黄色葡萄球菌Staphylococcus aureus、表皮葡萄球菌Staphylococcus epidermidis)、链球菌菌属(Streptococcus species)(包括肺炎链球菌Streptococcus pneumonia、无乳链球菌Streptococcus agalactiae)、肠球菌属(Enterococcus species)(包括粪肠球菌Enterococcus faecalis和屎肠球菌Enterococcus faecium)。
在革兰氏阴性细菌中,根据本发明的细菌优选选自不动杆菌属(Acinetobacterspecies)(包括鲍曼不动杆菌Acinetobacter baumannii)、柠檬酸杆菌属(Citrobacterspecies)、埃希氏菌属(Escherichia species)(包括大肠杆菌Escherichia coli)、流感嗜血杆菌(Haemophilus influenza)、莫尔甘内拉氏菌(Morganella morganii)、克雷伯氏杆菌(Klebsiella species)(包括肺炎克雷伯杆菌Klebsiella pneumonia)、肠杆菌属(Enterobacter species)(包括阴沟肠杆菌Enterobacter cloacae)、淋球菌(Neisseriagonorrhoeae)、伯克霍尔德氏菌属(Burkholderia species)(包括伯克霍尔德菌Burkholderia cepacia)、变形杆菌属(Proteus species)(包括奇异变形杆菌Proteusmirabilis)、沙雷氏菌属(Serratia species)(包括粘质沙雷氏菌Serratia marcescens)、铜绿假单胞菌(Pseudomonas aeruginosa)。
因此,本发明优选涉及选自根据本发明的式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(1C)、式(1C*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物中的化合物或根据本发明的药物组合物或根据本发明的套件用于治疗或预防细菌感染,优选由产生一种或多种β-内酰胺酶的细菌所引起的细菌感染。优选地,该细菌选自革兰氏阳性细菌或革兰氏阴性细菌,更优选革兰氏阴性细菌。
本发明还涉及选自根据本发明的式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(1C)、式(1C*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物中的化合物或根据本发明的药物组合物用于制备用于治疗或预防细菌感染,优选由产生一种或多种β-内酰胺酶的细菌所引起的细菌感染的药物的用途。优选地,该细菌选自革兰氏阳性细菌或革兰氏阴性细菌,更优选革兰氏阴性细菌。
本发明还涉及根据本发明的套件用于同时、间隔或依次对有需要的患者给药以治疗或预防细菌感染,优选由产生一种或多种β-内酰胺酶的细菌引起的细菌感染。优选地,该细菌选自革兰氏阳性细菌或革兰氏阴性细菌,更优选革兰氏阴性细菌。
本发明还涉及选自根据本发明的式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(1C)、式(1C*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物中的化合物与一种或多种额外的抗菌剂(优选地,额外的抗菌剂中的至少一种为β-内酰胺化合物)组合使用以治疗或预防细菌感染,优选由产生一种或多种β-内酰胺酶的细菌引起的细菌感染。优选地,该细菌选自革兰氏阳性细菌或革兰氏阴性细菌,更优选革兰氏阴性细菌,其中,将选自根据本发明的式(I)或式(I*)的化合物中的化合物和额外的抗菌剂同时、间隔或依次给药。
本发明还涉及选自根据本发明的式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(1C)、式(1C*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物中的化合物或根据本发明的药物组合物或根据本发明的套件用于预防或治疗细菌感染,优选一种细菌感染,优选由产生一种或多种β-内酰胺酶的细菌所引起的细菌感染的用途。优选地,该细菌选自革兰氏阳性细菌或革兰氏阴性细菌,更优选革兰氏阴性细菌。
本发明还涉及一种治疗或预防细菌感染,优选由产生一种或多种β-内酰胺酶的细菌所引起的细菌感染的方法,该方法包括将治疗有效量的选自根据本发明的式(I)、式(I*)、式(IA)、式(IA*)、式(IB)、式(IB*)、式(1C)、式(1C*)、式(ID)、式(ID*)、式(IE)、式(IE*)的化合物中的化合物或根据本发明的药物组合物或根据本发明的套件给药至有需要的患者。优选地,该细菌选自革兰氏阳性细菌或革兰氏阴性细菌,更优选革兰氏阴性细菌。
术语“患者”是指有被细菌感染风险的人或动物,或被细菌感染的人或动物,该细菌优选为革兰氏阳性细菌和革兰氏阴性细菌,更优选革兰氏阴性细菌。如本文所用,术语“患者”是指患有或潜在患有本文所述的一种或多种感染和病症的温血人或动物(诸如哺乳动物),优选人类或人类儿童。在本领域技术人员的能力和知识范围内,完全能够确定需要进行本文所述的疾病和病症治疗的那些对象。本领域的兽医或医师通过使用临床测试、身体检查、药物史或家族史、或生物和诊断测试能够容易地确定需要进行这种治疗的那些对象。
如本文所用的表述“治疗有效量”或“药学上的有效量”是指当给药至有需要的患者时,根据本发明的化合物的量足以有效地治疗疾病状态、病症、失调,从而使该化合物具有效用。这样的量将足以引发研究人员或临床医生所寻找的组织系统或患者的生物学响应或药物反应。根据本发明的化合物的构成“治疗有效量”的量将会变化,特别是取决于以下各项而变化:化合物本身及其生物活性,用于给药的组合物,给药时间,给药途径,化合物的排泄率、治疗的持续时间、所治疗的疾病状态或病症的类型及其严重性、与本发明化合物组合使用或一同使用的药物,以及患者的年龄、体重、一般健康状况、性别和饮食。这种“治疗有效量”可以由本领域普通技术人员根据其自身知识和本公开的内容来确定。优选地,根据本发明的化合物以介于每天0.1g至30g的量给药。
根据本发明的化合物可以提供在水性生理缓冲溶液中用于肠胃外给药。本发明化合物还能够以单位剂量的形式给药,其中,表述“单位剂量”是指能够给药至患者,并且能够容易地处理和包装的单一剂量,其保持为包括本文描述的活性化合物本身或药学上可接受的组合物的物理和化学稳定的单位剂量。本文所提供的化合物可通过与一种或多种药学上可接受的赋形剂混合而配制成药物组合物。这样的单位剂量组合物可以制备成通过以下方式来使用:口服给药,尤其是以片剂、简单胶囊或软凝胶胶囊的形式;或鼻内给药,尤其是以粉末、滴鼻剂或气雾剂的形式;或皮肤给药,例如局部用软膏、乳膏、乳液、凝胶或喷雾剂,或通过透皮贴剂。
所述药物组合物可以方便地以单位剂量形式给药,并且可以通过制药领域中所熟知的任何方法来制备,例如在Remington:The Science and Practice of Pharmacy,20thed.;Gennaro,A.R.,Ed.;Lippincott Williams&Wilkins:Philadelphia,PA,2000中记载的方法。
优选的制剂包括药物组合物,其中,根据本发明的化合物配制用于口服给药或肠胃外给药。
对于口服给药,片剂、丸剂、粉剂、胶囊、锭剂等可含有一种或多种以下成分或相似性质的化合物:粘合剂,诸如微晶纤维素或黄蓍胶;稀释剂,诸如淀粉或乳糖;崩解剂,诸如淀粉和纤维素衍生物;润滑剂,诸如硬脂酸镁;助滑剂,诸如胶体二氧化硅;甜味剂,诸如蔗糖或糖精;或调味剂,诸如薄荷或水杨酸甲酯。胶囊可以是硬胶囊或软胶囊的形式,其通常由任选地与增塑剂共混的明胶共混物制成,以及淀粉胶囊。此外,单位剂量形式可含有改变单位剂量的物理形式的各种其他物质,例如糖、虫胶或肠溶剂的包衣。其他口服剂型糖浆或酏剂可含有甜味剂、防腐剂、染料、着色剂和调味剂。此外,活性化合物可以掺入快速溶解、改性释放或缓释配制品和制剂中,并且其中,这种缓释制剂优选是双峰的。优选的片剂含有乳糖、玉米淀粉、硅酸镁、交联羧甲基纤维素钠、聚维酮、硬脂酸镁或滑石,以及它们的任意组合。
用于肠胃外给药的液体配制品包括无菌水性溶液或无菌非水性溶液、悬浮液和乳液。液体组合物还可包括粘合剂、缓冲剂、防腐剂、螯合剂、甜味剂、调味剂和着色剂等。非水性溶剂包括醇、丙二醇、聚乙二醇、橄榄油等植物油以及油酸乙酯等有机酯。水性载体包括醇和水的混合物、缓冲介质和盐水。具体而言,生物相容的、生物可降解的丙交酯聚合物、丙交酯/乙交酯共聚物或聚氧乙烯-聚氧丙烯共聚物可以用作控制活性化合物释放的赋形剂。静脉内注射载剂可包括液体和营养补充剂、电解质补充剂,例如基于林格氏葡萄糖的那些等。活性化合物的其他潜在有用的肠胃外递送系统包括乙烯-乙酸乙烯酯共聚物颗粒、渗透泵、可植入的输注系统和脂质体。
替代性的给药模式包括用于吸入的制剂,其包括诸如干粉、气雾剂或滴剂等手段。它们可以是包含例如聚氧乙烯-9-月桂基醚、甘氨胆酸盐和脱氧胆酸盐的水性溶液,或以滴鼻剂形式给药的油性溶液,或以鼻内方式施用的凝胶。用于口腔给药的制剂例如包括含片或锭剂,并且还可以包括调味的基质(诸如例如蔗糖或阿拉伯胶)以及其他赋形剂(诸如甘氨胆酸盐)。适于直肠给药的制剂优选作为具有基于固体的载体的单位剂量栓剂形式存在,并且可包括水杨酸盐。用于局部施用于皮肤的制剂优选采用软膏、霜剂、洗液、糊剂、凝胶、喷雾剂、气雾剂或油的形式。可以使用的载体包括凡士林、羊毛脂、聚乙二醇、醇,或它们的组合。
适合于经皮给药的制剂可以作为分离的贴剂存在,并且可以为溶解和/或分散在聚合物或粘合剂中的亲脂性乳液或缓冲的水性溶液。
具体实施方式
实施例
提供以下实施例,目的是用于说明本发明,并且绝不应该解释为限制本发明的范围。
第一部分描述了化合物(中间体和最终化合物)的制备,而第二部分描述了对根据本发明的化合物的抗菌活性的评价。
化合物的制备和生物活性:
本文所用的缩写词或符号包括:
ACHN: 1,1′-偶氮双(环己烷甲腈)
ACN: 乙腈
AcOH: 乙酸
Bn: 苄基
Boc: 叔丁氧羰基
Boc2O: 叔丁氧羰基酸酐
BocON: [2-(叔丁氧羰基氧亚氨基)-2-苯乙腈]
bs: 宽单峰
Burgess试剂: N-(三乙基氨磺酰)氨基甲酸甲酯
CFU: 集落形成单位
CLSI: 临床实验室标准研究所
d: 二重峰
DBU: 1,8-二氮杂二环[5.4.0]十一碳-7-烯
DCM: 二氯甲烷
dd: 双二重峰
ddd: 双二倍二重峰
ddt: 双二倍三重峰
dq: 双四重峰
dt: 双三重峰
DTAD: 偶氮二甲酸二叔丁酯
DEAD: 偶氮二甲酸二乙酯
Dess-Martin试剂:1,1,1-三(乙酰氧基)-1,1-二氢-1,2-苯碘酰-3-(1H)-酮
DHP: 3,4-二氢-2H-吡喃
DIAD: 偶氮二甲酸二异丙酯
DIPEA: N,N-二异丙基乙胺
DMAP: 4-二甲基氨基吡啶
DMF: N,N-二甲基甲酰胺
DMSO: 二甲基亚砜
EtOAc: 乙酸乙酯
Et2O: 二乙醚
h: 小时
HATU: 1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶
鎓-3-氧化物六氟磷酸盐
m: 多重峰
min: 分钟
MeOH: 甲醇
MeONa: 甲醇钠
MIC: 最低抑制浓度
MS: 质谱
MsCl: 甲磺酰氯
NBS: N-溴代琥珀酰亚胺
NMR: 核磁共振谱
Ns: 对硝基苯磺酰基(nosyl),硝基苯磺酰基
Pd(Ph3)4: 四(三苯基膦)钯(0)
PG: 保护基
PhSH: 苯硫酚
PMe3: 三甲基膦
PPh3: 三苯基膦
Ppm: 百万分之一份
q: 四重峰
rt: 室温
s: 单峰
SEM: [2-(三甲基硅基)乙氧基]甲基
t: 三重峰
TBAF: 四正丁基氟化铵
TBDMSCl: 叔丁基二甲基氯硅烷
TBDMSOTf: 叔丁基二甲硅基三氟甲磺酸酯
TBSOTf: 三氟甲磺酸三甲基硅酯
tBuOK: 叔丁醇钾
TEA: 三乙胺
TFA: 三氟乙酸
THF: 四氢呋喃
THP: 四氢吡喃基
TLC: 薄层色谱
TMSI: 三甲基碘硅烷
实施例1:
[2-(2-氨基乙基氨基甲酰基)-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e]
[1,3]二氮杂卓-7-基]磺酸的合成
步骤1:中间体7-[叔丁基(二甲基)硅烷基]氧基-6,7-二氢-4H-噻唑并[4,5-c]吡
啶-5-羧酸叔丁酯(1b)的制备
将中间体(la)(WO2017109025,4.86g,19mmol)溶解于DCM(38mL)中。加入TEA(5.87mL,42mmol)、TBDMSCl(3.15g,21mmol)和DMAP(催化量)。在室温下,搅拌混合物过夜。由于起始材料未完全消耗,因此加入TBDMSCl(1.14g,7.5mmol)并在室温下搅拌混合物过夜。用DCM稀释混合物,并用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩。通过硅胶柱色谱法(DCM/丙酮:10/0至8/2)对粗产物进行纯化,以得到中间体(lb)(5.45g,14.8mmol,78%)。MS m/z([M+H]+)371。1H NMR(400MHz,CDCl3):δ(ppm)0.18(s,3H),0.20(s,3H),0.93(s,9H),1.49(s,9H),3.05-3.35(m,1H),4.00-4.35(m,1H),4.45(d,J=16.8Hz,1H),4.80-5.05(m,2H),8.70(s,1H)。
步骤2:中间体5-叔丁氧基羰基-7-[叔丁基(二甲基)硅烷基]氧基-6,7-二氢-4H-
噻唑并[4,5-c]吡啶-2-羧酸锂(1c)的制备
在-78℃下,将1.6M nBuLi的己烷溶液(16.5mL,26mmol)加入到中间体(1b)(4.9g,13mmol)的THF溶液(100mL)中。30min后,在-78℃下将CO2气体鼓入混合物中5min。将混合物温热至室温下持续45min,然后浓缩,以得到粗产物,该粗产物不经纯化用于下一步骤。
MS m/z([M+H]+)415。
步骤3:中间体O5-叔丁基O2-甲基7-[叔丁基(二甲基)硅烷基]氧基-6,7-二氢-4H-
噻唑并[4,5-c]吡啶-2,5-二羧酸酯(1d)的制备
在室温下,将中间体(1c)(13mmol)、K2CO3(2.76g,20mmol)和Me2SO4(1.88mL,20mmol)的丙酮溶液(85mL)搅拌18h。由于转化不完全,加入Me2SO4(1.88mL,20mmol)并在室温下再搅拌混合物18h。通过加入TEA(5.8mL,42mmol)淬灭混合物,然后在室温下搅拌30min。用AcOEt稀释混合物,并用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩。通过硅胶色谱法(DCM/丙酮:10/0至8/2)对粗产物进行纯化,以得到中间体(1d)(3.75g,8.7mmol,2步共68%)。MS m/z([M+H]+)429。1H NMR(400MHz,CDCl3):δ(ppm)0.19(s,3H),0.22(s,3H),0.94(s,9H),1.49(s,9H),3.00-3.20(m,1H),4.00(s,3H),4.11-4.41(m,1H),4.40(dd,J=1.8,17.1Hz,1H),4.85-5.05(m,2H)。
步骤4:中间体O5-叔丁基O2-甲基7-羟基-6,7-二氢-4H-噻唑并[4,5-c]吡啶-2,5-
二羧酸酯(1e)的制备
在室温下,将1M TBAF的THF溶液(8.7mL,8.7mmol)加入到中间体(1d)(3.75g,8.7mmol)的THF溶液(44mL)中。30min后,用AcOEt稀释混合物,并用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩。通过硅胶色谱法(DCM/丙酮:10/0至5/5)对粗产物进行纯化,以得到中间体(1e)(2.2g,7.0mmol,80%)。MS m/z([M+H]+)315。1H NMR(400MHz,CDCl3):δ(ppm)1.48(s,9H),3.74-3.90(m,2H),4.01(s,3H),4.59(dd,J=1.3,17.2Hz,1H),4.78-4.88(m,1H),4.96-5.05(m,1H)。
步骤5:中间体O5-叔丁基O2-甲基7-[烯丙氧基-(2-硝基苯基)磺酰基-氨基]-6,7-
二氢-4H-噻唑并[4,5-c]吡啶-2,5-二羧酸酯(1f)的制备
在0℃下,将DTAD(2.09g,9.1mmol)分批加入到中间体(1e)(2.2g,7.0mmol)、N-烯丙氧基-2-硝基-苯磺酰胺(2.35g,9.1mmol)和PPh3(2.38g,9.1mmol)的甲苯溶液(70mL)中。在室温下搅拌混合物2小时30分钟,然后浓缩。通过快速硅胶色谱法(DCM/丙酮:10/0至7/3)对残余物进行粗略纯化,以得到中间体(1f),该中间体(1f)不经进一步纯化用于下一步骤。MS m/z([M+H]+)555。
步骤6:中间体O5-叔丁基O2-甲基7-(烯丙氧基氨基)-6,7-二氢-4H-噻唑并[4,5-
c]吡啶-2,5-二羧酸酯(1g)的制备
在0℃下,将K2CO3(7.25g,52.5mmol)和苯硫酚(3.59mL,35.0mmol)加入到中间体(1f)(7.0mmol)的ACN溶液(70mL)中。在室温下,3小时30分钟后,在硅藻土上过滤混合物,并用ACN和DCM洗涤。浓缩滤液,并通过快速硅胶色谱法(DCM/丙酮:10/0至7/3)对残余物进行纯化,以得到中间体(1g)(1.62g,4.4mmol,2步共62%)。MS m/z([M+H]+)370。1H NMR(400MHz,CDCl3):δ(ppm)1.48(s,9H),3.57-3.79(m,1H),4.00(s,3H),4.00-4.05(m,1H),4.31(d,J=6.0Hz,2H),4.39-4.45(m,1H),4.51-4.64(m,1H),4.73-4.92(m,1H),5.24(dd,J=1.5,10.5Hz,1H),5.33(dd,J=1.5 17.3Hz,1H),5.93(ddt,J=5.9,10.3,17.3Hz,1H)。
步骤7:中间体7-烯丙氧基-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]
二氮杂卓-2-羧酸甲酯(1h)的制备
在0℃下,将双光气(0.37mL,3.0mmol)加入到中间体(1g)(1.62g,4.4mmol)和TEA(0.92mL,6.6mmol)的DCM溶液(44mL)中。在0℃下搅拌混合物45min,然后加入MeSO3H(4.27mL,65.8mmol)的DCM溶液(22mL)。在0℃下1h后,加入TEA(12.23mL,87.8mmol)并在室温下搅拌混合物10min。在氮气下部分浓缩后,用DCM稀释混合物,并用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩。通过硅胶柱色谱法(DCM/丙酮:10/0至8/2)对粗产物进行纯化,以得到中间体(1h)(777mg,2.6mmol,60%)。MS m/z([M+H]+)296。1H NMR(400MHz,CDCl3):δ(ppm)3.26(d,J=11.3Hz,1H),3.78(dd,J=2.9,11.3Hz,1H),4.00(s,3H),4.37-4.53(m,3H),4.67(d,J=9.4Hz,1H),4.69(d,J=5.0Hz,1H),5.29-5.40(m,2H),6.00(dddd,J=6.0,6.7,10.3,17.1Hz,1H)。
步骤8:中间体7-烯丙氧基-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]
二氮杂卓-2-羧酸(1i)的制备
在0℃下,将1N LiOH(2.6mL,2.6mmol)加入到中间体(1h)(775mg,2.6mmol)的THF(26mL)和水(13mL)的混合物的溶液中。在0℃下搅拌混合物。40min后,起始材料有剩余,补充加入1N LiOH(0.26mL,0.26mmol)。在0℃下再搅拌混合物15min,直到将中间体(1h)完全消耗。在0℃下,通过加入1N HCl(2.88mL,2.88mmol)淬灭混合物,用AcOEt稀释混合物,并用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩,以得到中间体(1i)(639mg,2.27mmol,87%),该中间体(1i)不经进一步纯化用于下一步骤。MS m/z([M+H]+)282。
步骤9:中间体N-[2-[(7-烯丙氧基-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-
e][1,3]二氮杂卓-2-羰基)氨基]乙基]氨基甲酸叔丁酯(1j)的制备
将DIPEA(0.23mL,1.33mmol)和HATU(243mg,0.64mmol)加入到中间体(1i)(150mg,0.53mmol)的DCM溶液(5mL)中。10min后,加入N-(2-氨基乙基)氨基甲酸叔丁酯(128mg,0.80mmol),并在室温下搅拌混合物18h。用DCM稀释混合物,并用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩。通过硅胶柱色谱法(DCM/丙酮:10/0至7/3)对粗产物进行两次纯化,以得到中间体(1j)(5mg,0.123mmol)。MS m/z([M-H]-)422。
步骤10:中间体三苯基-丙烯基膦[2-[2-(叔丁氧基羰基氨基)乙基氨基甲酰基]-
5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮杂卓-7-基]硫酸盐(1k)的制备
将AcOH(14μL,0.24mmol)和Pd(PPh3)4(71mg,0.06mmol)依次加入到中间体(lj)(52mg,0.12mmol)的无水DCM溶液(1.2mL)中。在室温下,搅拌混合物2h。然后加入吡啶(1.2mL)和三氧化硫吡啶络合物(97mg,0.61mmol),并在室温下搅拌混合物过夜。用DCM稀释不均匀混合物,并将固体滤掉。浓缩滤液,并通过快速硅胶色谱法(DCM/丙酮:10/0至0/10)对粗产物进行纯化,以得到中间体(1k)(22mg,0.028mmol,24%)。MS m/z([M-H]-)462。
步骤11:[2-(2-氨基乙基氨基甲酰基)-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并
[4,5-e][1,3]二氮杂卓-7-基]磺酸(实施例1)的制备
在0℃下,将TFA(0.1mL)加入到中间体(1k)(22mg,0.028mmol)的DCM溶液(0.13mL)中。在0℃下搅拌混合物30min。在0℃下,加入Et2O以得到沉淀物,并除去上清液(进行3次操作)。用ACN将残余物研磨(triturate)两次,并每次除去上清液。将沉淀物在PTFE膜上进行过滤,并在真空下干燥。通过C18柱色谱法(水/ACN:99/1至70/30)对粗产物进行纯化。将含有期望化合物的部分合并,在氮气流下部分浓缩以除去ACN,冷冻并冻干以得到实施例1(6mg,0.016mmol,60%)。MS m/z([M+H]+)364。1H NMR(400MHz,D2O):δ(ppm)3.30(t,J=5.7Hz,2H),3.61(d,J=11.7Hz,1H),3.68-3.84(m,2H),3.97(dd,J=3.0,11.7Hz,1H),4.58(d,J=16.8Hz,1H),4.65(d,J=16.8Hz,1H),5.30(d,J=2.8Hz,1H)。19F NMR(377MHz,D2O):无氟。
实施例2:[2-(胍基甲基)-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]
二氮杂卓-7-基]磺酸的合成
步骤1:中间体7-[叔丁基(二甲基)硅烷基]氧基-2-甲酰基-6,7-二氢-4H-噻唑并
[4,5-c]吡啶-5-羧酸叔丁酯(2a)的制备
在-78℃下,将1.6M nBuLi的己烷溶液(2.16mL,5.4mmol)加入到中间体(1b)(2.0g,5.4mmol)的THF溶液(27mL)中。在-78℃下搅拌混合物30min,然后加入DMF(0.42mL,5.4mmol)的THF溶液(3mL)。在-78℃下搅拌混合物10min。使温度升高至0℃保持1h。通过加入NH4Cl溶液淬灭反应,用AcOEt稀释,用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩。将残余物不经纯化用于下一步骤。MS m/z([M+H]+)399。1H NMR(400MHz,CDCl3):δ(ppm)0.20(s,3H),0.22(s,3H),0.94(s,9H),1.50(s,9H),2.95-3.20(m,1H),4.15-4.43(m,1H),4.41(d,J=16.8Hz,1H),4.87-5.08(m,2H),9.91(s,1H)。
步骤2:中间体7-[叔丁基(二甲基)硅烷基]氧基-2-(羟甲基)-6,7-二氢-4H-噻唑
并[4,5-c]吡啶-5-羧酸叔丁酯(2b)的制备
在0℃下,将NaBH4(225mg,5.94mmol)加入到中间体(2a)(5.4mmol)的THF(5mL)/MeOH(15mL)的混合物的溶液中。在室温下搅拌混合物30min。通过加入丙酮和水淬灭反应。部分浓缩后,用AcOEt稀释残余物,并用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩。通过硅胶柱色谱法(DCM/丙酮:10/0至5/5)对粗产物进行纯化,以得到中间体(2b)(1.38g,3.5mmol,2步共64%)。MS m/z([M+H]+)401。1H NMR(400MHz,CDCl3):δ(ppm)0.18(s,3H),0.20(s,3H),0.93(s,9H),1.48(s,9H),2.74(bs,1H),3.04-3.30(m,1H),3.99-4.32(m,1H),4.39(dd,J=1.7,17.0Hz,1H),4.73-4.96(m,2H),4.93(s,2H)。
步骤3:中间体7-[叔丁基(二甲基)硅烷基]氧基-2-(四氢吡喃-2-基氧基甲基)-6,
7-二氢-4H-噻唑并[4,5-c]吡啶-5-羧酸叔丁酯(2c)的制备
将DHP(0.17mL,1.87mmol)和APTS(催化剂量)加入到中间体(2b)(500mg,1.25mmol)的DCM溶液(5mL)中。在室温下搅拌混合物3h,用DCM稀释并用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩。通过硅胶色谱法(DCM/丙酮:10/0至7/3)对粗产物进行纯化,以得到中间体(2c)(570mg,1.18mmol,95%)。MS m/z([M+H]+)485。1H NMR(400MHz,CDCl3):δ(ppm)0.18(s,3H),0.20(s,3H),0.93(s,9H),1.48(s,9H),1.52-1.92(m,6H),3.08-3.32(m,1H),3.53-3.60(m,1H),3.89(ddt,J=2.8,8.8,11.4Hz,1H),3.97-430(m,1H),4.39(d,J=16.8Hz,1H),4.76(d,J=13.7Hz,1H),4.77-4.81(m,2H),4.86-4.98(m,1H),4.94(d,J=13.7Hz,1H)。
步骤4:中间体7-羟基-2-(四氢吡喃-2-基氧基甲基)-6,7-二氢-4H-噻唑并[4,5-
c]吡啶-5-羧酸叔丁酯(2d)的制备
在0℃下,将1M TBAF的THF溶液(1.18mL,1.18mmol)加入到中间体(2c)(570mg,1.18mmol)的THF溶液(6mL)中。在0℃下搅拌混合物1h,用AcOEt稀释并用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩。通过硅胶柱色谱法(DCM/丙酮:10/0至4/6)对粗产物进行纯化,以得到中间体(2d)(413mg,1.12mmol,95%)。MS m/z([M+H]+)371。1H NMR(400MHz,CDCl3):δ(ppm)1.49(s,9H),1.51-1.90(m,6H),3.57(ddt,J=2.9,5.6,9.8Hz,1H),3.60-3.70(m,1H),3.83-3.92(m,1H),3.98(dd,J=4.2,13.7Hz,1H),4.42(d,J=17.0Hz,1H),4.74-4.86(m,3H),4.89-4.96(m,1H),4.95(d,J=14.0Hz,1H)。
步骤5:中间体7-(烯丙氧基氨基)-2-(四氢吡喃-2-基氧基甲基)-6,7-二氢-4H-噻
唑并[4,5-c]吡啶-5-羧酸叔丁酯(2e)的制备
在-78℃下,将Ms2O(580mg,3.33mmol)的DCM溶液(2.5mL)加入到TEA(0.61mL,4.44mmol)和中间体(2d)(410mg,1.11mmol)的DCM溶液(11mL)中。在-78℃下45min后,加入NH2OAll(566mg,7.76mmol)的DCM溶液(2.5mL)。在-78℃下,搅拌混合物15min。使温度升高至室温下保持1h。用DCM稀释混合物,并用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩。通过硅胶柱色谱法(DCM/AcOEt:10/0至2/8)对粗产物进行纯化,以得到中间体(2e)(375mg,0.88mmol,80%)。MS m/z([M+H]+)426。1H NMR(400MHz,CDCl3):δ(ppm)1.49(s,9H),1.51-1.92(m,6H),3.45-3.65(m,2H),3.88(ddd,J=3.1,8.9,11.4Hz,1H),4.10-4.53(m,5H),4.73-4.86(m,3H),4.98(dd,J=6.2,14.6Hz,1H),5.21-5.26(m,1H),5.29-5.36(m,1H),5.94(ddt,J=5.9,10.3,17.3Hz,1H)。
步骤6:中间体7-烯丙氧基-2-(羟甲基)-5,8-桥亚甲基-4,8-二氢噻唑并[4,5-e]
[1,3]二氮杂卓-6-酮(2f)的制备
在0℃下,将双光气(74μL,0.61mmol)加入到中间体(2e)(370mg,0.87mmol)和TEA(0.18mL,1.3mmol)的DCM(9mL)溶液中。在0℃下搅拌混合物45min,然后加入MeSO3H(0.85mL,13.05mmol)的DCM(1mL)溶液。在0℃下1h后,加入TEA(2.4mL,17.4mmol)并在室温下搅拌混合物1h。用DCM稀释混合物,并用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩。通过硅胶柱色谱法(DCM/丙酮:10/0至2/8)对粗产物进行纯化,以得到中间体(2f)(163mg,0.61mmol,71%)。MS m/z([M+H]+)268。1H NMR(400MHz,CDCl3):δ(ppm)3.17(d,J=11.0Hz,1H),3.66(dd,J=2.9,11.1Hz,1H),4.29(d,J=16.8Hz,1H),4.30-4.43(m,2H),4.49(d,J=16.8Hz,1H),4.55(d,J=2.3Hz,1H),4.78(s,2H),5.22-5.27(m,1H),5.30(dq,J=1.4,17.2Hz,1H),5.88-5.99(m,1H)。
步骤7:中间体N-[(7-烯丙氧基-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e]
[1,3]二氮杂卓-2-基)甲基]-N-(N-叔丁氧基羰基甲脒基)氨基甲酸叔丁酯(2g)的制备
在氩气气氛和0℃下,将DTAD(48mg,0.21mmol)分批加入到中间体(2f)(50mg,0.17mmol)、N-(N-叔丁氧基羰基甲脒基(carbamimidoyl))氨基甲酸叔丁酯(54mg,0.21mmol)和PPh3(55mg,0.21mmol)的甲苯(1.2mL)溶液中。在室温下搅拌混合物2h,然后浓缩。通过硅胶柱色谱法(DCM/AcOEt:10/0至4/6)对残余物进行纯化,以得到中间体(2g)(40mg,0.08mmol,47%)。MS m/z([M+H]+)509。1H NMR(400MHz,CDCl3):δ(ppm)1.39(s,9H),1.49(s,9H),3.21(d,J=10.9Hz,1H),3.70(dd,J=2.9,11.0Hz,1H),4.32(d,J=16.8Hz,1H),4.35-4.48(m,2H),4.52(d,J=16.8Hz,1H),4.56(d,J=2.7Hz,1H),5.26-5.38(m,3H),5.49(d,J=16.0Hz,1H),5.92-6.04(m,1H),9.40-9.43(m,2H)。
步骤8:中间体三苯基-丙烯基膦[2-[[叔丁氧基羰基-(N-叔丁氧基羰基甲脒基)氨
基]甲基]-5,8-二甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮杂卓-7-基]硫酸盐(2h)
的制备
将AcOH(9μL,0.16mmol)和Pd(PPh3)4(45mg,0.04mmol)依次加入到中间体(2g)(40mg,0.08mmol)的无水DCM(0.8mL)溶液中。在室温下搅拌1h30min后,加入吡啶(0.8mL)和三氧化硫吡啶络合物(62mg,0.39mmol),并在室温下搅拌混合物过夜。用DCM稀释不均匀的混合物,并将固体滤掉。浓缩滤液,并通过快速硅胶色谱法(DCM/丙酮:10/0至0/10)进行纯化,以得到具有痕量POPh3的中间体(2h)(38mg,0.05mmol,58%)。MS m/z([M+H]+)549和303。
步骤9:[2-(胍基甲基)-5,8-二甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮
杂卓-7-基]磺酸(实施例2)的制备
在0℃下,将TFA(0.15mL)加入到中间体(2h)(38mg,0.05mmol)的DCM(0.15mL)溶液中。在0℃下搅拌混合物3h30min。由于反应不完全,因此加入TFA(0.15mL)并在0℃下再搅拌混合物1h30min(重复操作2次)。在0℃下,通过加入Et2O获得沉淀物并除去上清液(重复操作3次)。用ACN研磨残余物并除去上清液(重复操作2次)。过滤沉淀物,在真空下干燥,并通过C18柱色谱法(水/ACN:99/1至50/50)进行纯化。将含有期望化合物的部分合并,在氮气流下部分浓缩以除去ACN,冷冻并冻干以得到实施例2的两性离子化合物(2.1mg,0.006mmol,14%)。MS m/z([M-H]-)347。1H NMR(400MHz,D2O):δ(ppm)3.59(d,J=11.6Hz,1H),3.92(dd,J=3.0,11.6Hz,1H),4.50(d,J=16.8Hz,1H),4.59(d,J=16.8Hz,1H),4.78(s,2H),5.20(d,J=2.8Hz,1H)。19F NMR(377MHz,D2O):无氟。
实施例3:[2-(2-胍基乙基氨基甲酰基)-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并
[4,5-e][1,3]二氮杂卓-7-基]磺酸的合成
步骤1:中间体N-[2-[(7-烯丙氧基-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-
e][1,3]二氮杂卓-2-羰基)氨基]乙基]-N-(N-叔丁氧基羰基甲脒基)氨基甲酸叔丁酯(3a)
的制备
将DIPEA(0.23mL,1.33mmol)和HATU(243mg,0.64mmol)加入到中间体(1i)(150mg,0.53mmol)的DCM(3.5mL)溶液中。10min后,加入N-[N'-(2-氨基乙基)-N-叔丁氧基羰基-甲脒基]氨基甲酸叔丁酯(193mg,0.64mmol),并在室温下搅拌混合物4h。由于起始材料未完全消耗,因此加入HATU(60mg,0.16mmol)并再搅拌混合物40min,用DCM稀释混合物,并用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩。通过硅胶柱色谱法(DCM/AcOEt:10/0至7/3)和制备TLC(洗脱DCM/AcOEt:9/1)对粗产物进行两次纯化,以得到中间体(3a)(105mg,0.160mmol)。MS m/z([M+H]+)566。
步骤2:中间体三苯基-丙烯基膦[2-[2-[叔丁氧基羰基-(N-叔丁氧基羰基甲脒基)
氨基]乙基氨基甲酰基]-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮杂卓-
7-基]硫酸盐(3b)的制备
将AcOH(19μL,0.32mmol)和Pd(PPh3)4(92mg,0.06mmol)依次加入到中间体(3a)(105mg,0.16mmol)的无水DCM(1.6mL)溶液中。在室温下,搅拌混合物2h。然后加入吡啶(1.6mL)和三氧化硫吡啶络合物(127mg,0.80mmol),并在室温下搅拌混合物过夜。用DCM稀释不均匀的混合物,并将固体滤掉。浓缩滤液,并通过快速硅胶色谱法(DCM/丙酮:10/0至0/10)对粗产物进行纯化,以得到中间体(3b)(38mg,0.041mmol,26%)。MS m/z([M+H]+)606和303。
步骤3:[2-(2-胍基乙基氨基甲酰基)-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,
5-e][1,3]二氮杂卓-7-基]磺酸(实施例3)的制备
在0℃下,将TFA(0.4mL)加入到中间体(3b)(38mg,0.041mmol)的DCM(0.4mL)溶液中。在0℃下搅拌混合物7h,并在-20℃下搅拌18h。在0℃下,加入Et2O以得到沉淀物,并除去上清液(重复操作3次)。用ACN将残余物研磨两次,并每次除去上清液。研磨后,将所得到的固体在PTFE膜上进行过滤并在真空下干燥。通过C18柱色谱法(水/ACN:99/1至80/20)对粗产物进行纯化。将含有期望化合物的部分合并,在氮气流下部分浓缩以除去ACN,冷冻并冻干以得到实施例3的两性离子化合物(2mg,0.005mmol,13%)。MS m/z([M-H]-)404。1H NMR(400MHz,D2O):δ(ppm)3.45-3.51(m,2H),3.54-3.64(m,2H),3.65-3.73(m,1H),3.96(dd,J=3.0,11.7Hz,1H),4.58(d,J=16.9Hz,1H),4.65(d,J=16.9Hz,1H),5.29(d,J=2.8Hz,1H)。19F NMR(377MHz,D2O):无氟。
实施例4(比较):[2-((氨基甲基)-5,8-二甲基-6-氧代-4,8-二氢噻唑并[4,5-e]
[1,3]二氮杂卓-7-基]硫酸氢酯的合成
步骤1:中间体(7-烯丙氧基-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,
3]二氮杂卓-2-基)甲基甲磺酸酯(4a)的制备
在氩气气氛和0℃下,将TEA(0.15mL,1.12mmol)和Ms2O(130mg,0.75mmol)加入到中间体(2f)(100mg,0.37mmol)的DCM(1.9mL)溶液中。在0℃下搅拌混合物1h30min,用DCM稀释并用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩,以得到中间体(4a)(118mg),该中间体(4a)不经纯化用于下一步骤。MS m/z([M+H]+)346。
步骤2:中间体7-烯丙氧基-2-(叠氮基甲基)-5,8-桥亚甲基-4,8-二氢噻唑并[4,
5-e][1,3]二氮杂卓-6-酮(4b)的制备
在氩气气氛下,将NaN3(111mg,1.71mmol)加入到中间体(4a)(118mg)的DMF(1.1mL)溶液中。在60℃下搅拌混合物1h,用AcOEt稀释并用H2O和盐水洗涤。用Na2SO4干燥有机层,过滤,并在真空下浓缩,以得到中间体(4b)(68mg,0.23mmol,2步共63%),该中间体(4b)不经纯化用于下一步骤。MS m/z([M+H]+)293。
步骤3:中间体N-[(7-烯丙氧基-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e]
[1,3]二氮杂卓-2-基)甲基]氨基甲酸叔丁酯(4c)的制备
在氩气气氛下和0℃下,将1M PMe3的THF溶液(0.35mL,0.35mmol)加入到中间体(4b)(68mg)的THF(2.4mL)溶液中。在0℃下搅拌混合物45min,然后加入BOC-ON(86mg,0.35mmol)的THF(0.5mL)溶液。在0℃下搅拌混合物1h,然后浓缩。通过快速硅胶色谱法(DCM/丙酮:10/0至4/6)对残余物进行纯化,以得到中间体(4c)(51mg,57%)。MS m/z([M+H]+)367。1H NMR(400MHz,CDCl3):δ(ppm)1.46(s,9H),3.21(d,J=11.0Hz,1H),3.70(dd,J=2.9,11.0Hz,1H),4.33(d,J=16.8Hz,1H),4.33-4.50(m,3H),4.53(d,J=16.8Hz,1H),4.57(d,J=16.8Hz,1H),5.25-5.38(m,3H),5.93-6.04(m,1H)。
步骤4:中间体N-[(7-羟基-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]
二氮杂卓-2-基)甲基]氨基甲酸叔丁酯(4d)的制备
将AcOH(16μL,0.27mmol)和Pd(PPh3)4(79mg,0.07mmol)依次加入到中间体(4c)(50mg,0.13mmol)的无水DCM(1.4mL)溶液中。在室温下搅拌1h30min后,加入吡啶(1.4mL)和三氧化硫吡啶络合物(108mg,0.68mmol),并在室温下搅拌混合物过夜。用DCM稀释混合物,并将固体滤掉。浓缩滤液,并通过快速硅胶色谱法(DCM/丙酮:10/0至0/10)对残余物进行纯化,以得到中间体(4d)(75mg,0.10mmol,78%)。MS m/z([M-H]-)405。
步骤5:[2-((氨基甲基)-5,8-二甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮
杂卓-7-基]硫酸氢酯(实施例4)的制备
在0℃下,将TFA(0.3mL)加入到中间体(4d)(75mg,0.10mmol)的DCM(0.1mL)溶液中。在0℃下30min后,转化不完全。因此在0℃下加入TFA直到完全转化。在0℃下,通过加入Et2O获得沉淀物并除去上清液(重复操作3次)。用ACN研磨残余物并除去上清液(重复操作2次)。过滤固体,在真空下干燥,并通过C18柱色谱法(水/ACN:99/1至50/50)纯化两次。将含有期望化合物的部分合并,在氮气流下部分浓缩以除去ACN,冷冻并冻干以得到实施例4的两性离子化合物(3.8mg,0.012mmol,12%)。MS m/z([M-H]-)306。1H NMR(400MHz,D2O):δ(ppm)3.60(d,J=11.6Hz,1H),3.94(dd,J=3.0,11.6Hz,1H),4.54(d,J=16.9Hz,1H),4.57(s,2H),4.62(d,J=16.9Hz,1H),5.23(d,J=2.9Hz,1H)。19F NMR(377MHz,D2O):无氟。
实施例9:[反式-4-(二甲基氨基甲酰基)-2-(2-胍基乙基氨基甲酰基)-5,8-桥亚
甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮杂卓-7-基]硫酸氢酯的合成
步骤1:中间体7-[烯丙氧基-(2-硝基苯基)磺酰基-氨基]-2-(四氢吡喃-2-基氧基
甲基)-6,7-二氢-4H-噻唑并[4,5-c]吡啶-5-羧酸叔丁酯(9a)的制备
在情性气氛下,将DIAD(10.47g,51.82mmol)分批加入到中间体(2d)(16g,43.18mmol)、N-烯丙氧基-2-硝基-苯磺酰胺(13.38g,51.82mmol)和PPh3(13.59g,51.8mmol)的甲苯(308mL)溶液中。在室温下搅拌混合物16h,然后浓缩。通过硅胶柱色谱法(DCM/丙酮:10/0至8/2)对粗产物进行纯化,以得到中间体(9a)(20.1g,31.27mmol,72%)。MS m/z([M+H]+)611。1H NMR(400MHz,CDCl3):δ(ppm)1.45(s,9H),1.53-1.94(m,6H),3.34-3.63(m,2H),3.87(t,J=10.2Hz,1H),4.18(s,2H),4.33(d,J=17.2Hz,2H),4.67-4.87(m,2H),4.87-5.01(m,2H),5.08(d,J=10.2Hz,2H),5.32(s,1H),5.57(s,1H),7.67(d,J=7.8Hz,1H),7.75-7.85(m,2H),8.16(dd,J=7.9,1.5Hz,1H)。
步骤2:中间体N-烯丙氧基-N-[2-(羟甲基)-4,5,6,7-四氢噻唑并[4,5-c]吡啶-7-
基]-2-硝基-苯磺酰胺盐酸盐(9b)的制备
在情性气氛下,将中间体(9a)(20g,32.88mmol)稀释在4N HCl的二噁烷(312mL)溶液中。在室温下,搅拌反应混合物1h20min。过滤沉淀物。依次用二噁烷和Et2O洗涤固体,以得到中间体(9b)(15.1g,31.27mmol,95%)。MS m/z([M+H]+)427。1H NMR(400MHz,D2O):δ(ppm)3.64-3.73(m,1H),3.81(dd,J=3.5,14.0Hz,1H),3.90-3.99(m,1H),4.05(dd,J=6.3,11.9Hz,1H),4.30(dd,J=1.5,16.0Hz,1H),4.44(d,J=15.9Hz,1H),4.82(d,J=1.1Hz,2H),4.89-5.02(m,2H),5.37(ddd,J=5.3,10.3,17.0Hz,1H),5.67(s,1H),7.88(ddd,J=1.6,7.3,8.0Hz,1H),7.92-8.03(m,2H),8.20(dd,J=1.4,8.0Hz,1H)。
步骤3:中间体N-烯丙氧基-N-[2-[[叔丁基(二甲基)硅烷基]氧甲基]-4,5,6,7-四
氢噻唑并[4,5-c]吡啶-7-基]-2-硝基-苯磺酰胺(9c)的制备
在情性气氛下,将中间体(9b)(15.1g,32.6mmol)稀释在无水DCM(65.2mL)中。在0℃下,加入TBDMSCl(7.4g,48.9mmol)、TEA(13.6mL,97.8mmol)和DMAP(398mg,3.3mmol)。在室温下,搅拌混合物16h。在减压下将混合物浓缩至干。通过硅胶柱色谱法(DCM/丙酮:10/0至6/4)对粗产物进行纯化,以得到中间体(9c)(15.7g,28.46mmol,87%)。MS m/z([M+H]+)541。1H NMR(400MHz,CDCl3):δ(ppm)0.00(s,6H),0.82(s,9H),2.88(dd,J=4.7,14.6Hz,1H),3.02(s,1H),3.67(d,J=17.0Hz,1H),3.86(d,J=17.0Hz,1H),3.97(s,1H),4.31(dd,J=6.2,11.3Hz,1H),4.78(s,2H),4.92-5.04(m,3H),5.40-5.53(m,1H),7.51(dd,J=1.3,7.9Hz,1H),7.62(td,J=1.4,7.7Hz,1H),7.66-7.72(m,1H),8.01(dd,J=1.5,7.9Hz,1H)。
步骤4:中间体N-烯丙氧基-N-[2-[[叔丁基(二甲基)硅烷基]氧甲基]-6,7-二氢噻
唑并[4,5-c]吡啶-7-基]-2-硝基-苯磺酰胺(9d)的制备
在情性气氛下,在0℃下,将中间体(9c)(4.94g,9.1mmol)稀释在DCM(55.4mL)中。滴加NCS(1.6g,11.9mmol)的DCM(55.4mL)溶液。在0℃下搅拌2h后,滴加DIPEA(5.9mL,33.8mmol)并在室温下搅拌反应混合物16h。通过硅胶柱色谱法(DCM/丙酮:10/0至6/4)对粗产物进行纯化,以得到中间体(9d)(4.44g,8.24mmol,83%)。MS m/z([M+H]+)539。1H NMR(400MHz,CDCl3):δ(ppm)0.14(s,6H),0.96(s,9H),3.76-3.91(m,1H),4.02(bs,2H),4.37(dd,J=6.3,11.2Hz,1H),4.92(d,J=5.4Hz,2H),5.04-5.15(m,2H),5.55(m,2H),7.66(dd,J=1.3,7.9Hz,1H),7.73(td,J=1.3,7.7Hz,1H),7.82(td,J=1.4,7.7Hz,1H),8.07(d,J=7.9Hz,1H),8.40(s,1H)。
步骤5:中间体N-烯丙氧基-N-[2-[[叔丁基(二甲基)硅烷基]氧甲基]-4-氰基-4,
5,6,7-四氢噻唑并[4,5-c]吡啶-7-基]-2-硝基-苯磺酰胺(9e)的制备
在情性气氛下,在0℃下,将中间体(9d)(4.44g,8.24mmol)稀释在无水DCM(57mL)中。加入TMSCN(10.3mL,82.4mmol)。在室温下,搅拌反应混合物46h。在减压下将混合物浓缩至干。通过硅胶柱色谱法(DCM/丙酮:10/0至8/2)对粗产物进行纯化,以得到中间体(9e)(4.45g,7.9mmol,87%)。MS m/z([M+H]+)566。1H NMR(400MHz,CDCl3):δ(ppm)0.00(s,6H),0.79(s,9H),2.11(s,1H),3.21(d,J=13.9Hz,1H),3.95(s,1H),4.28(dd,J=6.2,11.3Hz,1H),4.69-4.80(m,2H),4.85(s,1H),4.86-4.97(m,2H),4.99(dd,J=1.9,3.5Hz,1H),5.32-5.46(m,1H),7.46-7.53(m,1H),7.60(td,J=1.3,7.7Hz,1H),7.68(td,J=1.5,7.7Hz,1H),7.96(dd,J=1.4,7.9Hz,1H)。
步骤6:中间体7-[烯丙氧基-(2-硝基苯基)磺酰基-氨基]-2-(羟甲基)-4,5,6,7-
四氢噻唑并[4,5-c]吡啶-4-羧酸甲酯(9f)的制备
在情性气氛下,在0℃下,将乙酰氯(7.8mL,110.2mmol)稀释在无水MeOH(20mL)中。在室温下搅拌2h后,加入中间体(9e)(4.45g,7.9mmol)的无水MeOH(9.8mL)溶液。将反应混合物在50℃下加热16h30min。在减压下将混合物浓缩至干。用DCM和饱和NaHCO3稀释残余物。用DCM萃取水性层。用Na2SO4干燥合并的有机层,蒸发至干,以得到中间体(9f)(3.55g,7.34mmol,83%)。MS m/z([M+H]+)485。
步骤7:中间体7-[烯丙氧基-(2-硝基苯基)磺酰基-氨基]-2-[[叔丁基(二甲基)硅
烷基]氧甲基]-4,5,6,7-四氢噻唑并[4,5-c]吡啶-4-羧酸甲酯(9g)的制备
使用实施例9中描述的过程(步骤3),通过快速硅胶色谱法(DCM/丙酮:100/0至60/40)进行纯化后,将中间体(9f)(3.55g,7.34mmol)转化为中间体(9g)(3.31g,5.5mmol,71%)。MS m/z([M+H]+)599.
步骤8:中间体O5-叔丁基O4-甲基7-[烯丙氧基-(2-硝基苯基)磺酰基-氨基]-2-
[[叔丁基(二甲基)硅烷基]氧甲基]-6,7-二氢-4H-噻唑并[4,5-c]吡啶-4,5-二羧酸酯(9h)
的制备
在情性气氛下,将中间体(9g)(3.31g,5.5mmol)稀释在无水DCM(55mL)中。依次加入DIPEA(1.25mL,7.19mmol)和Boc2O(1,57g,7.2mmol)。在室温下搅拌65h后,在减压下将混合物浓缩至干。通过硅胶柱色谱法(环己烷/EtOAc:10/0至0/10)对粗产物进行纯化,以得到中间体(9h)(3.52g,5.04mmol,87%)。MS m/z([M+H]+)699。1H NMR(400MHz,CDCl3):δ(ppm)0.00(d,J=3.7Hz,6H),0.83(s,9H),1.30(d,J=9.2Hz,9H),3.38-3.73(m,4H),4.00-4.48(m,3H),4.80(s,2H),4.85-5.08(m,2H),5.09-5.31(m,1H),5.31-5.76(m,2H),7.54(dd,J=8.3,11.5Hz,1H),7.60-7.76(m,2H),7.95-8.10(m,1H)。
步骤9:中间体O5-叔丁基O4-甲基7-(烯丙氧基氨基)-2-[[叔丁基(二甲基)硅烷
基]氧甲基]-6,7-二氢-4H-噻唑并[4,5-c]吡啶-4,5-二羧酸酯(9i)的制备
在情性气氛下,将中间体(9h)(3.52g,5.04mmol)稀释在无水ACN(34mL)中。依次加入苯硫酚(2.6g,25.2mmol)和K2CO3(5.22g,37.8mmol)。在室温下,搅拌反应混合物2h。在垫上过滤混合物,并用ACN洗涤垫。在减压下将滤液浓缩至干。通过硅胶柱色谱法(环己烷/EtOAc:10/0至7/3)对粗产物进行纯化,以得到中间体(9i)(2.59g,5.04mmol,95%)。MS m/z([M+H]+)514。1H NMR(400MHz,CDCl3):δ(ppm)0.00(d,J=1.4Hz,6H),0.82(s,9H),1.24-1.43(m,9H),3.32-3.43(m,1H),3.66(d,J=1.5Hz,3H),4.07-4.68(m,4H),4.80(m,2H),5.00-5.33(m,2H),5.36-5.70(m,1H),5.82(m,1H)。
步骤10:中间体反式-7-烯丙氧基-2-(羟甲基)-5,8-桥亚甲基-6-氧代-4,8-二氢
噻唑并[4,5-e][1,3]二氮杂卓-4-羧酸甲酯(9j)的制备
在情性气氛下,在0℃下,将中间体(9i)(2.59g,5.05mmol)稀释在无水DCM(51mL)中。加入TEA(1.06mL,7.58mmol)。滴加双光气(427μL,3.54mmol)。在0℃下搅拌45min后,滴加MeSO3H(4.92mL,75.77mmol)的DCM(5.6mL)溶液。在0℃下搅拌1h后,滴加TEA(14.08mL,101.03mmol)。在室温下,搅拌反应混合物1h。用DCM稀释反应混合物,并用H2O和盐水洗涤该溶液。用Na2SO4干燥有机层,过滤,并在真空下浓缩。通过硅胶柱色谱法(DCM/丙酮:10/0至5/5)对粗产物进行纯化,以得到中间体(9j)(1.195g,3.67mmol,73%)。MS m/z([M+H]+)326。1HNMR(400MHz,CDCl3):δ(ppm)3.64(dd,J=2.9,11.5Hz,1H),3.77(dd,J=0.8,11.6Hz,1H),3.88(s,3H),4.46(qdt,J=1.2,6.7,12.3Hz,2H),4.65(dd,J=0.7,2.9Hz,1H),4.91(s,2H),5.28(s,1H),5.30-5.47(m,2H),6.00-6.05(m,1H)。
步骤11:中间体反式-7-烯丙氧基-4-甲氧基羰基-5,8-桥亚甲基-6-氧代-4,8-二
氢噻唑并[4,5-e][1,3]二氮杂卓-2-羧酸(9k)的制备
在情性气氛下,将高碘酸(1.38g,6.06mmol)稀释在ACN(16mL)和水(1.2mL)中。加入氧化铬(VI)(14.3mg,0.14mmol)。在情性气氛下,在0℃下,将中间体(9j)(464mg,1.43mmol)稀释在ACN(16mL)中。在30min内滴加前一溶液。在室温下搅拌反应混合物1h。用DCM稀释反应混合物,并用10%柠檬酸水溶液、盐水洗涤溶液,用Na2SO4干燥,并在真空下浓缩,以得到中间体(9k)(305mg,0.89mmol,60%),该中间体(9k)不经进一步纯化用于下一步骤。MS m/z([M+H]+)340。
步骤12:中间体反式-7-烯丙氧基-2-[2-(叔丁氧基羰基氨基)乙基氨基甲酰基]-
5,8-二甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮杂卓-4-羧酸甲酯(9l)的制备
在情性气氛下,在0℃下,将中间体(9k)(305mg,0.89mmol)稀释在无水DMF(3.9mL)中。依次加入N-Boc-乙二胺(171μL,1.08mmol)、EDC(248mg,1.29mmol)、HOBt(166mg,1.08mmol)和DIPEA(470μL,2.7mmol)。在50℃下搅拌19h后,用EtOAc稀释混合物,并用盐水洗涤溶液。用Na2SO4干燥有机层,过滤,并在真空下浓缩。通过硅胶柱色谱法(DCM/丙酮:10/0至8/2)对粗产物进行纯化,以得到中间体(9l)(183mg,0.32mmol,35%)。MS m/z([M+H]+)482。1H NMR(400MHz,CDCl3):δ(ppm)1.44(s,9H),3.38(s,2H),3.56(qd,J=7.2,13.8Hz,2H),3.66(dd,J=2.9,11.7Hz,1H),3.79(dd,J=0.8,11.8Hz,1H),3.89(s,3H),4.46(qdt,J=1.2,6.6,12.2Hz,2H),4.62-4.75(m,1H),4.89(s,1H),5.30-5.47(m,3H),5.98-6.03(m,1H),7.49(s,1H)。
步骤13:中间体反式-7-烯丙氧基-2-[2-(叔丁氧基羰基氨基)乙基氨基甲酰基]-
5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮杂卓-4-羧酸(9m)的制备
在惰性气氛下,在0℃下,将中间体(9l)(183mg,0.32mmol)稀释在THF(1.7mL)和水(1.1mL)的混合物中。滴加1N LiOH溶液(319μL,0.32mmol)。在室温下1h后,在0℃下加入额外的1N LiOH(62μL,0.06mmol)。2h20min后,在0℃下加入额外的1N LiOH(62μL,0.06mmol)。在室温下再搅拌混合物1h,直到将中间体(9l)完全消耗。在0℃下,通过加入1N HCl至pH=2来淬灭混合物。用DCM萃取混合物。用Na2SO4干燥有机层,过滤,并在真空下浓缩,以得到中间体(9m)(149mg,0.32mmol,100%),该中间体(9m)不经进一步纯化用于下一步骤。MS m/z([M+H]+)468。
步骤14:中间体N-[2-[[反式-7-烯丙氧基-4-(二甲基氨基甲酰基)-5,8-桥亚甲
基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮杂卓-2-羰基]氨基]乙基]氨基甲酸叔丁酯
(9n)的制备
在情性气氛下,在0℃下,将中间体(9m)(199mg,0.43mmol)稀释在无水DMF(1.8mL)中。依次加入二甲胺盐酸盐(69mg,0.85mmol)、DIPEA(222μL,1.28mmol)和HATU(178mg,0.47mmol)。在室温下搅拌2h后,用EtOAc稀释反应混合物,并用盐水洗涤溶液。用Na2SO4干燥有机层,过滤,并在真空下浓缩。通过硅胶柱色谱法(DCM/丙酮:10/0至5/5)对粗产物进行纯化,以得到中间体(9n)(274mg,0.40mmol,94%)。MS m/z([M+H]+)495。1H NMR(400MHz,CDCl3):δ(ppm)1.34-1.49(m,9H),3.04(d,J=1.5Hz,3H),3.30(s,2H),3.34(d,J=1.5Hz,3H),3.44-3.55(m,3H),3.70(d,J=11.3Hz,1H),4.34-4.50(m,2H),4.67(t,J=2.0Hz,1H),5.30-5.44(m,3H),5.95-6.03(m,1H).
步骤15:中间体N-[2-[[反式-7-烯丙氧基-4-(二甲基氨基甲酰基)-5,8-桥亚甲
基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮杂卓-2-羰基]氨基]乙基]-N-(N-叔丁氧基
羰基甲脒基)氨基甲酸叔丁酯(9o)的制备
在0℃下,将TFA(1.73mL)加入到中间体(9n)(210mg,0.425mmol)的DCM(4.2mL)溶液中。在0℃下搅拌1h后,在减压下将混合物浓缩至干。将残余物稀释在无水THF(4.25mL)中。依次加入TEA(180μL,1.27mmol)和2-(三氟甲基磺酰基)胍(332mg,0.85mmol)。在室温下搅拌1h30min后,在减压下将混合物浓缩至干。通过硅胶柱色谱法(DCM/丙酮:10/0至7/3)对粗产物进行纯化,以得到中间体(9o)(152mg,0.23mmol,53%)。MS m/z([M+H]+)637。1H NMR(400MHz,CDCl3):δ(ppm)1.43(m,18H),2.98(s,3H),3.28(s,3H),3.45(m,2H),3.53-3.69(m,3H),3.73(d,J=11.4Hz,1H),4.37(qdt,J=1.2,6.6,12.4Hz,2H),4.60(d,J=2.6Hz,1H),5.21-5.38(m,3H),5.86-5.99(m,1H),7.23(s,1H),8.48(s,1H)。
步骤16:中间体烯丙基(三苯基)膦[反式-2-[2-[叔丁氧基羰基-(N-叔丁氧基羰基
甲脒基)氨基]乙基氨基甲酰基]-4-(二甲基氨基甲酰基)-5,8-桥亚甲基-6-氧代-4,8-二氢
噻唑并[4,5-e][1,3]二氮杂卓-7-基]硫酸盐(9p)的制备
将AcOH(27μL,0.48mmol)和Pd(PPh3)4(138mg,0.12mmol)依次加入到中间体(9o)(152mg,0.24mmol)的无水DCM(4.9mL)溶液中。在室温下2h20min后,加入额外的AcOH(1.5μL,0.026mmol)和Pd(PPh3)4(70mg,0.06mmol)。在室温下3h40min后,加入额外的AcOH(7μL,0.122mmol)。在室温下4h30min后,转化不完全,加入额外的苯硅烷(10.3μL,0.084mmol)。在室温下再搅拌混合物1h30min,直到将中间体(9o)完全消耗。然后加入吡啶(2.4mL)和三氧化硫吡啶络合物(190mg,1.19mmol),并在室温下搅拌混合物过夜。用DCM稀释不均匀的混合物,并将固体滤掉。浓缩滤液,并通过硅胶柱色谱(DCM/丙酮:10/0至0/10)对粗产物进行纯化,以得到中间体(9p)(100mg,0.10mmol,39%),该中间体(9p)不经进一步纯化用于下一步骤。MS m/z([M+H]+)677。
步骤17:[反式-4-(二甲基氨基甲酰基)-2-(2-胍基乙基氨基甲酰基)-5,8-桥亚甲
基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮杂卓-7-基]硫酸氢酯(实施例9)的合成
在0℃下,将TFA(0.455mL)加入到中间体(9p)(100mg,0.102mmol)的DCM(1.02mL)溶液中。在0℃下,将额外的TFA以每2h、每次150μL分四次加入。再搅拌混合物5h30min,直到将中间体(9p)完全转化。在Et2O中稀释混合物。过滤沉淀物并在Et2O和ACN中研磨。通过C18柱色谱法(水/ACN:99/1至90/10)对粗产物进行纯化。将感兴趣的部分合并,在真空下部分浓缩,冷冻并冻干,以得到实施例9(27mg,0.057mmol,42%)。MS m/z([M+H]+)477。1H NMR(400MHz,D2O):δ(ppm)2.99(s,3H),3.33(s,3H),3.39(dd,J=5.1,6.4Hz,2H),3.52-3.60(m,3H),3.74(dd,J=2.9,12.1Hz,1H),5.23(d,J=2.5Hz,1H),5.66(s,1H)。
实施例10:[N-[[反式-4-(二甲基氨基甲酰基)-5,8-桥亚甲基-6-氧代-7-磺酰氧
基-4,8-二氢噻吩并[2,3-e][1,3]二氮杂卓-3-基]甲基]甲脒基]2,2,2-三氟乙酸铵的合成
步骤1:中间体2-(4-溴-3-噻吩基)-N,N-二甲基-2-氧代-乙酰胺(10a)的制备
在-78℃下,在氮气气氛下,向3,4-二溴噻吩(10g,41.33mmol)的无水Et2O(100mL)溶液中滴加2.5M正丁基锂的己烷溶液(18.2mL,45.47mmol)。在-78℃下搅拌混合物20min,然后在-78℃下(通过套管)将该混合物加入到N,N-二甲基草氨酸乙酯(6.18mL,45.47mmol)的无水Et2O(100mL)溶液中。在-78℃下搅拌混合物30min。加入水(100mL)并在室温下搅拌混合物5min。将各层分离。用Et2O(100mL)萃取水性层。用Na2SO4干燥合并的有机层,并在真空下浓缩,以得到黄色油状物中间体(10a)(8.72g,33.26mmol,80%),该中间体(10a)不经进一步纯化而使用。MS m/z([M+H]+)262/264。1H NMR(400MHz,CDCl3):δ(ppm)3.01(s,3H),3.07(s,3H),7.36(d,J=3.5Hz,1H),8.25(d,J=3.5Hz,1H)。
步骤2:中间体2-(4-溴-3-噻吩基)-2-羟基-N,N-二甲基-乙酰胺(10b)的制备
在0℃下,将硼氢化钠(1.26g,33.26mmol)分批加入到中间体(10a)(8.72g,33.26mmol)的甲醇(100mL)溶液中。在0℃下搅拌混合物40min,然后加入水(50mL)。在真空下蒸发甲醇。用AcOEt(2×60mL)萃取所得溶液。用Na2SO4干燥合并的有机层,并在真空下浓缩。通过快速硅胶色谱法(环己烷/AcOEt:50/50至0/100)对残余物进行纯化,以得到白色固体中间体(10b)(7.51g,28.43mmol,85%mmol)。MS m/z([M+H]+)264/266。1H NMR(400MHz,CDCl3):δ(ppm)2.74(s,3H),3.05(s,3H),4.00(bs,1H),5.35(s,1H),7.18(d,J=3.4Hz,1H),7.30(d,J=3.4Hz,1H)。
步骤3:中间体2-(4-溴-3-噻吩基)-2-(2,2-二乙氧基乙基氨基)-N,N-二甲基-乙
酰胺(10c)的制备
在0℃下,将甲磺酸酐(7.43g,42.65mmol)加入到中间体(10b)(7.51g,28.43mmol)的DCM(120mL)和TEA(7.9mL,56.86mmol)的溶液中。在0℃下搅拌混合物1h。加入氨基乙醛二乙缩醛(8.47mL,58.28mmol)、TEA(7.9mL,56.86mmol)和四丁基碘化铵(2.1g,5.68mmol),并在室温下搅拌混合物过夜。在真空下浓缩混合物。将残余物溶解于MTBE(100mL)和饱和NaHCO3溶液(100mL)中。将各层分离。用MTBE(100mL)萃取水性层。合并有机层,用Na2SO4干燥,并在真空下浓缩。通过快速硅胶色谱法(DCM/丙酮:100/0至60/40)对残余物进行纯化,以得到中间体(10c)(10.08g,26.57mmol,93%)。MS m/z([M+H]+)379/381。1H NMR(400MHz,CDCl3):δ(ppm)1.10-1.27(m,6H),2.59(dd,J=5.8,12.1Hz,1H),2.80(dd,J=5.2,12.1Hz,1H),2.89(s,3H),2.97(s,3H),3.43-3.59(m,2H),3.60-3.73(m,2H),4.60(t,J=5.5Hz,1H),4.85(s,1H),7.27(d,J=3.5Hz,1H),7.28(d,J=3.5Hz,1H)。
步骤4:中间体3-溴-4-(二甲基氨基甲酰基)-7-羟基-6,7-二氢-4H-噻吩并[3,2-
c]吡啶-5-羧酸叔丁酯(10d)的制备
将中间体(10c)(10.08g,26.57mmol)在盐酸溶液(6M的水溶液,180mL)中的混合物在80℃下加热过夜。过滤混合物,并在真空下浓缩滤液。将残余物溶解于水(150mL)中,并小心地加入NaHCO3(17.8g,212.6mmol)。加入二碳酸二叔丁酯(8.12g,37.20mmol)的THF(150mL)溶液,并在室温下搅拌混合物过夜。在真空下蒸发THF。用MTBE(2×150mL)萃取水性溶液。合并有机层,用0.1M HC1水性溶液、盐水洗涤,用Na2SO4干燥并在真空下浓缩。通过快速硅胶色谱法(DCM/AcOEt:10/0至5/5)对残余物进行纯化,以得到淡黄色泡沫状中间体(10d)(6.07g,14.97mmol,56%,反式异构体和顺式异构体的混合物)。MS m/z([M+H]+)405/407。1H NMR(400MHz,CDCl3):δ(ppm)1.48和1.49(s,9H),2.96-2.99(m,3H),3.35-3.60(m,3.5H),4.33(d,J=14.4Hz,0.5H),4.08(dd,J=4.5,12.7Hz,0.5H),4.33(d,J=14.4Hz,0.5H),4.73-4.85(m,1H),5.92和6.12(2s,1H),7.19和7.23(2s,1H)。
步骤5:中间体3-溴-7-[叔丁基(二甲基)硅烷基]氧基-4-(二甲基氨基甲酰基)-6,
7-二氢-4H-噻吩并[3,2-c]吡啶-5-羧酸叔丁酯(10e)的制备
向中间体(10d)(6.07g,14.97mmol)的DMF(60mL)溶液中依次加入DMAP(183mg,1.50mmol)、咪唑(2.04g,29.95mmol)和叔丁基二甲基氯硅烷(3.38g,22.46mmol)。在室温下,搅拌混合物2h。加入水(100mL)。用MTBE(2×100mL)萃取混合物。合并有机层,用盐水(100mL)洗涤,用Na2SO4干燥并在真空下浓缩。通过快速硅胶色谱法(正庚烷/AcOEt 10/0至5/5)对残余物进行纯化,以得到无色油状物中间体(10e)(6.61g,12.72mmol,84%,非对映异构体的混合物)。MS m/z([M+Na]+)541/543,([M+H]+)519/521。1H NMR(400MHz,CDCl3):δ(ppm)0.13-0.20(m,6H),0.88-0.95(m,9H),1.48(s,9H),2.96和2.99(s,3H),3.37-3.51(m,3.5H),3.88(dd,J=3.0,13.9Hz,0.5H),4.11(dd,J=5.4,12.9Hz,0.5H),4.17(d,J=14.0Hz,0.5H),4.75(dd,J=5.4,10.1Hz,0.5H),4.85(dd,J=2.0,2.9Hz,0.5H),5.95和6.12(2s,1H),7.13和7.18(2s,1H)。
步骤6:中间体4-(二甲基氨基甲酰基)-7-羟基-3-乙烯基-6,7-二氢-4H-噻吩并
[3,2-c]吡啶-5-羧酸叔丁酯(10f)的制备
向中间体(10e)(1.0g,1.92mmol)的二噁烷(6.4mL)的脱气溶液中加入三丁基(乙烯基)锡(692mg,2.11mmol)和Pd(PPh3)4(111mg,0.10mmol)。将烧瓶密封,并在100℃下将混合物加热8h。过滤混合物,并在真空下浓缩滤液。通过快速硅胶色谱法(石油醚/AcOEt:10/0至5/5)对残余物进行纯化,以得到固体中间体(10f)(897mg,1.92mmol,99%,非对映异构体的混合物)。MS m/z([M+H])467。1H NMR(400MHz,CDCl3):δ(ppm)0.15-0.20(m,6H),0.91-0.95(m,9H),1.48-1.54(m,9H),2.94-2.97(m,3H),3.32-3.44(m,3H),3.82-4.19(m,2H),4.79-4.86(m,1H),5.14-5.20(m,1H),5.44-5.51(m,1H),6.01-6.17(m,1H),6.29-6.42(m,1H),7.16-7.18(m,1H)。
步骤7:中间体4-(二甲基氨基甲酰基)-3-甲酰基-7-羟基-6,7-二氢-4H-噻吩并
[3,2-c]吡啶-5-羧酸叔丁酯(10g)的制备
向中间体(10f)(787mg,1.69mmol)的THF/H2O(17mL/17mL)溶液中加入OsO4(4%水溶液)(215mL,0.03mmol)和NaIO4(905mg,4.22mmol)。在室温下,搅拌混合物5h。加入饱和Na2S2O3溶液,并用AcOEt将混合物萃取两次。合并有机层,用盐水洗涤,用Na2SO4干燥并在真空下浓缩。通过快速硅胶色谱法(DCM/AcOEt:10/0至6/4)对残余物进行纯化,以得到固体中间体(10g)(800mg,1.69mmol,99%)。MS m/z([M+H]+)469。
步骤8:中间体4-(二甲基氨基甲酰基)-7-羟基-3-(羟甲基)-6,7-二氢-4H-噻吩并
[3,2-c]吡啶-5-羧酸叔丁酯(10h)的制备
在情性气氛下,在0℃下向中间体(10g)(700mg,1.49mmol)的MeOH(13mL)溶液中加入NaBH4(80mg,2.09mmol)。在0℃下搅拌混合物30min。加入水,并在真空下蒸发MeOH。用AcOEt萃取混合物两次。合并有机层,用盐水洗涤,用Na2SO4干燥,并在真空下浓缩,以得到白色固体粗产物(10h)(560mg,1.19mmol,80%)。MS m/z([M+H]+)471。
步骤9:中间体3-(叠氮基甲基)-4-(二甲基氨基甲酰基)-7-羟基-6,7-二氢-4H-噻
吩并[3,2-c]吡啶-5-羧酸叔丁酯(10i)的制备
在-10℃下,向中间体(10h)(415mg,0.88mmol)的无水DCM(8.8mL)溶液中依次加入TEA(0.5mL,3.53mmol)和甲磺酸酐(460mg,2.64mmol)。在-10℃下搅拌混合物30min,并在室温下搅拌3h。加入饱和NaHCO3溶液,并用DCM将混合物萃取两次。合并有机层,用Na2SO4干燥,并在真空下浓缩。将残余物溶解于无水DMF(4.3mL)中,并加入叠氮化钠(256mg,3.9mmol)。在室温下搅拌混合物30min,然后倒入饱和NaCl溶液中。用AcOEt萃取混合物两次。用盐水洗涤有机层,用Na2SO4干燥,并在真空下浓缩,以得到粗产物中间体(10i)(509mg,<100%)。MSm/z([M+H]+)496。
步骤10:中间体3-(叠氮基甲基)-4-(二甲基氨基甲酰基)-7-羟基-6,7-二氢-4H-
噻吩并[3,2-c]吡啶-5-羧酸叔丁酯(10j)的制备
在0℃下、惰性气氛下,向中间体(10i)(430mg,0.87mmol)的无水THF(4.3mL)溶液中加入1M TBAF的THF溶液(l mL,1.04mmol)。在室温下搅拌混合物20min,然后向混合物中加入水。用AcOEt萃取水性层两次。合并有机层,用Na2SO4干燥,并在真空下浓缩。通过快速硅胶色谱法(DCM/丙酮:10/0至8/2)对残余物进行纯化,以得到白色固体中间体(10j)(330mg,0.86mmol,72%)。MS m/z([M+H]+)382。
步骤11:中间体7-(烯丙氧基氨基)-3-(叠氮基甲基)-4-(二甲基氨基甲酰基)-6,
7-二氢-4H-噻吩并[3,2-c]吡啶-5-羧酸叔丁酯(10k)的制备
在-78℃下,向中间体(10j)(236mg,0.62mmol)的DCM(6.2mL)溶液中加入TEA(0.30mL,2.16mmol)和甲磺酸酐(222mg,1.24mmol)。在-78℃下搅拌混合物50min。加入o-烯丙基羟胺90%的DCM(350g,4.33mol)溶液,并在室温下搅拌混合物4h。加入水。将各层分离。用DCM萃取水性层。合并有机层,用Na2SO4干燥,并在真空下浓缩。通过快速硅胶色谱法(正庚烷/AcOEt:10/0至6/4)对残余物进行纯化,以得到非对映异构体的混合物形式的中间体(10k)(158mg,0.36mmol,60%)。MS m/z([M+H]+)437。1H NMR(400MHz,CDCl3):δ(ppm)1.49-1.51(m,9H),3.0(s,3H),3.34(s,3H),3.65(d,J=14.0Hz,1H),4.05-4.55(m,5H),5.19-5.40(m,2H),5.73(d,J=8.0Hz,1H),5.90-6.02(m,1H),6.09-6.18(m,1H),6.38-6.85(m,1H),7.0-7.2(m,1H)。
步骤12:中间体反式-7-烯丙氧基-3-(2-叠氮基甲基)-5,8-桥亚甲基-N,N-二甲 基-6-氧代-4,8-二氢噻吩并[2,3-e][1,3]二氮杂卓-4-甲酰胺(10l)的制备在惰性气氛、0℃下,向中间体(10k)(155mg,0.36mmol)的无水DCM(2mL)溶液中加入TEA(0.1mL,0.71mmol)和双光气(34μL,0.278mmol)。在0℃下搅拌混合物2h。加入饱和NaHCO3溶液。用DCM萃取水性层。合并有机层,用Na2SO4干燥,并在真空下浓缩。将残余物溶解于二噁烷(0.5mL)中,并加入4N HCl的二噁烷(2mL,7.1mmol)溶液。在室温下搅拌混合物5h,然后在真空下浓缩。将残余物溶解于DCM(2mL)中,并加入TEA(0.2mL,0.73mmol)。在室温下,搅拌混合物过夜。加入水。用DCM萃取水性层。合并有机层,用Na2SO4干燥,并在真空下浓缩。通过快速硅胶色谱法(DCM/AcOEt:10/0至5/5)对残余物进行纯化,以得到作为反式异构体(25mg,0.07mmol,19%,反式异构体)和顺式异构体(8mg,0.02mmol,5.5%)的白色固体中间体(10l)。
反式异构体:MS m/z([M+H]+)363。1H NMR(400MHz,CDCl3):δ(ppm)3.04(s,3H),3.34(s,3H),3.48(dd,J=2.9,11.0Hz,1H),3.55(dd,J=0.8,11.1Hz,1H),4.08(dd,J=1.1,14.2Hz,1H),4.25(dd,J=0.7,14.1Hz,1H),4.30-4.54(m,3H),5.27-5.41(m,3H),6.03(ddt,J=6.3,10.3,16.9Hz,1H),7.09(s,1H)。
顺式异构体:MS m/z([M+H]+)363。1H NMR(400MHz,CDCl3):δ(ppm)3.06(s,3H),3.20(d,J=10.8Hz,1H),3.33(s,3H),3.76(dd,J=2.9,10.7Hz,1H),4.38-4.42(m,4H),4.44(d,J=2.8Hz,1H),5.18(s,1H),5.24-5.35(m,2H),6.00(ddt,J=6.3,10.3,16.7Hz,1H),7.05(d,J=0.9Hz,1H)。
步骤13:中间体N-[[[反式-7-烯丙氧基-4-(二甲基氨基甲酰基)-5,8-桥亚甲基-
6-氧代-4,8-二氢噻吩并[2,3-e][1,3]二氮杂卓-3-基]甲氨基]-(叔丁氧基羰基氨基)亚甲
基]氨基甲酸叔丁酯(10m)的制备
在0℃下,向中间体(10l)(25mg,0.07mmol)的无水THF(0.7mL)溶液中加入1M三甲基膦的THF溶液(0.1mL,0.1mmol)。在0℃下搅拌混合物2h。然后,在室温下加入TEA(21μL,0.15mmol)和1,3-二-叔丁氧羰基-2-(三氟甲基磺酰基)胍(35mg,0.09mmol),并搅拌混合物2h。在真空下浓缩混合物。通过快速硅胶色谱法(正庚烷/AcOEt:10/0至2/8)对残余物进行纯化,以得到白色固体中间体(10m)(25mg,0.04mmol,62%)。MS m/z([M+H]+)579。1H NMR(400MHz,CDCl3):δ(ppm)1.49(s,9H),1.51(s,9H),3.00(s,3H),3.31(s,3H),3.45(dd,J=2.9,11.0Hz,1H),3.58(d,J=11.0Hz,1H),3.99-4.29(m,2H),4.30-4.59(m,4H),5.14-5.47(m,2H),6.02(ddt,J=6.3,10.3,17.0Hz,1H),7.10(d,J=0.9Hz,1H),8.45(s,1H),11.46(s,1H)。
步骤14:中间体N-[(叔丁氧基羰基氨基)-[[反式-4-(二甲基氨基甲酰基)-7-羟
基-5,8-桥亚甲基-6-氧代-4,8-二氢噻吩并[2,3-e][1,3]二氮杂卓-3-基]甲氨基]亚甲基]
氨基甲酸叔丁酯(10n)的制备
向中间体(10m)(24mg,0.04mmol)的DCM(0.4mL)溶液中依次加入Pd(PPh3)4(24mg,0.02mmol)和AcOH(17μL,0.304mmol)。在室温下搅拌混合物45min。加入额外的Pd(PPh3)4(88mg,0.078mmol)和AcOH(5μL,0.08mmol)。再搅拌混合物50min。在真空下浓缩混合物。通过快速硅胶色谱法(DCM/丙酮:10/0至5/5)对残余物进行纯化,以得到中间体(10n)(29mg)。
步骤15:中间体N-[(叔丁氧基羰基氨基)-[[反式-4-(二甲基氨基甲酰基)-5,8-桥
亚甲基-6-氧代-7-磺基氧基-4,8-二氢噻吩并[2,3-e][1,3]二氮杂卓-3-基]甲氨基]亚甲
基]氨基甲酸叔丁酯(10o)的制备
将中间体(10n)的吡啶(400μL)溶液在三氧化硫吡啶络合物(33mg,0.2mmol)存在下于40℃下加热2h。在真空下浓缩混合物。将残余物在DCM中研磨并过滤。在真空下浓缩滤液。通过快速硅胶色谱法(DCM/丙酮:10/0至0/10)对残余物进行纯化,以得到中间体(10o)(22mg,0.036mmol,89.5%)。MS m/z([M+H]+)619。MS m/z([M-H]-)617。
步骤16:[N-[[反式-4-(二甲基氨基甲酰基)-5,8-桥亚甲基-6-氧代-7-磺基氧基-
4,8-二氢噻吩并[2,3-e][1,3]二氮杂卓-3-基]甲基]甲脒基]2,2,2-三氟乙酸铵(实施例
10)的制备
将中间体(10o)(22mg,0.036mmol)在DCM(0.4mL)和TFA(3.3mL)中的混合物在0℃下搅拌6h。用Et2O稀释混合物,并除去上清液(两次)。固体用ACN研磨并过滤。用ACN洗涤固体,并在P2O5存在下真空干燥,以得到为TFA盐的实施例10(6mg,0.030mmol,36%)。MS m/z([M+H]+)419。1H NMR(400MHz,DMSO-d6):δ(ppm)2.93(s,3H),3.26(s,3H),3.48(dd,J=3.0,11.2Hz,1H),3.95(dd,J=4.2,15.7Hz,1H),4.12(dd,J=6.4,15.8Hz,1H),4.81(d,J=2.7Hz,1H),5.35(s,1H),7.28(s,1H),7.74(d,J=6.0Hz,1H)。
实施例11:[(反式-4-(二甲基氨基甲酰基)-3-(2-胍基乙基)-5,8-桥亚甲基-6-氧
代-4,8-二氢噻吩并[2,3-e][1,3]二氮杂卓-7-基]硫酸氢酯的合成
步骤1:中间体7-[叔丁基(二甲基)硅烷基]氧基-4-(二甲基氨基甲酰基)-3-(2-四
氢吡喃-2-基氧乙基)-6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-羧酸叔丁酯(11a)的制备
向中间体(10e)(1.35g,2.60mmol)的甲苯(15mL)和水(5mL)的脱气溶液中加入2-(四氢-2H-吡喃-2-基氧基)乙基三氟硼酸钾(613mg,2.60mmol)、碳酸铯(2.54g,7.79mmol)、RuPhos(121mg,0.26mmol)和乙酸钯(II)(29mg,0.13mmol)。将烧瓶密封,并在95℃下将混合物加热5h。将混合物冷却至室温并加入水。将各层分离。用甲苯萃取水性层。用盐水洗涤合并的有机层,用Na2SO4干燥,并在真空下浓缩。通过快速硅胶色谱法(环己烷/AcOEt:10/0至5/5)对残余物进行纯化,以得到黄色油状物中间体(11a)(1.21g,2.12mmol,81%)。MS m/z([M+Na]+)591。
步骤2:中间体4-(二甲基氨基甲酰基)-7-羟基-3-(2-四氢吡喃-2-基氧乙基)-6,
7-二氢-4H-噻吩并[3,2-c]吡啶-5-羧酸叔丁酯(11b)的制备
在0℃下、惰性气氛下,向中间体(11a)(890mg,1.56mmol)的无水THF溶液中加入1MTBAF的THF溶液(2.35mL,2.35mmol)。在0℃下搅拌混合物2.5h,然后在真空下浓缩。通过快速硅胶色谱法(DCM/丙酮:10/0至7/3)对残余物进行纯化,以得到黄色油状物中间体(11b)(761mg,定量)。MS m/z([M+H]+)455。
步骤3:中间体7-(烯丙氧基氨基)-4-(二甲基氨基甲酰基)-3-(2-四氢吡喃-2-基
氧乙基)-6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-羧酸叔丁酯(11c)的制备
在-78℃下,向中间体(11b)(755mg,1.66mmol)的DCM(10mL)溶液中加入TEA(0.68mL,4.98mmol)和甲磺酸酐(434mg,2.49mmol)。在-78℃下搅拌混合物45min。加入50%的o-烯丙基羟胺的乙醚(1.14g,8.30mmol)溶液,并在室温下搅拌混合物2.5h。加入水。将各层分离。用DCM萃取水性层。合并有机层,用Na2SO4干燥,并在真空下浓缩。通过快速硅胶色谱法(DCM/丙酮:10/0至8/2)对残余物进行纯化,以得到黄色油状物中间体(11c)(603mg,1.18mmol,71%)。MS m/z([M+Na]+)532,m/z([M+H]+)510。
步骤4:中间体7-(烯丙氧基氨基)-4-(二甲基氨基甲酰基)-3-(2-羟乙基)-6,7-二
氢-4H-噻吩并[3,2-c]吡啶-5-羧酸叔丁酯(11d)的制备
将中间体(11c)(443mg,0.87mmol)和PPTS(328mg,1.30mmol)在甲醇(12mL)中的混合物回流1h。过滤混合物,并在真空下浓缩滤液。通过快速硅胶色谱法(DCM/丙酮:10/0至8/2)对残余物进行纯化,以得到无色油状物中间体(11d)(250mg,0.58mmol,67%)。MS m/z([M+H]+)426。
步骤5:中间体7-(烯丙氧基氨基)-3-(2-叠氮基乙基)-4-(二甲基氨基甲酰基)-6,
7-二氢-4H-噻吩并[3,2-c]吡啶-5-羧酸叔丁酯(11e)的制备
在0℃下,向中间体(11d)(200mg,0.47mmol)的无水DCM(10mL)溶液中依次加入DIPEA(0.123mL,0.705mmol)和甲磺酰氯(44μL,0.564mmol)。在0℃下搅拌混合物1h。加入水。将各层分离。用DCM萃取水性层。合并有机层,用Na2SO4干燥,并在真空下浓缩。将残余物溶解于无水DMF(2.5mL)中,并加入叠氮化钠(61mg,0.94mmol)。在50℃下将混合物加热过夜,然后倒入饱和NaHCO3溶液中。用AcOEt萃取混合物两次。用盐水洗涤有机层,用Na2SO4干燥,并在真空下浓缩。通过快速硅胶色谱法(DCM/丙酮:10/0至7/3)对残余物进行纯化,以得到无色油状物中间体(11e)(143mg,0.32mmol,67%,异构体混合物)。MS m/z([M+Na]+)473,m/z([M+H]+)451。1H NMR(400MHz,CDCl3):δ(ppm)1.47和1.48(2s,9H),2.50-2.74(m,2H),2.97(s,3H),3.19-3.62(m,6H),4.12-4.57(m,4H),5.11-5.42(m,2H),5.85-6.12(m,2H),6.91和6.96(2s,1H)。
步骤6:中间体反式-7-烯丙氧基-3-(2-叠氮基乙基)-5,8-桥亚甲基-N,N-二甲基- 6-氧代-4,8-二氢噻吩并[2,3-e][1,3]二氮杂卓-4-甲酰胺(11f)的制备在惰性气氛、0℃下,向中间体(11e)(179mg,0.397mmol)的无水DCM(5mL)溶液中加入TEA(83μL,0.596mmol)和双光气(34μL,0.278mmol)。在0℃下搅拌混合物40min。加入饱和NaHCO3溶液(5mL)。用DCM萃取水性层。合并有机层,用Na2SO4干燥,并在真空下浓缩。将4N HCl的二噁烷溶液(3.97mL,15.89mmol)加入到残余物中,并在室温下搅拌混合物2h,然后在真空下浓缩。将残余物溶解于DCM(5mL)中,并加入TEA(0.277mL,1.98mmol)。在室温下,搅拌混合物过夜。加入水。用DCM萃取水性层。合并有机层,用Na2SO4干燥,并在真空下浓缩。通过快速硅胶色谱法(环己烷/AcOEt:5/5至0/10)对残余物进行纯化,以得到作为反式异构体(70mg,0.185mmol,46%)和顺式异构体(40mg,0.106mmol,26%)的白色固体中间体(11f)。
反式异构体:MS m/z([M+Na]+)399,m/z([M+H]+)377。1H NMR(400MHz,CDCl3):δ(ppm)2.51(t,J=7.4Hz,2H),3.03(s,3H),3.34(s,3H),3.36-3.53(m,3H),3.56(d,J=11.0Hz,1H),4.34-4.49(m,3H),5.23(s,1H),5.25-5.41(m,2H),5.93-6.08(m,1H),6.93(s,1H)。
顺式异构体:MS m/z([M+Na]+)399,m/z([M+H]+)377。1H NMR(400MHz,CDCl3):δ(ppm)2.51-2.64(m,1H),2.66-2.75(m,1H),3.03(s,3H),3.13(d,J=10.7Hz,1H),3.32(s,3H),3.35-3.44(m,1H),3.51-3.61(m,1H),3.73(dd,J=2.9,10.7Hz,1H),4.39(d,J=6.3Hz,2H),4.42(d,J=2.8Hz,1H),5.12(s,1H),5.20-5.37(m,2H),5.89-6.07(m,1H),6.92(s,1H)。
步骤7:中间体N-[2-[反式-7-烯丙氧基-4-(二甲基氨基甲酰基)-5,8-桥亚甲基-
6-氧代-4,8-二氢噻吩并[2,3-e][1,3]二氮杂卓-3-基]乙基]-N-(N-叔丁氧基羰基甲脒基)
氨基甲酸叔丁酯(11g)的制备
在0℃下,向中间体(11f)(70mg,0.186mmol)的无水THF(2mL)溶液中加入1M三甲基膦的THF溶液(0.28mL,0.28mmol)。在室温下搅拌混合物1h,然后加入额外的1M三甲基膦的THF溶液(0.34mL,0.34mmol)。继续搅拌3h。加入TEA(52μL,0.37mmol)和1,3-二-叔丁氧羰基-2-(三氟甲基磺酰基)胍(95mg,0.242mmol),并搅拌混合物30min。在真空下浓缩混合物。通过快速硅胶色谱法(环己烷/AcOEt:8/2至2/8)对残余物进行纯化,以得到无色油状物中间体(11g)(90mg,0.152mmol,81%)。MS m/z([M+H]+)593。1H NMR(400MHz,CDCl3):δ(ppm)1.47(s,9H),1.49(s,9H),2.40-2.60(m,2H),3.02(s,3H),3.33(s,3H),3.44(dd,J=2.9,11.0Hz,1H),3.57(d,J=11.0Hz,1H),3.59-3.67(m,2H),4.30-4.52(m,3H),5.16(s,1H),5.22-5.44(m,2H),5.89-6.10(m,1H),6.94(s,1H),8.38(s,1H),11.45(s,1H)。
步骤8:中间体烯丙基(三苯基)膦[反式-3-[2-[叔丁氧基羰基(乙亚氨基)氨基]乙
基]-4-(二甲基氨基甲酰基)-5,8-桥亚甲基-6-氧代-4,8-二氢噻吩并[2,3-e][1,3]二氮杂
卓-7-基]硫酸盐(11h)的制备
向中间体(11g)(90mg,0.152mmol)的DCM(2mL)溶液中依次加入Pd(PPh3)4(88mg,0.078mmol)和AcOH(17μL,0.304mmol)。在室温下搅拌混合物45min。加入额外的Pd(PPh3)4(88mg,0.078mmol)和AcOH(17μL,0.304mmol)。继续搅拌45min。加入额外的Pd(PPh3)4(44mg,0.038mmol)和AcOH(9μL,0.15mmol)。继续搅拌1h。在真空下浓缩混合物。将残余物与甲苯共蒸发两次。将残余物在吡啶(2mL)和三氧化硫吡啶络合物(121mg,0.76mmol)存在下于40℃下加热2h。在真空下浓缩混合物。将残余物在DCM中研磨并过滤。在真空下浓缩滤液。通过快速硅胶色谱法(DCM/丙酮:10/0至0/10)对残余物进行纯化,以得到中间体(11h)(90mg,0.096mmol,63%)。MS m/z([M-H]-)631。
步骤9:[(反式-4-(二甲基氨基甲酰基)-3-(2-胍基乙基)-5,8-桥亚甲基-6-氧代-
4,8-二氢噻吩并[2,3-e][1,3]二氮杂卓-7-基]硫酸氢酯(实施例11)的制备
将中间体(11h)(90mg,0.096mmol)在DCM(0.2mL)和TFA(2mL)中的混合物在0℃下搅拌5h。加入正庚烷,并真空下浓缩混合物。该操作进行两次。通过C18反相色谱法(水/乙腈:10/0至0/10)对残余物进行纯化。将含有目标化合物的部分合并,冷冻并冻干。将残余物在水(1.5mL)中搅拌10min。过滤固体。用水冲洗固体,并在P2O5存在下真空干燥,以得到为白色固体的实施例11(13.3mg,0.030mmol,32%)。MS m/z([M+H]+)433。MS m/z([M-H]-)431。MSm/z([M-H]-)431.1H NMR(400MHz,DMSO-d6):δ(ppm)2.34-2.45(m,1H),2.50-2.57(m,1H),2.93(s,3H),3.29(s,3H),3.31-3.37(m,3H),3.46(dd,J=3.0,11.2Hz,1H),4.78(d,J=2.7Hz,1H),5.29(s,1H),7.15(s,1H),7.40(t,J=5.8Hz,1H)。
生物学活性
针对细菌隔离群(bacterial isolates),化合物的MIC及其与头孢他啶的协同作
用的MIC(表1和表2)
针对基因分型的细菌菌株,对单独使用或与β-内酰胺头孢他啶组合使用的本发明的化合物进行了评价。在测定中,通过临床实验室标准研究所(CLSI-M7-A7)的微量肉汤稀释法来测定所述化合物的MIC或固定浓度的所述化合物与头孢他啶的MIC。简而言之,根据本发明的化合物单独制备在DMSO中,并在无菌聚苯乙烯板(Corning,3788)上进行点样(每次2μL)。化合物和头孢他啶的稀释液制备在DMSO中,并在无菌聚苯乙烯板(Corning,3788)上点样(每次1μL)。在阳离子调节的Mueller-Hinton肉汤(Beckton-Dickinson)中将对数期的细菌悬浮液调节至5×105cfu/mL的最终密度,并加入到各个孔(98μL)中。在35℃下、在环境空气中,将微孔板孵育16-20h。化合物的MIC定义为通过目测读取的所述化合物阻止细菌生长的最低浓度。在各化合物浓度下,头孢他啶的MIC定义为通过目测读取的孢他啶阻止细菌生长的最低浓度。
表1:MIC测定中使用的细菌种类
表2:头孢他啶(CAZ)以及化合物单独使用时的MIC(μg/mL)
表3:头孢他啶(CAZ)单独使用时以及CAZ/化合物组合使用时的MIC
Claims (11)
1.一种化合物及其外消旋体、对映异构体、非对映异构体、几何异构体或其药学上可接受的盐,
所述化合物选自:
[2-(2-氨基乙基氨基甲酰基)-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮杂卓-7-基]磺酸,
[2-(胍基甲基)-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮杂卓-7-基]磺酸,
[2-(2-胍基乙基氨基甲酰基)-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮杂卓-7-基]磺酸,
[反式-4-(二甲基氨基甲酰基)-2-(2-胍基乙基氨基甲酰基)-5,8-桥亚甲基-6-氧代-4,8-二氢噻唑并[4,5-e][1,3]二氮杂卓-7-基]硫酸氢酯,
[N-[[反式-4-(二甲基氨基甲酰基)-5,8-桥亚甲基-6-氧代-7-磺酰氧基-4,8-二氢噻吩并[2,3-e][1,3]二氮杂卓-3-基]甲基]甲脒基]2,2,2-三氟乙酸铵,和
[(反式-4-(二甲基氨基甲酰基)-3-(2-胍基乙基)-5,8-桥亚甲基-6-氧代-4,8-二氢噻吩并[2,3-e][1,3]二氮杂卓-7-基]硫酸氢酯。
2.一种药物组合物,所述药物组合物包含至少一种根据权利要求1所述的化合物和药学上可接受的赋形剂。
3.根据权利要求2所述的药物组合物,所述药物组合物进一步包含选自抗菌化合物的至少一种化合物。
4.根据权利要求2或3所述的药物组合物,所述药物组合物包含:根据权利要求1所述的化合物和一种或多种β-内酰胺化合物。
5.根据权利要求3所述的药物组合物,其中,所述抗菌化合物选自氨基糖苷类、β-内酰胺类、甘氨酰环素类、四环素类、喹诺酮类、氟喹诺酮类、糖肽类、脂肽类、大环内酯类、酮内酯类、林可酰胺类、链阳性菌素、噁唑烷酮类、多粘菌素类。
6.根据权利要求4所述的药物组合物,其中,所述β-内酰胺化合物选自青霉素、头孢菌素、青霉烯类、碳青霉烯类、单菌霉素。
7.一种药物组合物,所述药物组合物包含至少一种根据权利要求1所述的化合物和头孢他啶。
8.一种套件,所述套件包括第一药物组合物和至少一种第二药物组合物,所述第一药物组合物为根据权利要求2至3中任一项所述的药物组合物,所述第二药物组合物为根据权利要求2至3中任一项所述的药物组合物。
9.一种套件,所述套件包括:
包含至少一种根据权利要求1所述的化合物的药物组合物;和
包含头孢他啶的药物组合物。
10.根据权利要求1所述的化合物或根据权利要求3至7中任一项所述的药物组合物在制备用于治疗或预防由埃希氏菌属、肠杆菌属或铜绿假单胞菌所引起的细菌感染的药物中的用途。
11.根据权利要求8或9所述的套件在制备用于通过同时、间隔或依次给药至有需要的患者来治疗或预防由埃希氏菌属、肠杆菌属或铜绿假单胞菌所引起的细菌感染的药物中的用途。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004052891A1 (fr) * | 2002-12-06 | 2004-06-24 | Aventis Pharma S.A. | Composes heterocyclique, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens et inhibiteurs de beta-lactamases |
WO2017109025A1 (en) * | 2015-12-23 | 2017-06-29 | Mutabilis | Heterocyclic compounds and their use in preventing or treating bacterial infections |
CN107438614A (zh) * | 2015-04-03 | 2017-12-05 | 拜欧蒂姆公司 | 杂环化合物及它们在预防或治疗细菌感染中的应用 |
EP3300736A1 (en) * | 2016-09-30 | 2018-04-04 | Mutabilis | Composition comprising antibiotic compound and an heterocyclic compound and their use in preventing or treating bacterial infections |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2825705B1 (fr) | 2001-06-08 | 2005-05-20 | Aventis Pharma Sa | Nouveaux composes heterocycliques, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens |
US7439253B2 (en) * | 2002-12-06 | 2008-10-21 | Novexel | Heterocyclic compounds, their preparation and their use as medicaments, in particular as antibacterials and beta-lactamase inhibitors |
FR2936798B1 (fr) * | 2008-10-03 | 2012-09-28 | Novexel | Nouveaux composes heterocycliques azotes, leur preparation et leur utilisation comme medicaments antibacteriens. |
WO2014141132A1 (en) | 2013-03-14 | 2014-09-18 | Naeja Pharmaceutical Inc. | NEW HETEROCYCLIC COMPOUNDS AND THEIR USE AS ANTIBACTERIAL AGENTS AND β-LACTAMASE INHIBITORS |
-
2018
- 2018-07-30 EP EP18306026.8A patent/EP3604315A1/en not_active Withdrawn
-
2019
- 2019-07-29 US US17/263,662 patent/US11865118B2/en active Active
- 2019-07-29 WO PCT/EP2019/070368 patent/WO2020025543A1/en unknown
- 2019-07-29 EP EP19745612.2A patent/EP3830094A1/en active Pending
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004052891A1 (fr) * | 2002-12-06 | 2004-06-24 | Aventis Pharma S.A. | Composes heterocyclique, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens et inhibiteurs de beta-lactamases |
CN107438614A (zh) * | 2015-04-03 | 2017-12-05 | 拜欧蒂姆公司 | 杂环化合物及它们在预防或治疗细菌感染中的应用 |
WO2017109025A1 (en) * | 2015-12-23 | 2017-06-29 | Mutabilis | Heterocyclic compounds and their use in preventing or treating bacterial infections |
EP3300736A1 (en) * | 2016-09-30 | 2018-04-04 | Mutabilis | Composition comprising antibiotic compound and an heterocyclic compound and their use in preventing or treating bacterial infections |
TW201815390A (zh) * | 2016-09-30 | 2018-05-01 | 法商木塔比利斯公司 | 包含抗生素化合物及雜環化合物之組合物及其於預防或治療細菌感染之用途 |
Non-Patent Citations (1)
Title |
---|
临床研究中的抗生素新药;张婷婷等;《国外医药抗生素分册》;第34卷(第6期);第241-244、249页 * |
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CN112513049A (zh) | 2021-03-16 |
TW202007689A (zh) | 2020-02-16 |
JP2021533114A (ja) | 2021-12-02 |
US11865118B2 (en) | 2024-01-09 |
WO2020025543A1 (en) | 2020-02-06 |
AR115867A1 (es) | 2021-03-03 |
EP3604315A1 (en) | 2020-02-05 |
US20210275542A1 (en) | 2021-09-09 |
EP3830094A1 (en) | 2021-06-09 |
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