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1. 发明申请

US20110143359A1 Method for Identifying Drug-Sensitizing Antisense DNA Fragments and Use Thereof 审中-公开
标题翻译：鉴定药物敏感反义DNA片段及其用途的方法
公开(公告)号：US20110143359A1
公开(公告)日：2011-06-16
申请号：US13033128
申请日：2011-02-23
申请人： Robert Haselbeck , Mark Hilgers , Karen Shaw , Vickie Brown-Driver , Kedar GC , John M. Finn , Mark Stidham
发明人： Robert Haselbeck , Mark Hilgers , Karen Shaw , Vickie Brown-Driver , Kedar GC , John M. Finn , Mark Stidham
IPC分类号： C12Q1/68
CPC分类号： C12N15/111 , C12N15/1137 , C12N2310/11 , C12N2320/11 , C12N2330/30 , C12Y101/01158 , C12Y105/01003 , C12Y205/01031 , C12Y601/0101
摘要： The invention provides a method for generating and selecting drug-sensitizing antisense DNA fragments. In one embodiment, the method includes identifying a gene of interest using knowledge of bacterial physiology, biochemistry, genetics, genomics, and other means. The method includes PCR amplification of a gene of interest using genomic DNA as a template; fragmentation of the DNA by sonication or other means; selecting DNA fragments no longer than 400 base pairs; ligating the DNA fragments into a suitable expression plasmid with a selectable marker; transforming the plasmids containing the DNA fragments into the organism from which the gene of interest originated; and selecting clones from transformed cells that show a phenotypic difference of the clone grown in the presence of the inducer relative to the phenotype in the absence of inducer.
摘要翻译：本发明提供了生产和选择药物敏化反义DNA片段的方法。在一个实施方案中，该方法包括使用细菌生理学，生物化学，遗传学，基因组学和其他方法的知识来鉴定感兴趣的基因。该方法包括使用基因组DNA作为模板对感兴趣的基因进行PCR扩增; 通过超声处理或其他方法破碎DNA; 选择不超过400个碱基对的DNA片段; 将DNA片段连接到具有选择性标记的合适的表达质粒中; 将含有DNA片段的质粒转化为目标基因来源的生物体; 并选择来自转化细胞的克隆，其在不存在诱导物的情况下显示在诱导物存在下生长的克隆相对于表型的表型差异。

2. 发明授权

US07910337B2 Method for identifying drug-sensitizing antisense DNA fragments and use thereof 有权
标题翻译：用于鉴定药物敏化反义DNA片段的方法及其用途
公开(公告)号：US07910337B2
公开(公告)日：2011-03-22
申请号：US11636394
申请日：2006-12-08
申请人： Robert Haselbeck , Mark Hilgers , Karen Shaw , Vickie Brown-Driver , Kedar Gc , John M. Finn , Mark Stidham
发明人： Robert Haselbeck , Mark Hilgers , Karen Shaw , Vickie Brown-Driver , Kedar Gc , John M. Finn , Mark Stidham
IPC分类号： C12P19/34 , C07H21/04 , C12N15/63 , C07K16/00
CPC分类号： C12N15/111 , C12N15/1137 , C12N2310/11 , C12N2320/11 , C12N2330/30 , C12Y101/01158 , C12Y105/01003 , C12Y205/01031 , C12Y601/0101
摘要： The invention provides a method for generating and selecting drug-sensitizing antisense DNA fragments. In one embodiment, the method includes identifying a gene of interest using knowledge of bacterial physiology, biochemistry, genetics, genomics, and other means. The method includes PCR amplification of a gene of interest using genomic DNA as a template; fragmentation of the DNA by sonication or other means; selecting DNA fragments no longer than 400 base pairs; ligating the DNA fragments into a suitable expression plasmid with a selectable marker; transforming the plasmids containing the DNA fragments into the organism from which the gene of interest originated; and selecting clones from transformed cells that show a phenotypic difference of the clone grown in the presence of the inducer relative to the phenotype in the absence of inducer.
摘要翻译：本发明提供了生产和选择药物敏化反义DNA片段的方法。在一个实施方案中，该方法包括使用细菌生理学，生物化学，遗传学，基因组学和其他方法的知识来鉴定感兴趣的基因。该方法包括使用基因组DNA作为模板对感兴趣的基因进行PCR扩增; 通过超声处理或其他方法破碎DNA; 选择不超过400个碱基对的DNA片段; 将DNA片段连接到具有选择性标记的合适的表达质粒中; 将含有DNA片段的质粒转化为目标基因来源的生物体; 并选择来自转化细胞的克隆，其在不存在诱导物的情况下显示在诱导物存在下生长的克隆相对于表型的表型差异。

3. 发明申请

US20070218481A1 Method for identifying drug-sensitizing antisense DNA fragments and use thereof 有权
标题翻译：用于鉴定药物敏化反义DNA片段的方法及其用途
公开(公告)号：US20070218481A1
公开(公告)日：2007-09-20
申请号：US11636394
申请日：2006-12-08
申请人： Robert Haselbeck , Mark Hilgers , Karen Shaw , Vickie Brown-Driver , Kedar Gc , John M. Finn , Mark Stidham
发明人： Robert Haselbeck , Mark Hilgers , Karen Shaw , Vickie Brown-Driver , Kedar Gc , John M. Finn , Mark Stidham
IPC分类号： C12Q1/68 , C07H21/02 , C12N15/74 , C12N1/21
CPC分类号： C12N15/111 , C12N15/1137 , C12N2310/11 , C12N2320/11 , C12N2330/30 , C12Y101/01158 , C12Y105/01003 , C12Y205/01031 , C12Y601/0101
摘要： The invention provides a method for generating and selecting drug-sensitizing antisense DNA fragments. In one embodiment, the method includes identifying a gene of interest using knowledge of bacterial physiology, biochemistry, genetics, genomics, and other means. The method includes PCR amplification of a gene of interest using genomic DNA as a template; fragmentation of the DNA by sonication or other means; selecting DNA fragments no longer than 400 base pairs; ligating the DNA fragments into a suitable expression plasmid with a selectable marker; transforming the plasmids containing the DNA fragments into the organism from which the gene of interest originated; and selecting clones from transformed cells that show a phenotypic difference of the clone grown in the presence of the inducer relative to the phenotype in the absence of inducer.
摘要翻译：本发明提供了生产和选择药物敏化反义DNA片段的方法。在一个实施方案中，该方法包括使用细菌生理学，生物化学，遗传学，基因组学和其他方法的知识来鉴定感兴趣的基因。该方法包括使用基因组DNA作为模板对感兴趣的基因进行PCR扩增; 通过超声处理或其他方法破碎DNA; 选择不超过400个碱基对的DNA片段; 将DNA片段连接到具有选择性标记的合适的表达质粒中; 将含有DNA片段的质粒转化为目标基因来源的生物体; 并选择来自转化细胞的克隆，其在不存在诱导物的情况下显示在诱导物存在下生长的克隆相对于表型的表型差异。

4. 发明授权

US08298543B2 Identification and application of antibiotic synergy 有权
标题翻译：鉴定和应用抗生素协同作用
公开(公告)号：US08298543B2
公开(公告)日：2012-10-30
申请号：US13102856
申请日：2011-05-06
申请人： Vickie Brown-Driver , Kedar GC , John M. Finn , Robert Haselbeck , Mark Hilgers , Karen Shaw , Mark Stidham
发明人： Vickie Brown-Driver , Kedar GC , John M. Finn , Robert Haselbeck , Mark Hilgers , Karen Shaw , Mark Stidham
IPC分类号： A61K31/00 , A61K31/43 , A61K39/00
CPC分类号： A61K31/43 , A61K31/545 , A61K39/40 , A61K45/06 , Y02A50/469 , Y02A50/47 , Y02A50/482 , Y02A50/484 , A61K2300/00
摘要： The present invention provides a pharmaceutical composition useful for treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof, an antibacterially effective combination of a β-lactam antibiotic and an inhibitor of any bacterial peptidoglycan biosynthesis enzyme, especially GlmU, GlmU, MurA, MurB, MurC, MurD, MurE, MurF, MurG, MraY, and UppS. Further provided is a method of discovering synergists for antibiotics including: a) expressing in a cell an antisense nucleic acid against a nucleic acid encoding a gene product so as to reduce the activity or amount of the gene product in the cell, thereby producing a cell sensitized to an antibiotic; b) characterizing the sensitization of the cell to the antibiotic and selecting pairs of antibiotics and genes that result in antibiotic efficacy at one-fifth or less the concentration required in the absence of the antisense gene; c) screening for chemical compounds that inhibit the gene product corresponding to the selected synergistic gene; and d) selecting or creating chemical analogs that inhibit the gene product corresponding to the selected synergistic gene such that the inhibition occurs in the bacteria.
摘要翻译：本发明提供了一种可用于治疗人和动物细菌感染的药物组合物，其包括对有需要的人或动物施用抗生素有效组合的β-内酰胺抗生素和任何细菌肽聚糖生物合成酶的抑制剂，特别是 GlmU，GlmU，MurA，MurB，MurC，MurD，MurE，MurF，MurG，MraY，和UppS。进一步提供了发现抗生素增效剂的方法，包括：a）在细胞中表达反义核酸对编码基因产物的核酸，以降低细胞中基因产物的活性或数量，从而产生细胞对抗生素敏感; b）表征细胞对抗生素的致敏性，并选择一组抗生素和基因，其抗生素效力为不存在反义基因所需浓度的五分之一或更低。 c）筛选抑制与所选协同基因相对应的基因产物的化合物; 和d）选择或产生抑制与所选择的协同基因相对应的基因产物的化学类似物，使得在细菌中发生抑制。

5. 发明申请

US20110294774A1 IDENTIFICATION AND APPLICATION OF ANTIBIOTIC SYNERGY 有权
标题翻译：抗生素合成的鉴定与应用
公开(公告)号：US20110294774A1
公开(公告)日：2011-12-01
申请号：US13102856
申请日：2011-05-06
申请人： Vickie Brown-Driver , Kedar GC , John M. Finn , Robert Haselbeck , Mark Hilgers , Karen Shaw , Mark Stidham
发明人： Vickie Brown-Driver , Kedar GC , John M. Finn , Robert Haselbeck , Mark Hilgers , Karen Shaw , Mark Stidham
IPC分类号： A61K31/545 , A61P31/04 , A61K31/43 , A61K31/431 , A61K31/546 , A61K31/5365
CPC分类号： A61K31/43 , A61K31/545 , A61K39/40 , A61K45/06 , Y02A50/469 , Y02A50/47 , Y02A50/482 , Y02A50/484 , A61K2300/00
摘要： The present invention provides a pharmaceutical composition useful for treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof, an antibacterially effective combination of a β-lactam antibiotic and an inhibitor of any bacterial peptidoglycan biosynthesis enzyme, especially GlmU, GlmU, MurA, MurB, MurC, MurD, MurE, MurF, MurG, MraY, and UppS. Further provided is a method of discovering synergists for antibiotics including: a) expressing in a cell an antisense nucleic acid against a nucleic acid encoding a gene product so as to reduce the activity or amount of the gene product in the cell, thereby producing a cell sensitized to an antibiotic; b) characterizing the sensitization of the cell to the antibiotic and selecting pairs of antibiotics and genes that result in antibiotic efficacy at one-fifth or less the concentration required in the absence of the antisense gene; c) screening for chemical compounds that inhibit the gene product corresponding to the selected synergistic gene; and d) selecting or creating chemical analogs that inhibit the gene product corresponding to the selected synergistic gene such that the inhibition occurs in the bacteria.
摘要翻译：本发明提供了一种可用于治疗人和动物细菌感染的药物组合物，其包括对有需要的人或动物施用抗生素有效组合的β-内酰胺抗生素和任何细菌肽聚糖生物合成酶的抑制剂，特别是 GlmU，GlmU，MurA，MurB，MurC，MurD，MurE，MurF，MurG，MraY和UppS。进一步提供了发现抗生素增效剂的方法，包括：a）在细胞中表达反义核酸对抗编码基因产物的核酸，以降低细胞中基因产物的活性或数量，从而产生细胞对抗生素敏感; b）表征细胞对抗生素的致敏性，并选择一组抗生素和基因，其抗生素效力为不存在反义基因所需浓度的五分之一或更低。 c）筛选抑制与所选协同基因相对应的基因产物的化合物; 和d）选择或产生抑制与所选择的协同基因相对应的基因产物的化学类似物，使得在细菌中发生抑制。

6. 发明授权

US08021665B2 Identification and application of antibiotic synergy 有权
标题翻译：鉴定和应用抗生素协同作用
公开(公告)号：US08021665B2
公开(公告)日：2011-09-20
申请号：US11636379
申请日：2006-12-08
申请人： Vickie Brown-Driver , Kedar GC , John M. Finn , Robert Haselbeck , Mark Hilgers , Karen Shaw , Mark Stidham
发明人： Vickie Brown-Driver , Kedar GC , John M. Finn , Robert Haselbeck , Mark Hilgers , Karen Shaw , Mark Stidham
IPC分类号： A61K31/00 , A61K31/43 , A61K39/00
CPC分类号： A61K31/43 , A61K31/545 , A61K39/40 , A61K45/06 , Y02A50/469 , Y02A50/47 , Y02A50/482 , Y02A50/484 , A61K2300/00
摘要： The present invention provides a pharmaceutical composition useful for treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof, an antibacterially effective combination of a β-lactam antibiotic and an inhibitor of any bacterial peptidoglycan biosynthesis enzyme, especially GlmU, GlmU, MurA, MurB, MurC, MurD, MurE, MurF, MurG, MraY, and UppS. Further provided is a method of discovering synergists for antibiotics including: a) expressing in a cell an antisense nucleic acid against a nucleic acid encoding a gene product so as to reduce the activity or amount of the gene product in the cell, thereby producing a cell sensitized to an antibiotic; b) characterizing the sensitization of the cell to the antibiotic and selecting pairs of antibiotics and genes that result in antibiotic efficacy at one-fifth or less the concentration required in the absence of the antisense gene; c) screening for chemical compounds that inhibit the gene product corresponding to the selected synergistic gene; and d) selecting or creating chemical analogs that inhibit the gene product corresponding to the selected synergistic gene such that the inhibition occurs in the bacteria.
摘要翻译：本发明提供了一种可用于治疗人和动物细菌感染的药物组合物，其包括对有需要的人或动物施用抗生素有效组合的β-内酰胺抗生素和任何细菌肽聚糖生物合成酶的抑制剂，特别是 GlmU，GlmU，MurA，MurB，MurC，MurD，MurE，MurF，MurG，MraY和UppS。进一步提供了发现抗生素增效剂的方法，包括：a）在细胞中表达反义核酸对抗编码基因产物的核酸，以降低细胞中基因产物的活性或数量，从而产生细胞对抗生素敏感; b）表征细胞对抗生素的致敏性，并选择一组抗生素和基因，其抗生素效力为不存在反义基因所需浓度的五分之一或更低。 c）筛选抑制与所选协同基因相对应的基因产物的化合物; 和d）选择或产生抑制与所选择的协同基因相对应的基因产物的化学类似物，使得在细菌中发生抑制。

7. 发明申请

US20070178111A1 Identification and application of antibiotic synergy 有权
标题翻译：鉴定和应用抗生素协同作用
公开(公告)号：US20070178111A1
公开(公告)日：2007-08-02
申请号：US11636379
申请日：2006-12-08
申请人： Vickie Brown-Driver , Kedar GC , John Finn , Robert Haselbeck , Mark Hilgers , Karen Shaw , Mark Stidham
发明人： Vickie Brown-Driver , Kedar GC , John Finn , Robert Haselbeck , Mark Hilgers , Karen Shaw , Mark Stidham
IPC分类号： A61K48/00 , A61K39/40 , A61K31/43 , A61K31/545
CPC分类号： A61K31/43 , A61K31/545 , A61K39/40 , A61K45/06 , Y02A50/469 , Y02A50/47 , Y02A50/482 , Y02A50/484 , A61K2300/00
摘要： The present invention provides a pharmaceutical composition useful for treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof, an antibacterially effective combination of a β-lactam antibiotic and an inhibitor of any bacterial peptidoglycan biosynthesis enzyme, especially GlmU, GlmU, MurA, MurB, MurC, MurD, MurE, MurF, MurG, MraY, and UppS. Further provided is a method of discovering synergists for antibiotics including: a) expressing in a cell an antisense nucleic acid against a nucleic acid encoding a gene product so as to reduce the activity or amount of the gene product in the cell, thereby producing a cell sensitized to an antibiotic; b) characterizing the sensitization of the cell to the antibiotic and selecting pairs of antibiotics and genes that result in antibiotic efficacy at one-fifth or less the concentration required in the absence of the antisense gene; c) screening for chemical compounds that inhibit the gene product corresponding to the selected synergistic gene; and d) selecting or creating chemical analogs that inhibit the gene product corresponding to the selected synergistic gene such that the inhibition occurs in the bacteria.
摘要翻译：本发明提供了用于治疗人和动物细菌感染的药物组合物，其包括对有需要的人或动物施用β-内酰胺抗生素和任何细菌肽聚糖生物合成酶的抑制剂的抗菌有效组合，特别是GlmU ，GlmU，MurA，MurB，MurC，MurD，MurE，MurF，MurG，MraY和UppS。进一步提供了发现抗生素增效剂的方法，包括：a）在细胞中表达反义核酸对抗编码基因产物的核酸，以降低细胞中基因产物的活性或数量，从而产生细胞对抗生素敏感; b）表征细胞对抗生素的致敏性，并选择一组抗生素和基因，其抗生素效力为不存在反义基因所需浓度的五分之一或更低。 c）筛选抑制与所选协同基因相对应的基因产物的化合物; 和d）选择或产生抑制与所选择的协同基因相对应的基因产物的化学类似物，使得在细菌中发生抑制。

8. 发明授权

US08835445B2 Dihydrofolate reductase inhibitors 有权
标题翻译：二氢叶酸还原酶抑制剂
公开(公告)号：US08835445B2
公开(公告)日：2014-09-16
申请号：US13151683
申请日：2011-06-02
申请人： Zhiyong Chen , Christopher J. Creighton , Mark Cunningham , John Finn , Mark Hilgers , Michael Jung , Lucy Aguirre Kohnen , Thanh Lam , Xiaoming Li , Mark Stidham , Les Tari , Michael Trzoss , Junhu Zhang
发明人： Zhiyong Chen , Christopher J. Creighton , Mark Cunningham , John Finn , Mark Hilgers , Michael Jung , Lucy Aguirre Kohnen , Thanh Lam , Xiaoming Li , Mark Stidham , Les Tari , Michael Trzoss , Junhu Zhang
IPC分类号： A01N43/54 , A61K31/517 , C07D239/72 , C07D401/00
CPC分类号： C07D401/14 , C07D239/95 , C07D417/14
摘要： The present disclosure provides compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein R5, R6 and Z are as described herein. The disclosure also provides pharmaceutical compositions thereof; and methods for inhibiting DHFR activity; and methods for treating cell proliferative diseases, autoimmune disease, inflammatory disease or bacterial, fungal or parasitic infection by administering a compound of Formula I.
摘要翻译：本公开提供式I化合物或其药学上可接受的盐，其中R 5，R 6和Z如本文所述。本公开还提供其药物组合物; 和抑制DHFR活性的方法; 以及通过给予式I化合物治疗细胞增殖性疾病，自身免疫疾病，炎性疾病或细菌，真菌或寄生虫感染的方法。

9. 发明申请

US20120136014A1 DIHYDROFOLATE REDUCTASE INHIBITORS 有权
标题翻译：二氢叶酸还原酶抑制剂
公开(公告)号：US20120136014A1
公开(公告)日：2012-05-31
申请号：US13151683
申请日：2011-06-02
申请人： Zhiyong Chen , Christopher J. Creghton , Mark Cunningham , John Finn , Mark Hilgers , Michael Jung , Lucy Aguirre Kohnen , Thanh Lam , Xiaoming Li , Mark Stidham , Les Tari , Michael Trzoss , Junhu Zhang
发明人： Zhiyong Chen , Christopher J. Creghton , Mark Cunningham , John Finn , Mark Hilgers , Michael Jung , Lucy Aguirre Kohnen , Thanh Lam , Xiaoming Li , Mark Stidham , Les Tari , Michael Trzoss , Junhu Zhang
IPC分类号： A61K31/517 , C07D401/14 , C07D239/72 , A61P31/10 , A61P33/00 , A61P31/04 , A61P29/00 , C12N9/99 , C07D417/14
CPC分类号： C07D401/14 , C07D239/95 , C07D417/14
摘要： The present disclosure provides compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein R5, R6 and Z are as described herein. The disclosure also provides pharmaceutical compositions thereof; and methods for inhibiting DHFR activity; and methods for treating cell proliferative diseases, autoimmune disease, inflammatory disease or bacterial, fungal or parasitic infection by administering a compound of Formula I.
摘要翻译：本公开提供式I化合物或其药学上可接受的盐，其中R 5，R 6和Z如本文所述。本公开还提供其药物组合物; 和抑制DHFR活性的方法; 以及通过给予式I化合物治疗细胞增殖性疾病，自身免疫疾病，炎性疾病或细菌，真菌或寄生虫感染的方法。

10. 发明授权

US09481675B2 Gyrase inhibitors 有权
标题翻译：促旋酶抑制剂
公开(公告)号：US09481675B2
公开(公告)日：2016-11-01
申请号：US13394985
申请日：2010-09-10
申请人： Christopher J Creighton , Leslie William Tari , Zhiyong Chen , Mark Hilgers , Thanh To Lam , Xiaoming Li , Michael Trzoss , Junhu Zhang , John Finn , Daniel Bensen
发明人： Christopher J Creighton , Leslie William Tari , Zhiyong Chen , Mark Hilgers , Thanh To Lam , Xiaoming Li , Michael Trzoss , Junhu Zhang , John Finn , Daniel Bensen
IPC分类号： C07D487/04 , C07D519/00 , C07D471/04 , C07D487/16 , C07D491/048 , C07D513/04
CPC分类号： C07D519/00 , C07D471/04 , C07D471/16 , C07D487/04 , C07D487/16 , C07D491/048 , C07D513/04
摘要： Novel gyrase inhibitors and related compositions and methods are useful for impeding bacterial growth. Compounds of Formula I are disclosed: wherein Y is N or CH; Z is N or CR5; R5 is H, a substituted or unsubstituted hydrocarbyl residue (1-3C) containing 0-2 heteroatoms selected from O, S and N, or is an inorganic residue; L is O, S, NR7, or CR8R9; R7 is H or C1-3 alkyl; R8 and R9 are each independently H or C1-3 alkyl; R2 is H, a hydrocarbyl residue (1-40C) containing 0-10 heteroatoms selected from O, S and N optionally substituted with an inorganic residue; R4 is H, an inorganic residue, or a hydrocarbyl residue (1-30C) containing 0-12 heteroatoms selected from O, S and N and containing 0-10 inorganic residues, wherein R5 and R4 together may join to form a fused ring; and R6 is selected from the group consisting of H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, halo C1-5 alkyl, halo C2-5 alkenyl, halo C2-5 alkynyl, C1-5 hydroxyalkyl, C1-5 alkyl chloride, C2-5 alkenyl chloride, and C2-5 alkynyl chloride; or a pharmaceutically-acceptable salt, ester, or prodrug thereof.
摘要翻译：新型促旋酶抑制剂和相关组合物和方法可用于阻止细菌生长。公开了式（I）的化合物：式（I），其中Y是N或CH; Z为N或CR5; R5是H，含有0-2个选自O，S和N的杂原子的取代或未取代的烃基残基（1-3C），或是无机残基; L是O，S，NR7或CR8R9; R7是H或C1-3烷基; R 8和R 9各自独立地为H或C 1-3烷基; R2是H，含有0-10个选自O，S和N的杂原子的烃基残基（1-40℃），任选被无机残基取代; R4是H，无机残基或含有0-12个选自O，S和N的杂原子并含有0-10个无机残基的烃基残基（1-30C），其中R 5和R 4可以连接形成稠环; 并且R 6选自H，C 1-5烷基，C 2-5烯基，C 2-5炔基，卤代C 1-5烷基，卤素C 2-5烯基，卤代C 2-5炔基，C 1-5羟基烷基，C 1 -5烷基氯，C2-5烯基氯和C2-5炔基氯; 或其药学上可接受的盐，酯或前药。

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