CN109415297A - 新型抗生素 - Google Patents
新型抗生素 Download PDFInfo
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- CN109415297A CN109415297A CN201780041303.XA CN201780041303A CN109415297A CN 109415297 A CN109415297 A CN 109415297A CN 201780041303 A CN201780041303 A CN 201780041303A CN 109415297 A CN109415297 A CN 109415297A
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- 230000003115 biocidal effect Effects 0.000 title description 7
- -1 aryl compound Chemical class 0.000 claims abstract description 103
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 208000027096 gram-negative bacterial infections Diseases 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 96
- 238000002360 preparation method Methods 0.000 claims description 52
- 229910003827 NRaRb Inorganic materials 0.000 claims description 46
- 241000894006 Bacteria Species 0.000 claims description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 150000002148 esters Chemical class 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 208000015181 infectious disease Diseases 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 13
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 239000005864 Sulphur Substances 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 9
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- 150000001299 aldehydes Chemical class 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
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- 239000012988 Dithioester Substances 0.000 claims description 6
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- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
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- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 4
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- POCJOGNVFHPZNS-ZJUUUORDSA-N (6S,7R)-2-azaspiro[5.5]undecan-7-ol Chemical compound O[C@@H]1CCCC[C@]11CNCCC1 POCJOGNVFHPZNS-ZJUUUORDSA-N 0.000 claims description 3
- XNMWTPWQILTFRI-UHFFFAOYSA-N 2-chloro-N-[[4-[2-(N-cyano-S-methylsulfinimidoyl)phenyl]phenyl]methyl]-N-[(4-methylphenyl)methyl]benzamide Chemical compound Cc1ccc(CN(Cc2ccc(cc2)-c2ccccc2\S(C)=N\C#N)C(=O)c2ccccc2Cl)cc1 XNMWTPWQILTFRI-UHFFFAOYSA-N 0.000 claims description 3
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- 125000005277 alkyl imino group Chemical group 0.000 claims description 3
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- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 3
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- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 claims description 3
- 150000004659 dithiocarbamates Chemical class 0.000 claims description 3
- 125000005022 dithioester group Chemical group 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 150000007857 hydrazones Chemical class 0.000 claims description 3
- 150000002466 imines Chemical class 0.000 claims description 3
- 150000002513 isocyanates Chemical class 0.000 claims description 3
- POCJOGNVFHPZNS-UHFFFAOYSA-N isonitramine Natural products OC1CCCCC11CNCCC1 POCJOGNVFHPZNS-UHFFFAOYSA-N 0.000 claims description 3
- FMXOEQQPVONPBU-UHFFFAOYSA-N methylidene(dioxido)azanium Chemical compound [O-][N+]([O-])=C FMXOEQQPVONPBU-UHFFFAOYSA-N 0.000 claims description 3
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 3
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 claims description 3
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical compound [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 claims description 3
- 150000002923 oximes Chemical class 0.000 claims description 3
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 claims description 3
- 239000004576 sand Substances 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 150000003457 sulfones Chemical class 0.000 claims description 3
- 150000003462 sulfoxides Chemical class 0.000 claims description 3
- 150000003566 thiocarboxylic acids Chemical class 0.000 claims description 3
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- 125000005323 thioketone group Chemical group 0.000 claims description 3
- 150000005215 alkyl ethers Chemical class 0.000 claims description 2
- 150000008051 alkyl sulfates Chemical class 0.000 claims description 2
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- 150000008301 phosphite esters Chemical class 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 claims description 2
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- 125000005843 halogen group Chemical group 0.000 claims 4
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 1
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- 239000000126 substance Substances 0.000 description 13
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- 238000003786 synthesis reaction Methods 0.000 description 1
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- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
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- 108091005703 transmembrane proteins Proteins 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- 210000001215 vagina Anatomy 0.000 description 1
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- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A61K31/13—Amines
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- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/49—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton
- C07C211/50—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton with at least two amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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Abstract
新型芳基化合物或其药学上可接受的盐,及其用于治疗革兰氏阴性细菌感染的用途。
Description
技术领域
本发明涉及新型芳基化合物。更具体地,本发明涉及新型芳基化合物及其作为抗微生物剂用于治疗由革兰氏阴性细菌造成的细菌感染或疾病的用途。
背景技术
由于革兰氏阴性细菌造成的感染的流行的增加,导致严重或致命的疾病,具有抗微生物特性的化合物最近已经吸引了极大的兴趣。对一些抗微生物制剂具有耐受性的细菌菌株的出现也有所增加。
新型抗微生物化合物具有对这些类型的治疗耐受细菌非常有效的潜力。先前未暴露于抗微生物制剂的病原体可能对治疗具有很少或没有耐受性。
上述背景技术讨论仅旨在促使理解本发明。该讨论并非认可或承认所提及的任何材料在本申请的优先权日时是公知常识的一部分。
发明简述
本发明提供式(I)化合物:
式(I)
其中;
V共价键合至W;
W共价键合至Z;
V是六元芳香环;
n是0,1,2,3或4;
所述或每个W独立地选自以下基团:
C2-4烷基;C2-4取代烷基;C2E-烯烃,V和Z在1和2位;C2Z-烯烃,V和Z在1和2位;C2-炔烃;
所述或每个Z独立地选自以下基团:
其中Wn是W1、W2或者所述或每个W中的一个;
并且其中;
W1、W2或者所述或每个W中的至少一个上的R1,R2,R3,R4或R5中的至少一个选自以下基团:
式的烷基膦,式的烷基胺;
其中Rf和Rg各自独立地选自:
H,C1-C8烷基;m是1-8;
并且其中;
其余R1,R2,R3,R4或R5各自独立地选自:
选自F,Cl,Br,I的卤素;C1-8烷基;式-C(O)OH的羧酸;式-(CH2)nC(O)OH的烷基羧酸;式-C(S)OH的硫代羧酸;式-(CH2)nC(S)OH的烷基硫代羧酸;式-C(O)ORa的酯;式-(CH2)nC(O)ORa的烷基酯;式-C(S)ORa的硫代酯;式-(CH2)nC(S)ORa的烷基硫代酯;式-C(S)SRa的二硫酯;式-(CH2)nC(S)SRa的烷基二硫酯;式-C(O)NRaRb的酰胺;式-(CH2)nC(O)NRaRb的烷基酰胺;式-C(S)NRaRb的硫代酰胺;式-(CH2)nC(S)NRaRb的烷基硫代酰胺;式-C(O)H的醛;式-(CH2)nC(O)H的烷基醛;式-C(S)H的硫醛;式-(CH2)nC(S)H的烷基硫醛;式-C(O)Ra的酮;式-(CH2)nC(O)Ra的烷基酮;式-C(S)Ra的硫酮;式-(CH2)nC(S)Ra的烷基硫酮;式之一的缩醛;式之一的烷基缩醛;式之一的烷基二硫代缩醛;式-NRaRb的胺;式-(CH2)nNRaRb的烷基胺;式-N+RaRbRc G-的铵盐;式-(CH2)nN+RaRbRc G-的烷基铵盐;式-NRaC(O)Rb的酰胺;式-(CH2)nNRaC(O)Rb的烷基酰胺;式-NRaC(S)Rb的硫代酰胺;式之一的烷基硫代酰胺;式之一的亚胺;式之一的烷基亚胺;式的胍;式的烷基胍;式的脒;式的烷基脒;式-CN的腈(氰基);式-(CH2)nCN的烷基腈;式-N+C-的异腈:式-(CH2)nN+C-的烷基异腈;式-OCN的氰酸酯;式-(CH2)nOCN的烷基氰酸酯;式-N=C=O的异氰酸酯;式-(CH2)nN=C=O的烷基异氰酸酯;式-SCN的硫氰酸酯;式-(CH2)nSCN的烷基硫氰酸酯;式-N=C=S的异硫氰酸酯;式-(CH2)nN=C=S的烷基异硫氰酸酯;式-N=NH的偶氮;式-(CH2)nN=NH的烷基偶氮;式-NO2的硝基;式-(CH2)nNO2的烷基硝基;式-O-N=O的亚硝酸酯;式-(CH2)nO-N=O的烷基亚硝酸酯;式-N=O的亚硝基(nitriso);式-(CH2)nN=O的烷基亚硝基;式的N-端肽序列;式的C-端肽序列;式的N-端肽烷基序列;式的C-端肽烷基序列;式-PRaRb的膦;式-(CH2)nPRaRb的烷基膦;式-P+RaRbRc G-的鏻盐;式-(CH2)nP+RaRbRc G-的烷基鏻盐;式-P(O)RaRb的氧化膦;式-(CH2)nP(O)RaRb的烷基氧化膦;式-O-P(ORa)ORb的亚磷酸酯;式-(CH2)nO-P(ORa)ORb的烷基亚磷酸酯;式-OP(O)(ORa)(ORb)的磷酸酯;式-(CH2)nOP(O)(ORa)(ORb)的烷基磷酸酯;式-OPRaRb或-P(Ra)ORb之一的亚膦酸酯;式-(CH2)nOPRaRb或-(CH2)nP(Ra)ORb之一的烷基亚膦酸酯;式-OP(O)(Ra)(Rb)或-P(O)(Ra)(ORb)之一的次膦酸酯;式-(CH2)nOP(O)(Ra)(Rb)或-(CH2)nP(O)(Ra)(ORb)之一的烷基次膦酸酯;式-OP(ORa)(Rb)或-P(ORa)(ORb)之一的亚膦酸酯;式-(CH2)nOP(ORa)(Rb)或-(CH2)nP(ORa)(ORb)之一的烷基亚膦酸酯;式-OP(O)(ORa)(Rb)或-P(O)(ORa)(ORb)之一的膦酸酯;式-(CH2)nOP(O)(ORa)(Rb)或-(CH2)nP(O)(ORa)(ORb)之一的烷基膦酸酯;式-S(O)(O)Ra的硫酸酯;式-(CH2)nS(O)(O)Ra的烷基硫酸酯;式-S(O)(O)Ra的砜;式-(CH2)nS(O)(O)Ra的烷基砜;式-S(O)Ra的亚砜;式-(CH2)nS(O)Ra的烷基亚砜;式-S(O)ORa的亚磺酸;式-(CH2)nS(O)ORa的烷基亚磺酸;式-S(Ra)=N-Rb或-N=SRaRb之一的硫亚胺;式-(CH2)nS(Ra)=N-Rb或-(CH2)nN=SRaRb之一的烷基硫亚胺;式-S(O)(O)NRaRb的磺酰胺;式-(CH2)nS(O)(O)NRaRb的烷基磺酰胺;式-B(OH)2的硼酸;式-(CH2)nB(OH)2的烷基硼酸;式-B(ORa)(ORb)的硼酸酯;式-(CH2)nB(ORa)(ORb)的烷基硼酸酯;式的缩氨基脲;式的烷基缩氨基脲;式的硫代缩氨基脲;式的烷基硫代缩氨基脲;式-N(Ra)CN的氰基酰亚胺(cyanimide);式-(CH2)nN(Ra)CN的烷基氰基酰亚胺;式-C(Ra)=N-NH2的腙;式-(CH2)nC(Ra)=N-NH2的烷基腙;式-C(Ra)=N-OH的肟;式-(CH2)nC(Ra)=N-OH的烷基肟;式N(Ra)NO2的硝胺;式-(CH2)nN(Ra)NO2的烷基硝胺;式的氮酸酯;式的烷基氮酸酯;式的硝酮;式的烷基硝酮;式-OC(O)ORa的碳酸酯;式-(CH2)nOC(O)ORa的烷基碳酸酯;式-OC(O)NRaRb或-N(Ra)C(O)ORb之一的氨基甲酸酯;式-(CH2)nOC(O)NRaRb或-(CH2)nN(Ra)C(O)ORb之一的烷基氨基甲酸酯;式-SC(S)NRaRb或-N(Ra)C(S)SRb中的一种或多种的二硫代氨基甲酸酯;式-(CH2)nSC(S)NRaRb或-(CH2)nN(Ra)C(S)SRb中的一种或多种的烷基二硫代氨基甲酸酯;式-CRrRsRf的取代甲烷;式-(CH2)nCRrRsRf的烷基取代甲烷;式-OH的羟基;式-(CH2)nOH的烷基羟基;式-ORa的醚;式-(CH2)nORa的烷基醚;式-NH-C(O)-Rb的酰胺;式-(CH2)nNH-C(O)-Rb的烷基酰胺;式-OC(O)Rb的酯;式-(CH2)nOC(O)Rb的烷基酯;苯基;式-(CH2)nPh的烷基苯基;式-C=C(Ra)(Rb)的乙烯基;式-(CH2)nC=C(Ra)(Rb)的烷基乙烯基;含有1至3个独立地选自氮、硫和氧的杂原子的5或6元饱和杂环,含有1至5个独立地选自氮、硫和氧的杂原子的5或6元饱和杂芳环,含有一个或两个双键且含有1至5个独立地选自氮、硫和氧的杂原子的5元不饱和杂环,含有1至3个双键且根据环大小而含有1至5个独立地选自氮、硫和氧的杂原子的6元环;
其中Ra,Rb,Rc和Rd独立地选自;H或C1-4烷基,Rpep是导致形成氨基酸的任何基团;X是卤素;并且n=1-4;并且Rr,Rs和Rt独立地选自H,C1-4烷基或卤素,Rr,Rs或Rt中的至少一个是卤素;G-是阴离子;
并且其中,在W1,W2或W中的任一个上,R1,R2,R3,R4或R5均不选自:
式的烷基膦;式的烷基胺;
其中Rf和Rg各自独立地选自:
H或C1-C8烷基;并且m是1-8;R1,R2,R3,R4或R5均不可以选自:
选自F,Cl,Br,I的卤素;式-(CH2)n-X的烷基卤素;式-C(O)OH的羧酸,式-(CH2)nC(O)OH的烷基羧酸;式-OC(O)Rb的酯;式-(CH2)nOC(O)Rb的烷基酯;式-C(O)H的醛;式-(CH2)nC(O)H的烷基醛;式-C(O)Ra的酮;式-(CH2)nC(O)Ra的烷基酮;式-S(O)(O)Ra的硫酸酯;式-(CH2)nS(O)(O)Ra的烷基硫酸酯;式-CN的腈(氰基);式-(CH2)nCN的烷基腈;式-NO2的硝基;式-(CH2)nNO2的烷基硝基;式-C(O)NRaRb的酰胺;式-(CH2)nC(O)NRaRb的烷基酰胺;式-NRaC(O)Rb的酰胺;式-(CH2)nNRaC(O)R的烷基酰胺;
并且其中Ra,Rb,Rc和Rd独立地选自H或C1-4烷基;X是卤素;并且n=1-4;
或其药学上可接受的盐。
本发明的化合物具有抗微生物活性,因此可用于治疗或预防革兰氏阴性细菌感染。因此,本发明还提供了治疗或预防受试者的革兰氏阴性细菌感染的方法,其包括向所述受试者施用有效量的本文所述的式(I)化合物或其药学上可接受的盐的步骤。
本发明进一步提供了式(I)化合物或其药学上可接受的盐在制备用于治疗性治疗或预防有需要的受试者的细菌感染或疾病的药物中的用途,其中所述细菌感染或疾病是由革兰氏阴性细菌造成。
本发明提供了式(I)化合物或其药学上可接受的盐,其用于治疗或预防有需要的受试者的革兰氏阴性细菌感染的方法,所述方法包括向所述受试者施用治疗有效量的式(I)化合物或其治疗上可接受的盐,其中所述细菌感染或疾病是由革兰氏阴性细菌造成。
附图说明
本发明的进一步特征在本发明的多个非限制性实施方式的以下描述中更全面地描述。该描述是仅出于示例本发明的目的而被包括。不应将其理解为对如上所述的本发明的宽泛总结、公开或描述的限制。将参考附图进行描述,其中:
图1提供了通过Heck Cross偶联方法合成目标化合物的通用途径。
图2提供了根据式(I)化合物的结构。
图3提供了根据式(I)化合物的结构。
图4A和4B提供了根据式(I)化合物的结构。
发明详述
具体实施方式
化合物
本发明提供式(I)化合物:
(式(I))
其中;
V与W共价键合;
W与Z共价键合;
V是六元芳香环;
n是0,1,2,3或4;
所述或每个W独立地选自以下基团:
C2-4烷基;C2-4取代烷基;C2E-烯烃,V和Z在1和2位;C2Z-烯烃,V和Z在1和2位;C2-炔烃;
所述或每个Z独立地选自以下基团:
其中Wn是W1、W2或者所述或每个W中的一个;
并且其中;
W1、W2或者所述或每个W中的至少一个上的R1,R2,R3,R4或R5中的至少一个选自以下基团:
式的烷基膦,式的烷基胺;
其中Rf和Rg各自独立地选自:
H,C1-C8烷基;m是1-8;
并且其中;
其余R1,R2,R3,R4或R5各自独立地选自:
选自F,Cl,Br,I的卤素;C1-8烷基;式-C(O)OH的羧酸;式-(CH2)nC(O)OH的烷基羧酸;式-C(S)OH的硫代羧酸;式-(CH2)nC(S)OH的烷基硫代羧酸;式-C(O)ORa的酯;式-(CH2)nC(O)ORa的烷基酯;式-C(S)ORa的硫代酯;式-(CH2)nC(S)ORa的烷基硫代酯;式-C(S)SRa的二硫酯;式-(CH2)nC(S)SRa的烷基二硫酯;式-C(O)NRaRb的酰胺;式-(CH2)nC(O)NRaRb的烷基酰胺;式-C(S)NRaRb的硫代酰胺;式-(CH2)nC(S)NRaRb的烷基硫代酰胺;式-C(O)H的醛;式-(CH2)nC(O)H的烷基醛;式-C(S)H的硫醛;式-(CH2)nC(S)H的烷基硫醛;式-C(O)Ra的酮;式-(CH2)nC(O)Ra的烷基酮;式-C(S)Ra的硫酮;式-(CH2)nC(S)Ra的烷基硫酮;式之一的缩醛;式之一的烷基缩醛;式之一的烷基二硫代缩醛;式-NRaRb的胺;式-(CH2)nNRaRb的烷基胺;式-N+RaRbRc G-的铵盐;式-(CH2)nN+RaRbRc G-的烷基铵盐;式-NRaC(O)Rb的酰胺;式-(CH2)nNRaC(O)Rb的烷基酰胺;式-NRaC(S)Rb的硫代酰胺;式之一的烷基硫代酰胺;式之一的亚胺;式之一的烷基亚胺;式的胍;式的烷基胍;式的脒;式的烷基脒;式-CN的腈(氰基);式-(CH2)nCN的烷基腈;式-N+C-的异腈:式-(CH2)nN+C-的烷基异腈;式-OCN的氰酸酯;式-(CH2)nOCN的烷基氰酸酯;式-N=C=O的异氰酸酯;式-(CH2)nN=C=O的烷基异氰酸酯;式-SCN的硫氰酸酯;式-(CH2)nSCN的烷基硫氰酸酯;式-N=C=S的异硫氰酸酯;式-(CH2)nN=C=S的烷基异硫氰酸酯;式-N=NH的偶氮;式-(CH2)nN=NH的烷基偶氮;式-NO2的硝基;式-(CH2)nNO2的烷基硝基;式-O-N=O的亚硝酸酯;式-(CH2)nO-N=O的烷基亚硝酸酯;式-N=O的亚硝基;式-(CH2)nN=O的烷基亚硝基;式的N-端肽序列;式的C-端肽序列;式的N-端肽烷基序列;式的C-端肽烷基序列;式-PRaRb的膦;式-(CH2)nPRaRb的烷基膦;式-P+RaRbRc G-的鏻盐;式-(CH2)nP+RaRbRcG-的烷基鏻盐;式-P(O)RaRb的氧化膦;式-(CH2)nP(O)RaRb的烷基氧化膦;式-O-P(ORa)ORb的亚磷酸酯;式-(CH2)nO-P(ORa)ORb的烷基亚磷酸酯;式-OP(O)(ORa)(ORb)的磷酸酯;式-(CH2)nOP(O)(ORa)(ORb)的烷基磷酸酯;式-OPRaRb或-P(Ra)ORb之一的亚膦酸酯;式-(CH2)nOPRaRb或-(CH2)nP(Ra)ORb之一的烷基亚膦酸酯;式-OP(O)(Ra)(Rb)或-P(O)(Ra)(ORb)之一的次膦酸酯;式-(CH2)nOP(O)(Ra)(Rb)或-(CH2)nP(O)(Ra)(ORb)之一的烷基次膦酸酯;式-OP(ORa)(Rb)或-P(ORa)(ORb)之一的亚膦酸酯;式-(CH2)nOP(ORa)(Rb)或-(CH2)nP(ORa)(ORb)之一的烷基亚膦酸酯;式-OP(O)(ORa)(Rb)或-P(O)(ORa)(ORb)之一的膦酸酯;式-(CH2)nOP(O)(ORa)(Rb)或-(CH2)nP(O)(ORa)(ORb)之一的烷基膦酸酯;式-S(O)(O)Ra的硫酸酯;式-(CH2)nS(O)(O)Ra的烷基硫酸酯;式-S(O)(O)Ra的砜;式-(CH2)nS(O)(O)Ra的烷基砜;式-S(O)Ra的亚砜;式-(CH2)nS(O)Ra的烷基亚砜;式-S(O)ORa的亚磺酸;式-(CH2)nS(O)ORa的烷基亚磺酸;式-S(Ra)=N-Rb或-N=SRaRb之一的硫亚胺;式-(CH2)nS(Ra)=N-Rb或-(CH2)nN=SRaRb之一的烷基硫亚胺;式-S(O)(O)NRaRb的磺酰胺;式-(CH2)nS(O)(O)NRaRb的烷基磺酰胺;式-B(OH)2的硼酸;式-(CH2)nB(OH)2的烷基硼酸;式-B(ORa)(ORb)的硼酸酯;式-(CH2)nB(ORa)(ORb)的烷基硼酸酯;式的缩氨基脲;式的烷基缩氨基脲;式的硫代缩氨基脲;式的烷基硫代缩氨基脲;式-N(Ra)CN的氰基酰亚胺;式-(CH2)nN(Ra)CN的烷基氰基酰亚胺;式-C(Ra)=N-NH2的腙;式-(CH2)nC(Ra)=N-NH2的烷基腙;式-C(Ra)=N-OH的肟;式-(CH2)nC(Ra)=N-OH的烷基肟;式N(Ra)NO2的硝胺;式-(CH2)nN(Ra)NO2的烷基硝胺;式的氮酸酯;式的烷基氮酸酯;式的硝酮;式的烷基硝酮;式-OC(O)ORa的碳酸酯;式-(CH2)nOC(O)ORa的烷基碳酸酯;式-OC(O)NRaRb或-N(Ra)C(O)ORb之一的氨基甲酸酯;式-(CH2)nOC(O)NRaRb或-(CH2)nN(Ra)C(O)ORb之一的烷基氨基甲酸酯;式-SC(S)NRaRb或-N(Ra)C(S)SRb中的一种或多种的二硫代氨基甲酸酯;式-(CH2)nSC(S)NRaRb或-(CH2)nN(Ra)C(S)SRb中的一种或多种的烷基二硫代氨基甲酸酯;式-CRrRsRf的取代甲烷;式-(CH2)nCRrRsRf的烷基取代甲烷;式-OH的羟基;式-(CH2)nOH的烷基羟基;式-ORa的醚;式-(CH2)nORa的烷基醚;式-NH-C(O)-Rb的酰胺;式-(CH2)nNH-C(O)-Rb的烷基酰胺;式-OC(O)Rb的酯;式-(CH2)nOC(O)Rb的烷基酯;苯基;式-(CH2)nPh的烷基苯基;式-C=C(Ra)(Rb)的乙烯基;式-(CH2)nC=C(Ra)(Rb)的烷基乙烯基;含有1至3个独立地选自氮、硫和氧的杂原子的5或6元饱和杂环,含有1至5个独立地选自氮、硫和氧的杂原子的5或6元饱和杂芳环,含有一个或两个双键且含有1至5个独立地选自氮、硫和氧的杂原子的5元不饱和杂环,含有1至3个双键且根据环大小而含有1至5个独立地选自氮、硫和氧的杂原子的6元环;
其中Ra,Rb,Rc和Rd独立地选自;H或C1-4烷基,Rpep是导致形成氨基酸的任何基团;X是卤素;并且n=1-4;并且Rr,Rs和Rt独立地选自H,C1-4烷基或卤素,Rr,Rs或Rt中的至少一个是卤素;G-是阴离子;
并且其中,在W1,W2或W中的任一个上,R1,R2,R3,R4或R5均不选自:
式的烷基膦;式的烷基胺;
其中Rf和Rg各自独立地选自:
H或C1-C8烷基;并且m是1-8;R1,R2,R3,R4或R5均不可以选自:
选自F,Cl,Br,I的卤素;式-(CH2)n-X的烷基卤素;式-C(O)OH的羧酸,式-(CH2)nC(O)OH的烷基羧酸;式-OC(O)Rb的酯;式-(CH2)nOC(O)Rb的烷基酯;式-C(O)H的醛;式-(CH2)nC(O)H的烷基醛;式-C(O)Ra的酮;式-(CH2)nC(O)Ra的烷基酮;式-S(O)(O)Ra的硫酸酯;式-(CH2)nS(O)(O)Ra的烷基硫酸酯;式-CN的腈(氰基);式-(CH2)nCN的烷基腈;式-NO2的硝基;式-(CH2)nNO2的烷基硝基;式-C(O)NRaRb的酰胺;式-(CH2)nC(O)NRaRb的烷基酰胺;式-NRaC(O)Rb的酰胺;式-(CH2)nNRaC(O)R的烷基酰胺;
并且其中Ra,Rb,Rc和Rd独立地选自H或C1-4烷基;X是卤素;并且n=1-4;
或其药学上可接受的盐。
不希望受到理论的束缚,据信式(I)化合物的活性基本上取决于在周边W环上的烷基胺和烷基膦R基团的孤对电子的定位。通过包含烷基部分,膦和胺固有的共轭键排布得以避免。虽然不认为每个周边W环需要被烷基胺或烷基膦R基团取代,但本发明人已经观察到在未取代的环上的某些官能团,特别是吸电子基团,使化合物的活性失效。
进一步地,并且不希望受到理论的束缚,通过相对于烷基胺或烷基膦基团适当设置吸电子或给电子基团,可以进一步增强孤对电子的定位,据信这将进一步增强本发明化合物的活性。
Rpep优选具有由一个或多个α-氨基酸组成的肽,所述α-氨基酸独立地选自丙氨酸,精氨酸,天冬酰胺,天冬氨酸,半胱氨酸,谷氨酰胺,谷氨酸,甘氨酸,组氨酸,异亮氨酸,亮氨酸,赖氨酸,蛋氨酸,苯丙氨酸,脯氨酸,丝氨酸,苏氨酸,色氨酸,酪氨酸或缬氨酸。
用于本发明目的的药学上可接受的盐包括无毒阳离子和阴离子盐。实例包括但不限于钠,钾,铝,钙,锂,镁,锌和以下碱,例如铵,乙二胺,N-甲基-谷氨酰胺,赖氨酸,精氨酸,鸟氨酸,胆碱,N,N’-二苯甲基乙二胺,二乙胺,哌嗪,三(羟甲基)氨基甲烷,四甲基铵,乙酸盐,乳糖酸盐,苯磺酸盐,月桂酸盐,苯甲酸盐,苹果酸盐,碳酸氢盐,马来酸盐,硫酸氢盐,扁桃酸盐,苦味酸盐,甲酸盐,硼酸盐,甲基溴,溴化物,硝酸甲酯,乙二胺四乙酸钙,甲基硫酸酯,右旋樟脑磺酸盐(camsylate),粘酸盐(mucate),碳酸盐,萘磺酸盐,氯化物,硝酸盐,克拉维酸盐,N-甲基葡糖胺,柠檬酸盐,盐酸盐,油酸盐,乙二胺四乙酸盐,草酸盐,乙二磺酸盐,双羟萘酸盐(恩波酸盐),依托酸盐(estolate),棕榈酸盐,乙磺酸盐,泛酸盐,富马酸盐,磷酸盐,二磷酸盐,glucepate,聚半乳糖醛酸盐,葡萄糖酸盐,水杨酸盐,谷氨酸盐,硬脂酸盐,glycollylarsanilate,硫酸盐,己基间苯二酚,碱式醋酸盐,hydrabamine,琥珀酸盐,氢溴酸盐,单宁酸盐,酒石酸盐,羟基萘酸盐,茶氯酸盐,碘化物,甲苯磺酸盐,异硫氰酸盐,三乙基碘,乳酸盐,panoate和戊酸盐。
可以使用例如PCT/AU2010/001709和PCT/AU2016/095003(基于临时申请AU2015903284)中公开的那些合成方法制备本发明的化合物。
抗生素使用
本发明化合物具有抗微生物活性,因此可用于治疗或预防革兰氏阴性细菌感染。因此,本发明还提供了治疗或预防受试者的革兰氏阴性细菌感染的方法,其包括向所述受试者施用有效量的式(I)化合物或其药学上可接受的盐的步骤。
优选使用本发明化合物对抗的革兰氏阴性细菌的实例包括:鲍氏不动杆菌,嗜水气单胞菌,弓形杆菌,拟杆菌,Brachyspira aalborgi,Brachyspira pilosicoli,人心杆菌,弗氏柠檬酸杆菌,贝氏柯克斯体,阴沟肠杆菌,大肠杆菌,费格森埃希菌,坏死梭杆菌,核梭杆菌,多形性梭杆菌,Haemophilus felis,溶血嗜血杆菌,流感嗜血杆菌,Haemophiluspittmaniae,Haemophilus pylori,金格金氏菌(Kingella kingae),Klebsiellaedwardsii,肺炎克雷伯氏菌,军团菌,卡他莫拉菌,结膜炎莫拉菌,摩氏摩根菌,淋病奈瑟菌,脑膜炎奈瑟菌,奇异变形杆菌,彭氏变形杆菌,铜绿假单胞菌,绿脓假单胞菌,立克次氏体立克次氏体,沙门氏菌,粘质沙雷氏菌,志贺氏菌,嗜麦芽寡养单胞菌,霍乱弧菌(非产毒性),小肠结肠炎耶尔森氏菌和鼠疫耶尔森氏菌。
式(I)的抗生素属于新类别的基于苯乙烯基苯的衍生物抗生素。这一代的抗生素已显示出对大电导率的机械敏感性离子通道(MscL)(新型且备受追捧的细菌靶标)的活性。MscL是高度保守的跨膜蛋白,见于所有细菌(包括革兰氏阴性细菌)中,但不见于人类基因组中,使其成为理想的药物靶标。该通道负责使细菌细胞在高渗透环境中免于裂解。它通过开放并允许细菌释放渗透物从而降低内部压力而响应于高膨胀压力。基于苯乙烯基苯的抗生素降低了这些通道开放的阈值并延长其开放时间,导致重要的渗透物和其他生物分子的损失,从而削弱细菌。
本发明提供了治疗或预防受试者的革兰氏阴性细菌感染的方法,其包括向所述受试者施用有效量的式(I)化合物的步骤,其中式(I)化合物的R1至R5均不是:
式的铵盐;式的烷基铵盐;式的鏻盐;或式的烷基鏻盐。
据信这些化合物可能是有毒的并且可能不适合用作抗生素治疗剂。然而,可能的是将这些化合物用于非体内用途,例如喷洒在表面上以除去革兰氏阴性细菌污染物。
药剂的制造
本发明进一步提供了式(I)化合物或其药学上可接受的盐在制备用于治疗或预防有需要的受试者的细菌感染或疾病的药物中的用途,其中所述细菌感染或疾病是由革兰氏阴性细菌造成。
本发明还提供了式(I)化合物或其药学上可接受的盐,其用于治疗或预防有需要的受试者的革兰氏阴性细菌感染的方法,所述方法包括向所述受试者施用治疗有效量的式(I)化合物或其治疗上可接受的盐,其中所述细菌感染或疾病是由革兰氏阴性细菌造成。
制剂
可以将本发明的化合物制成用于施用的制剂。
因此,本发明还提供了制剂,其包含治疗有效量的式(I)化合物及其药学上可接受的盐,和药学上可接受的载体或稀释剂。该制剂将优选用于治疗或预防革兰氏阴性细菌的感染。
本发明的精确制剂将根据广泛的商业和科学标准而变化。用于制备包含一种或多种活性成分的药物制剂的方法通常是本领域已知的。这样的制剂通常将配制成用于待使用的递送方式,并且通常包含一种或多种药学上可接受的载体。
通常,合适的载体、赋形剂和稀释剂的实例包括但不限于水,盐水,乙醇,右旋糖,甘油,乳糖,右旋糖,蔗糖,山梨糖醇,甘露醇,淀粉,阿拉伯树胶,磷酸钙,藻酸盐,黄蓍胶,明胶,硅酸钙,微晶纤维素,聚乙烯吡咯烷酮,纤维素,水糖浆,甲基纤维素,甲基和丙基羟基苯甲酸酯,滑石,硬脂酸镁和矿物油或其组合。制剂可另外包含润滑剂,pH缓冲剂,润湿剂,乳化剂和悬浮剂,防腐剂,甜味剂或调味剂。
(a)局部制剂
药物制剂可适于局部施用。在这方面,取决于优选的治疗方案,各种局部递送系统可适用于施用本发明的制剂。局部制剂可以通过将本发明化合物溶解或组合在水性或非水性载体中而制备。通常,与化合物或可以引入制剂中的任何其它活性成分没有明显反应且是无刺激性的任何液体,乳膏或凝胶或者类似物质是合适的。还可以使用合适的不可喷雾的粘性、半固体或固体形式,其包含与局部施用相容且具有优选大于水的动态粘度的载体。
合适的制剂是本领域技术人员公知的,并且包括但不限于溶液,悬浮液,乳液,乳膏,凝胶,软膏,粉末,搽剂,油膏,气雾剂,透皮贴剂等,其(如果期望)用助剂灭菌或与助剂混合,所述助剂是例如防腐剂,稳定剂,乳化剂,润湿剂,香味剂,着色剂,气味控制剂,增稠剂如天然树胶,等。特别优选的局部制剂包括软膏,乳膏或凝胶。
软膏通常使用(1)油质基底,即由不挥发油或烃(例如白凡士林或矿物油)组成的基底,或(2)吸收性基底,即由无水物质或可吸收水的物质(例如无水羊毛脂)组成的基底制备。通常,在形成基底后,无论是油质的还是吸收性的,将活性成分加入至提供期望浓度的量。
乳膏是油/水乳液。它们由油相(内部相)和水相(连续相)组成,所述油相通常包含不挥发油,烃等,蜡,石油,矿物油等,所述水相包括水和任何水溶性物质,例如添加的盐。通过使用乳化剂,例如表面活性剂,如月桂基亚硫酸钠;亲水性胶体,如金合欢胶体粘土,veegum等,使两相稳定化。在形成乳液后,可以加入一定量的化合物以达到期望浓度。
凝胶包含选自油质基底,水,或乳液-悬浮液基底的基底。向基底中加入在基底中形成基质的胶凝剂,增加其粘度。胶凝剂的实例是羟丙基纤维素,丙烯酸聚合物等。通常,在加入胶凝剂之前的某个点,将化合物以期望浓度加入到制剂中。
引入局部制剂中的化合物的量并不关键;浓度应在足以允许准备好施用制剂的范围内,使得递送有效量的化合物。
(b)口服制剂
药物制剂可以适于口服递送。在这方面,化合物可以作为适于使得促进递送治疗有效的浓度的化合物的方式的口服制剂施用。
当口服施用时,化合物的有效剂量必须考虑稀释剂,优选水。制剂优选含有0.05重量%至约100重量%的活性成分,更优选约10%至约80重量%。当摄入制剂时,期望的是空腹服用它们。
考虑用于本文的是口服固体剂型,包括片剂,胶囊,丸剂(pills),锭剂(troches)或锭剂(lozenges),扁囊剂或丸剂(pellets)。而且,脂质体或类蛋白质包封可用于配制本发明的制剂。可以使用脂质体包封,并且脂质体可以用各种聚合物衍生化。通常,制剂将包含化合物和允许保护免受胃环境和肠中生物活性物质的释放影响的惰性成分。
释放的位置可以是胃,小肠(十二指肠,空肠或回肠)或大肠。本领域技术人员知悉不溶解在胃中,但在十二指肠中或肠中其他部位释放物质的可获得的制剂。优选地,释放将通过保护制剂或通过将化合物释放到胃环境之外(例如在肠中)而避免胃环境的有害作用。
为了确保完全的胃抗性,可以使用对至少pH 5.0不可渗透的包衣。用作肠溶包衣的更常见的惰性成分的实例是乙酸纤维素偏苯三酸酯(CAT),羟丙基甲基纤维素邻苯二甲酸酯(HPMCP),HPMCP 50,HPMCP 55,聚醋酸乙烯邻苯二甲酸酯(PVAP),Eudragit L30D,Aquateric,醋酸纤维素邻苯二甲酸酯(CAP),Eudragit L,Eudragit S和Shellac。这些包衣可用作混合膜。
不旨在用于保护免受胃影响的包衣或包衣混合物也可用于片剂。这可以包括糖衣,或使片剂更容易吞咽的包衣。胶囊可以由硬壳(例如明胶)组成,用于递送干燥的治疗剂,即粉末;对于液体形式,可以使用软明胶壳。扁囊剂的壳材料可以是厚淀粉或其他可食用纸。对于丸剂,锭剂,模制片剂或片剂磨碎物,可以使用湿成块技术。
可以用惰性材料稀释或增加制剂的体积。这些稀释剂可包括碳水化合物,尤其是甘露醇,α-乳糖,无水乳糖,纤维素,蔗糖,改性葡聚糖和淀粉。某些无机盐也可用作填料,包括三磷酸钙,碳酸镁和氯化钠。一些可商购稀释剂是Fast-Flo,Emdex,STA-Rx 1500,Emcompress和Avicell。
崩解剂可以包含在化合物的制剂中成固体剂型。用作崩解剂的材料包括但不限于淀粉,包括基于淀粉的商业崩解剂,Explotab。淀粉乙醇酸钠,Amberlite,羧甲基纤维素钠,超支链淀粉,海藻酸钠,明胶,桔皮,酸性羧甲基纤维素,天然海绵和膨润土都可以使用。另一种形式的崩解剂是不溶性阳离子交换树脂。粉末状树胶可以用作崩解剂和粘合剂,这些可以包括粉末状树胶,如琼脂,刺梧桐胶或黄蓍胶。海藻酸及其钠盐也可用作崩解剂。
粘合剂可用于保持制剂在一起以形成硬片剂,并且包括来自天然产物如阿拉伯胶,黄蓍胶,淀粉和明胶的材料。其他包括甲基纤维素(MC),乙基纤维素(EC)和羧甲基纤维素(CMC)。聚乙烯吡咯烷酮(PVP)和羟丙基甲基纤维素(HPMC)均可用于醇溶液中以使化合物成粒。
制剂中可包含抗摩擦剂以防止在配制过程中粘着。润滑剂可用作化合物和模壁之间的层,这些可包括但不限于:硬脂酸,包括其镁盐和钙盐,聚四氟乙烯(PTFE),液体石蜡,植物油和蜡。还可以使用可溶性润滑剂,例如月桂基硫酸钠,月桂基硫酸镁,各种分子量的聚乙二醇和Carbowax 4000和6000。
可以添加可以在配制期间改善制剂的流动性质并有助于在压制期间重排的助流剂。助流剂可包括淀粉,滑石,热解二氧化硅和水合硅铝酸盐。
为了有助于化合物的溶解,可以加入表面活性剂作为润湿剂。表面活性剂可包括阴离子洗涤剂,例如月桂基硫酸钠,二辛基磺基琥珀酸钠和二辛基磺酸钠。可以使用阳离子洗涤剂,可以包括苯扎氯铵或苄索氯铵。可作为表面活性剂包含在制剂中的潜在非离子洗涤剂的列表是聚桂醇400,聚氧乙烯40硬脂酸酯,聚氧乙烯氢化蓖麻油10、50和60,甘油单硬脂酸酯,聚山梨醇酯40、60、65和80,蔗糖脂肪酸酯,甲基纤维素和羧甲基纤维素。这些表面活性剂可以单独或作为不同比率的混合物存在于制剂中。
控释制剂可以是期望的。可以将化合物引入允许通过扩散或浸出机制释放的惰性基质中,即树胶。缓慢退化的基质也可以引入制剂中。另一种形式的控释制剂是通过基于Oros治疗系统(Alza Corp.)的方法,即制剂被封装在允许水进入并且由于渗透效应而将制剂经过单个小开口推出的半透膜中。一些肠溶包衣也具有延迟释放效果。
可以使用材料混合物以提供最佳薄膜包衣。薄膜包衣可以在盘式涂布机中或在流化床中进行或通过压制包衣进行。
化合物可以以粒径为约1mm的颗粒或丸剂形式的细小多颗粒形式包含在制剂中。用于胶囊施用的材料的制剂也可以是粉末,轻微压制的塞状物或甚至片剂。化合物可通过压制制备。
(c)可注射制剂
化合物还可以配制用于肠胃外递送。适合于可注射使用的药物形式包括:无菌水溶液(水溶性的)或分散体和用于临时制备无菌可注射溶液或分散体的无菌粉末。或者,本发明化合物可以包封在脂质体中并以可注射溶液形式递送,以帮助它们跨细胞膜转运。溶液可以是溶剂或分散介质,其含有例如水,乙醇,多元醇(例如甘油,丙二醇和液体聚乙二醇等),其合适的混合物和植物油。例如通过使用诸如卵磷脂的包衣,通过在分散体的情况下保持所需的粒度,和通过使用表面活性剂,可以保持适当的流动性。通过在制剂中使用延迟吸收剂例如单硬脂酸铝和明胶,可以实现可注射制剂的延长吸收。
无菌可注射溶液可以通过将所需量的活性化合物与需要时上文列举的各种其他成分引入适当的溶剂中,然后过滤灭菌而制备。通常,通过将化合物引入含有基础分散介质和其他成分的无菌载体中而制备分散体。在用于制备无菌可注射溶液的无菌粉末的情况下,优选的制备方法是真空干燥和冻干技术,其从先前无菌过滤的溶液产生化合物粉末加上任何另外的期望成分。
因此,本发明还提供了可注射的、稳定的、无菌的制剂,其包含在密封容器中的单位剂量形式的式(I)化合物或其盐。所述化合物或盐可以以能够用合适的药学上可接受的载体重构以形成适于将其注射到受试者中的液体制剂的冻干形式提供。单位剂量形式通常包含约10mg至约10g的化合物或其盐。当化合物或盐基本上不溶于水时,可以以足以在水性载体中乳化化合物或盐的量采用足够量的生理学可接受的乳化剂。一种这样的有用乳化剂是磷脂酰胆碱。
(d)气雾剂
还提供了作为适合于通过吸入施用的气雾剂的药物制剂。这些制剂包含期望的化合物或其盐的溶液或悬浮液或者所述化合物或盐的多个固体颗粒。可以将期望的制剂置于小室中并雾化。雾化可以通过压制空气或超声能量来完成,以形成包含化合物或盐的多个液滴或固体颗粒。
固体颗粒可以通过以本领域已知的任何适当方式例如通过微粉化处理固体化合物或其盐而获得。商业喷雾器也可用于提供任何期望尺寸的液滴。
液滴或固体颗粒的粒度应为约0.5至约5微米,优选约1至约2微米。最优选地,固体颗粒或液滴的尺寸为约1至约2微米。这样的颗粒或液滴可以通过可商购雾化器或通过技术人员已知的其他方式分配。
当适合作为气雾剂施用的药物制剂是液体形式时,制剂将在包含水的载体中包含水溶形式的化合物或其盐。可以存在表面活性剂,其充分降低制剂的表面张力以在进行雾化时导致形成期望尺寸范围内的液滴。
(e)粘膜递送
还提供了药物制剂,其适于通过口服(例如口腔,舌下),直肠,阴道,鼻腔或其他粘膜表面施用。
这样的制剂可以是冻干晶片,柔性聚合物膜,快速崩解片剂,可喷雾溶液等形式。这样的递送优选绕过经由胃系统口服递送的首过效果。
(f)其他试剂
此外,上文讨论的药物制剂还可以包含其他试剂。例如,可以使用防腐剂,共溶剂,表面活性剂,油,保湿剂,润肤剂,螯合剂,染料,稳定剂或抗氧化剂。可以使用的水溶性防腐剂包括但不限于苯扎氯铵,氯丁醇,硫柳汞,硫酸氢钠,醋酸苯汞,硝酸苯汞,乙醇,对羟基苯甲酸甲酯,聚乙烯醇,苯甲醇和苯乙醇。表面活性剂可以是吐温80。其它合适的添加剂包括润滑剂和增滑剂,例如硬脂酸镁,硬脂酸,滑石和膨润土;促进崩解的物质,如淀粉或交联聚乙烯吡咯烷酮;粘合剂,例如淀粉,明胶或线性聚乙烯吡咯烷酮;和干燥粘合剂,如微晶纤维素。
可以使用的其他载体包括但不限于聚乙烯醇,聚维酮,羟丙基甲基纤维素,泊洛沙姆,羧甲基纤维素,羟乙基纤维素,纯化水等。可以包含张力调节剂,例如氯化钠,氯化钾,甘露醇,甘油等。抗氧化剂包括但不限于偏亚硫酸氢钠,硫代硫酸钠,乙酰半胱氨酸,丁基化羟基苯甲醚,丁基化羟基甲苯等。
制剂中的化合物的适应症,有效剂量,制剂,禁忌症,供应商等是本领域技术人员可获得的或已知的。这些试剂可以各自以约0.001重量%至约5重量%,优选约0.01重量%至约2重量%的量存在。
电解质例如但不限于氯化钠和氯化钾也可包含在制剂中。
此外,制剂可含有微生物防腐剂。有用的微生物防腐剂包括对羟基苯甲酸甲酯,对羟基苯甲酸丙酯和苯甲醇。当将制剂置于设计用于多剂量使用的小瓶中时,通常使用微生物防腐剂。
可以使用的赋形剂都是生理学可接受的固体惰性物质,无论性质上是无机的还是有机的。无机物质是例如氯化钠;碳酸盐,如碳酸钙,碳酸氢盐;铝氧化物;硅酸;氧化铝;沉淀或胶体二氧化硅;和磷酸盐。有机物质是例如糖;纤维素;食品和饲料,如奶粉,动物粉,谷物粉和谷物碎片和淀粉。
最后,应理解,本发明的制剂可包含多种如本文所述的化合物。
通用
本领域技术人员将理解,除了具体描述的那些之外,本文描述的发明易于进行变化和修改。应理解,本发明包括所有这些变化和修改。本发明还包括单独或共同地,在说明书中提及或指出的所有步骤,特征,制剂和化合物,以及任何两个或更多个步骤或特征的任何和所有组合。
本发明不限于本文所述的具体实施方式的范围,所述实施方式仅用于举例说明的目的。功能等同的产品,制剂和方法显然在本文所述的本发明的范围内。
本文引用的所有出版物(包括专利,专利申请,期刊文章,实验室手册,书籍或其他文献)的全部公开内容通过引用并入本文。不承认任何参考文献构成现有技术或者是本发明涉及的领域中的工作人员的公知常识的一部分。
本文中引用的每篇文献,参考文献,专利申请或专利均通过引用以其整体明确并入本文,这意味着读者应阅读并将其视为本文的一部分。本文中引用的文献,参考文献,专利申请或专利在本文中不再重复仅仅是为了简明起见。
本文或通过引用并入本文的任何文献提及的任何产品的任何制造商说明书,描述,产品说明书和产品页通过引用并入本文,并且可以用于本发明的实践中。
如本文所用,术语“衍生”和“衍生自”应表示可以从特定来源获得特定要素,但不一定直接来自该来源。
如本文所用,单数形式“一个/一种(a/an)”和“所述/该(the)”包括复数指代,除非上下文另有明确说明。
在整个说明书中,除非上下文另有要求,否则词语“包含”或诸如“包含”或“包含”的变体将被理解为暗示包括所陈述的要素或要素的组,但不排除任何其他要素或要素的组。
除了在操作实施例中或另有说明之外,在说明书和权利要求中使用的表示成分量,反应条件等的所有数字应理解为在所有情况下均由术语“约”修饰。因此,除非有相反的指示,否则说明书和权利要求书中列出的数值参数是近似值,其可以根据本发明寻求获得的期望性质而变化。因此,“约80%”表示“约80%”,也表示“80%”。至少,每个数值参数应根据有效数字的数量和普通的舍入方法来解释。
尽管阐述本发明的宽泛范围的数值范围和参数是近似值,但具体实施例中陈述的数值尽可能精确地报告。然而,任何数值固有地含有必然由其各自测试测量中发现的标准偏差造成的某些误差
本文使用的所选术语的其他定义可见于本发明的详细描述并适用于全文。除非另外定义,否则本文使用的所有其他科学和技术术语具有与本发明所属领域的普通技术人员通常理解的含义相同的含义。
以下实施例用于更全面地描述使用上述发明的方式,以及阐述用于实施本发明的各个方面的最佳模式。应理解,这些方法决不是用于限制本发明的真实范围,而是出于说明目的而呈现。
实施例
实施例1
通过肉汤微量稀释法测定MIC
在临床和实验室标准研究所描述的测定条件下使用体外肉汤微量稀释测定法测量测试物的抗细菌效力。在该测定中,最小抑制浓度(MIC)定义为完全抑制微生物体外可见生长的试剂的最低浓度。将测试物质溶解在100%DMSO中,通过超声处理或涡旋完全悬浮,在相同载体中通过2倍连续滴定进行稀释,总共11个测试浓度。将4μL等分试样的每种稀释液加入到在96孔板的孔中用生物悬浮液接种的196μL肉汤培养基中(细菌计数:最终为2-8×105菌落形成单位/mL)。最终体积在每个孔中为200μL,最终DMSO浓度为2%。在36℃温育1天后,目测检查测试板,对孔进行生长或完全生长抑制的评分,以确定最小抑制浓度。每种测试物质一式两份进行评估,结果报告为重复测试值。载体对照和活性参照剂分别用作空白对照和阳性对照。测试的微生物是鲍曼不动杆菌(ATCC 17978),粪肠球菌(ATCC 29212),屎肠球菌VanA(ATCC 700221),大肠杆菌(ATCC 25922),大肠杆菌外排缺陷型DEL-tolC(JW5503),流感嗜血杆菌(ATCC 49247),肺炎克雷伯氏菌(ATCC 43816),铜绿假单胞菌(ATCC 27853),铜绿假单胞菌MDR(NTUH-974),金黄色葡萄球菌(ATCC 29213),金黄色葡萄球菌MRSA(ATCC 33591)和肺炎链球菌(ATCC 46919)。流感嗜血杆菌在嗜血杆菌测试培养基中生长,肺炎链球菌在含有5%裂解的马血的阳离子调节的Muller-Hinton肉汤II中培养。所有其他微生物在阳离子调节的Muller-Hinton肉汤II中生长。
以下结果中的化合物1显示在图2中,化合物2显示在图3中。两种化合物都具有对抗革兰氏阴性细菌的活性。不希望受到理论的束缚,这是因为化合物1具有定域正电荷,并且化合物2在氮上具有不能容易地离域到环的孤对电子,使得氮是碱性的。
表1:化合物1和2对抗细菌的活性
实施例2
化合物的测试
在临床和实验室标准研究所描述的测定条件下使用体外肉汤微量稀释测定法测量测试物的抗细菌效力。在该测定中,最小抑制浓度(MIC)定义为完全抑制微生物体外可见生长的试剂的最低浓度。将测试物质溶解在100%DMSO中(除非下文说明),通过超声处理或涡旋完全悬浮,在相同载体中通过2倍连续滴定进行稀释,总共11个测试浓度。将4μL等分试样的每种稀释液加入到在96孔板的孔中用生物悬浮液接种的196μL肉汤培养基中(细菌计数:最终为2-8×105菌落形成单位/mL)。最终体积在每个孔中为200μL,最终DMSO浓度为2%。培养基,温育时间和温度在测试方法的表格中列出。在温育后,目测检查测试板,对孔进行生长或完全生长抑制的评分,以确定最小抑制浓度。每种测试物质一式两份进行评估,以下结果是重复测试值。载体对照和活性参照剂分别用作空白对照和阳性对照。
所测试的化合物的结构在图4中提供。
表2:化合物对抗细菌的活性
可以看出,除化合物12和13外(其对应于实施例1中讨论的化合物1和2),上述含N化合物是无效的。甚至具有一个烷基胺的化合物14,15和16也是无效的。
实施例3
合成
Claims (28)
1.具有式(I)化合物,或其药学上可接受的盐:
(式(I))
其中;
V共价键合至W;
W共价键合至Z;
V是六元芳香环;
n是0,1,2,3或4;
所述或每个W独立地选自以下基团:
C2-4烷基;C2-4取代烷基;C2 E-烯烃,V和Z分别位于1和2位;C2 Z-烯烃,V和Z分别位于1和2位;C2-炔烃;
所述或每个Z独立地选自以下基团:
其中Wn是W1、W2或者所述或每个W中的一个;
并且其中;
W1、W2或者所述或每个W中的至少一个上的R1,R2,R3,R4或R5中的至少一个选自以下基团:
式的烷基膦,式的烷基胺;
其中Rf和Rg各自独立地选自:
H,C1-C8烷基;m是1-8;
并且其中;
其余R1,R2,R3,R4或R5各自独立地选自:
选自F,Cl,Br,I的卤素;C1-8烷基;式-C(O)OH的羧酸;式-(CH2)nC(O)OH的烷基羧酸;式-C(S)OH的硫代羧酸;式-(CH2)nC(S)OH的烷基硫代羧酸;式-C(O)ORa的酯;式-(CH2)nC(O)ORa的烷基酯;式-C(S)ORa的硫代酯;式-(CH2)nC(S)ORa的烷基硫代酯;式-C(S)SRa的二硫酯;式-(CH2)nC(S)SRa的烷基二硫酯;式-C(O)NRaRb的酰胺;式-(CH2)nC(O)NRaRb的烷基酰胺;式-C(S)NRaRb的硫代酰胺;式-(CH2)nC(S)NRaRb的烷基硫代酰胺;式-C(O)H的醛;式-(CH2)nC(O)H的烷基醛;式-C(S)H的硫醛;式-(CH2)nC(S)H的烷基硫醛;式-C(O)Ra的酮;式-(CH2)nC(O)Ra的烷基酮;式-C(S)Ra的硫酮;式-(CH2)nC(S)Ra的烷基硫酮;式之一的缩醛;式之一的烷基缩醛;式之一的烷基二硫代缩醛;式-NRaRb的胺;式-(CH2)nNRaRb的烷基胺;式-N+RaRbRc G-的铵盐;式-(CH2)nN+RaRbRc G-的烷基铵盐;式-NRaC(O)Rb的酰胺;式-(CH2)nNRaC(O)Rb的烷基酰胺;式-NRaC(S)Rb的硫代酰胺;式之一的烷基硫代酰胺;式之一的亚胺;式之一的烷基亚胺;式的胍;式的烷基胍;式的脒;式的烷基脒;式-CN的腈(氰基);式-(CH2)nCN的烷基腈;式-N+C-的异腈:式-(CH2)nN+C-的烷基异腈;式-OCN的氰酸酯;式-(CH2)nOCN的烷基氰酸酯;式-N=C=O的异氰酸酯;式-(CH2)nN=C=O的烷基异氰酸酯;式-SCN的硫氰酸酯;式-(CH2)nSCN的烷基硫氰酸酯;式-N=C=S的异硫氰酸酯;式-(CH2)nN=C=S的烷基异硫氰酸酯;式-N=NH的偶氮;式-(CH2)nN=NH的烷基偶氮;式-NO2的硝基;式-(CH2)nNO2的烷基硝基;式-O-N=O的亚硝酸酯;式-(CH2)nO-N=O的烷基亚硝酸酯;式-N=O的亚硝基;式-(CH2)nN=O的烷基亚硝基;式的N-端肽序列;式的C-端肽序列;式的N-端肽烷基序列;式的C-端肽烷基序列;式-PRaRb的膦;式-(CH2)nPRaRb的烷基膦;式-P+RaRbRc G-的鏻盐;式-(CH2)nP+RaRbRcG-的烷基鏻盐;式-P(O)RaRb的氧化膦;式-(CH2)nP(O)RaRb的烷基氧化膦;式-O-P(ORa)ORb的亚磷酸酯;式-(CH2)nO-P(ORa)ORb的烷基亚磷酸酯;式-OP(O)(ORa)(ORb)的磷酸酯;式-(CH2)nOP(O)(ORa)(ORb)的烷基磷酸酯;式-OPRaRb或-P(Ra)ORb之一的亚膦酸酯;式-(CH2)nOPRaRb或-(CH2)nP(Ra)ORb之一的烷基亚膦酸酯;式-OP(O)(Ra)(Rb)或-P(O)(Ra)(ORb)之一的次膦酸酯;式-(CH2)nOP(O)(Ra)(Rb)或-(CH2)nP(O)(Ra)(ORb)之一的烷基次膦酸酯;式-OP(ORa)(Rb)或-P(ORa)(ORb)之一的亚膦酸酯;式-(CH2)nOP(ORa)(Rb)或-(CH2)nP(ORa)(ORb)之一的烷基亚膦酸酯;式-OP(O)(ORa)(Rb)或-P(O)(ORa)(ORb)之一的膦酸酯;式-(CH2)nOP(O)(ORa)(Rb)或-(CH2)nP(O)(ORa)(ORb)之一的烷基膦酸酯;式-S(O)(O)Ra的硫酸酯;式-(CH2)nS(O)(O)Ra的烷基硫酸酯;式-S(O)(O)Ra的砜;式-(CH2)nS(O)(O)Ra的烷基砜;式-S(O)Ra的亚砜;式-(CH2)nS(O)Ra的烷基亚砜;式-S(O)ORa的亚磺酸;式-(CH2)nS(O)ORa的烷基亚磺酸;式-S(Ra)=N-Rb或-N=SRaRb之一的硫亚胺;式-(CH2)nS(Ra)=N-Rb或-(CH2)nN=SRaRb之一的烷基硫亚胺;式-S(O)(O)NRaRb的磺酰胺;式-(CH2)nS(O)(O)NRaRb的烷基磺酰胺;式-B(OH)2的硼酸;式-(CH2)nB(OH)2的烷基硼酸;式-B(ORa)(ORb)的硼酸酯;式-(CH2)nB(ORa)(ORb)的烷基硼酸酯;式的缩氨基脲;式的烷基缩氨基脲;式的硫代缩氨基脲;式的烷基硫代缩氨基脲;式-N(Ra)CN的氰基酰亚胺;式-(CH2)nN(Ra)CN的烷基氰基酰亚胺;式-C(Ra)=N-NH2的腙;式-(CH2)nC(Ra)=N-NH2的烷基腙;式-C(Ra)=N-OH的肟;式-(CH2)nC(Ra)=N-OH的烷基肟;式N(Ra)NO2的硝胺;式-(CH2)nN(Ra)NO2的烷基硝胺;式的氮酸酯;式的烷基氮酸酯;式的硝酮;式的烷基硝酮;式-OC(O)ORa的碳酸酯;式-(CH2)nOC(O)ORa的烷基碳酸酯;式-OC(O)NRaRb或-N(Ra)C(O)ORb之一的氨基甲酸酯;式-(CH2)nOC(O)NRaRb或-(CH2)nN(Ra)C(O)ORb之一的烷基氨基甲酸酯;式-SC(S)NRaRb或-N(Ra)C(S)SRb中的一种或多种的二硫代氨基甲酸酯;式-(CH2)nSC(S)NRaRb或-(CH2)nN(Ra)C(S)SRb中的一种或多种的烷基二硫代氨基甲酸酯;式-CRrRsRf的取代甲烷;式-(CH2)nCRrRsRf的烷基取代甲烷;式-OH的羟基;式-(CH2)nOH的烷基羟基;式-ORa的醚;式-(CH2)nORa的烷基醚;式-NH-C(O)-Rb的酰胺;式-(CH2)nNH-C(O)-Rb的烷基酰胺;式-OC(O)Rb的酯;式-(CH2)nOC(O)Rb的烷基酯;苯基;式-(CH2)nPh的烷基苯基;式-C=C(Ra)(Rb)的乙烯基;式-(CH2)nC=C(Ra)(Rb)的烷基乙烯基;含有1至3个独立地选自氮、硫和氧的杂原子的5或6元饱和杂环,含有1至5个独立地选自氮、硫和氧的杂原子的5或6元饱和杂芳环,含有一个或两个双键且含有1至5个独立地选自氮、硫和氧的杂原子的5元不饱和杂环,含有1至3个双键且根据环大小而含有1至5个独立地选自氮、硫和氧的杂原子的6元环;
其中Ra,Rb,Rc和Rd独立地选自;H或C1-4烷基,Rpep是导致形成氨基酸的任何基团;X是卤素;并且n=1-4;并且Rr,Rs和Rt独立地选自H,C1-4烷基或卤素,Rr,Rs或Rt中的至少一个是卤素;G-是阴离子;
并且其中,在W1,W2或W中的任一个上,R1,R2,R3,R4或R5均不选自:
式的烷基膦;式的烷基胺;
其中Rf和Rg各自独立地选自:
H或C1-C8烷基;并且m是1-8;R1,R2,R3,R4或R5均不可以选自:
选自F,Cl,Br,I的卤素;式-(CH2)n-X的烷基卤素;式-C(O)OH的羧酸,式-(CH2)nC(O)OH的烷基羧酸;式-OC(O)Rb的酯;式-(CH2)nOC(O)Rb的烷基酯;式-C(O)H的醛;式-(CH2)nC(O)H的烷基醛;式-C(O)Ra的酮;式-(CH2)nC(O)Ra的烷基酮;式-S(O)(O)Ra的硫酸酯;式-(CH2)nS(O)(O)Ra的烷基硫酸酯;式-CN的腈(氰基);式-(CH2)nCN的烷基腈;式-NO2的硝基;式-(CH2)nNO2的烷基硝基;式-C(O)NRaRb的酰胺;式-(CH2)nC(O)NRaRb的烷基酰胺;式-NRaC(O)Rb的酰胺;式-(CH2)nNRaC(O)R的烷基酰胺;
并且其中Ra,Rb,Rc和Rd独立地选自H或C1-4烷基;X是卤素;并且n=1-4。
2.根据权利要求1所述的式(I)化合物,其中W1,W2和所述或每个W中的每个上的R1,R2,R3,R4或R5中的至少一个独立地选自:
式的烷基膦;式的烷基胺;
其中Rf和Rg各自独立地选自:
H,C1-C8烷基;并且m是1-8。
3.根据前述权利要求中任一项所述的式(I)化合物,其中W1,W2和所述或每个W中的至少一个上的R1,R2,R3,R4或R5中的2个或更多个独立地选自:
式的烷基膦;式的烷基胺;
其中Rf和Rg各自独立地选自:
H,C1-C8烷基;并且m是1-8。
4.根据前述权利要求中任一项所述的式(I)化合物,其特征在于R1,R2,R3,R4或R5均不是位于相对于选自以下的所述或每个R1,R2,R3,R4或R5的邻位或对位的吸电子基团:
式的烷基膦;式的烷基胺;
其中Rf和Rg各自独立地选自:
H,C1-C8烷基;并且m是1-8。
5.根据前述权利要求中任一项所述的式(I)化合物,其特征在于R1,R2,R3,R4或R5均不是位于相对于选自以下的所述或每个R1,R2,R3,R4或R5的间位的给电子基团:
式的烷基膦;式的烷基胺;
其中Rf和Rg各自独立地选自:
H,C1-C8烷基;并且m是1-8。
6.根据前述权利要求中任一项所述的式(I)化合物,其特征在于R1,R2,R3,R4或R5中的至少一个是位于相对于选自以下的所述或每个R1,R2,R3,R4或R5的邻位或对位的给电子基团:
式的烷基膦;式的烷基胺;
其中Rf和Rg各自独立地选自:
H,C1-C8烷基;并且m是1-8。
7.根据前述权利要求中任一项所述的式(I)化合物,其特征在于R1,R2,R3,R4或R5中的至少一个是位于相对于选自以下的所述或每个R1,R2,R3,R4或R5的间位的吸电子基团:
式的烷基膦;式的烷基胺;
其中Rf和Rg各自独立地选自:
H,C1-C8烷基;并且m是1-8。
8.根据权利要求4或7所述的式(I)化合物,其中所述吸电子基团选自:
选自F,Cl,Br,I的卤素;式-(CH2)nX的烷基卤素;式-C(O)OH的羧酸,式-(CH2)nC(O)OH的烷基羧酸;式-OC(O)Rb的酯;式-(CH2)nOC(O)Rb的烷基酯;式-C(O)H的醛;式-(CH2)nC(O)H的烷基醛;式-C(O)Ra的酮;式-(CH2)nC(O)Ra的烷基酮;式-S(O)(O)Ra的硫酸酯;式-(CH2)nS(O)(O)Ra的烷基硫酸酯;式-CN的腈(氰基);式-(CH2)nCN的烷基腈;式-NO2的硝基;式-(CH2)nNO2的烷基硝基;式-C(O)NRaRb的酰胺;式-(CH2)nC(O)NRaRb的烷基酰胺;式-NRaC(O)Rb的酰胺;式-(CH2)nNRaC(O)Rb的烷基酰胺;
其中Ra,Rb,Rc和Rd独立地选自H或C1-4烷基,其中X是卤素,并且n=1-4。
9.根据权利要求5或6所述的式(I)化合物,其中所述给电子基团选自:
式-NRaRb的胺;式-(CH2)nNRaRb的烷基胺;式-PRaRb的膦;式-(CH2)nPRaRb的烷基膦;式-OH的羟基;式-(CH2)nOH的烷基羟基;式-ORa的醚;式-(CH2)nORa的烷基醚;式-NH-C(O)-Rb的酰胺;式-(CH2)nNH-C(O)-Rb的烷基酰胺;式-OC(O)Rb的酯;式-(CH2)nOC(O)Rb的烷基酯;苯基;式-(CH2)nPh的烷基苯基;式-C=C(Ra)(Rb)的乙烯基;式-(CH2)nC=C(Ra)(Rb)的烷基乙烯基;式的胍;式的烷基胍;式的脒;和式的烷基脒;
其中Ra,Rb,Rc和Rd独立地选自H或C1-4烷基,其中X是卤素,并且n=1-4。
10.根据前述权利要求中任一项所述的式(I)化合物,其中W1,W2和每个或所述W中的每个是相同的。
11.根据前述权利要求中任一项所述的式(I)化合物,其中W1,W2和每个或所述W各自独立地选自:C2-4烷基;C2 E-烯烃,V和Z在1和2位,和C2 Z-烯烃,V和Z在1和2位。
12.根据前述权利要求中任一项所述的式(I)化合物,其中W1,W2和每个或所述W各自独立地选自:C2 E-烯烃,V和Z在1和2位,和C2 Z-烯烃,V和Z在1和2位。
13.根据前述权利要求中任一项所述的式(I)化合物,其中W1,W2和所述或每个W中的至少一个上的R1,R2,R3,R4或R5中的至少一个选自:
式的烷基胺;
其中Rf和Rg各自独立地选自:
H,C1-C8烷基;并且m是1-8。
14.根据前述权利要求中任一项所述的式(I)化合物,其中W1,W2和所述或每个W中的至少一个上的R1,R2,R3,R4或R5中的至少一个选自:
式的烷基胺;
其中Rf和Rg各自独立地选自:H,C1-C8烷基;并且m是1-8。
15.根据前述权利要求中任一项所述的式(I)化合物,其中W1,W2和所述或每个W中的至少一个上的R1,R2,R3,R4或R5中的至少一个选自:
式的烷基胺;
其中Rf和Rg各自独立地选自:H,C1-C4烷基。
16.根据前述权利要求中任一项的式(I)化合物,其中W1,W2和所述或每个W中的至少一个上的R1,R2,R3,R4或R5中的至少一个选自:
式的烷基胺;
其中Rf和Rg各自独立地选自:H,C1-C2烷基。
17.根据前述权利要求中任一项所述的式(I)化合物,其中W1,W2和所述或每个W中的至少一个上的R1,R2,R3,R4或R5中的至少一个选自:
式的烷基胺;
其中m是1-4。
18.根据前述权利要求中任一项所述的式(I)化合物,其中W1,W2和所述或每个W中的至少一个上的R1,R2,R3,R4或R5中的至少一个选自:
式的烷基胺;
其中m是1。
19.根据前述权利要求中任一项所述的式(I)化合物,其中V是苯环。
20.根据前述权利要求中任一项所述的式(I)化合物,其中每个Z是苯环。
21.具有以下结构式的式(I)化合物,或其药学上可接受的盐:
22.具有以下结构式的式(I)化合物,或其药学上可接受的盐:
23.一种治疗受试者的革兰氏阴性细菌感染的方法,其包括向所述受试者施用有效量的根据权利要求1所述的式(I)化合物或其药学上可接受的盐的步骤。
24.根据权利要求23所述的方法,其中根据权利要求1所述的式(I)化合物或其药学上可接受的盐的R1至R5均不是:
式的铵盐;式的烷基铵盐;式的鏻盐;或式的烷基鏻盐。
25.根据权利要求1所述的式(I)化合物或其药学上可接受的盐在制备用于治疗或预防有需要的受试者的细菌感染或疾病的药物中的用途,其中所述细菌感染或疾病是由革兰氏阴性细菌造成。
26.一种制剂,其包含治疗有效量的根据权利要求1所述的式(I)化合物及其药学上可接受的盐,和药学上可接受的载体或稀释剂。
27.根据权利要求1所述的式(I)化合物或其药学上可接受的盐,其用于治疗或预防有需要的受试者的革兰氏阴性细菌感染的方法,所述方法包括向所述受试者施用治疗有效量的式(I)化合物或其治疗上可接受的盐,其中所述细菌感染或疾病是由革兰氏阴性细菌造成。
28.根据权利要求1所述的式(I)化合物或其药学上可接受的盐用于治疗或预防有需要的受试者的细菌感染或疾病的用途,其中所述细菌感染或疾病是由革兰氏阴性细菌造成。
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PCT/AU2017/050654 WO2018000028A1 (en) | 2016-07-01 | 2017-06-27 | Novel antibiotics |
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JP (1) | JP2019529338A (zh) |
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CN (1) | CN109415297A (zh) |
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WO2011075766A1 (en) * | 2009-12-21 | 2011-06-30 | The University Of Western Australia | Antimicrobial compounds |
WO2012017119A2 (es) * | 2010-08-02 | 2012-02-09 | Universidad Castilla La Mancha | Vectores no virales para terapia génica |
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JP2010512366A (ja) * | 2006-12-11 | 2010-04-22 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Mch拮抗活性を有する新規ピリダジン誘導体及びこれらの化合物を含む薬物 |
US20090092574A1 (en) * | 2006-12-29 | 2009-04-09 | Scott Richard W | Ophthalmic And Otic Compositions Of Facially Amphiphilic Polymers And Oligomers And Uses Thereof |
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US9951097B2 (en) * | 2012-12-04 | 2018-04-24 | The Board Of Trustees Of The University Of Illinois | Antibacterial compounds targeting isoprenoid biosynthesis |
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EP3478654A1 (en) | 2019-05-08 |
KR20190025611A (ko) | 2019-03-11 |
US20190185417A1 (en) | 2019-06-20 |
RU2019102149A (ru) | 2020-08-03 |
EP3478654A4 (en) | 2020-02-26 |
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