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RU2018122505A - Макроциклические антибиотики широкого спектра действия - Google Patents

Макроциклические антибиотики широкого спектра действия Download PDF

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RU2018122505A
RU2018122505A RU2018122505A RU2018122505A RU2018122505A RU 2018122505 A RU2018122505 A RU 2018122505A RU 2018122505 A RU2018122505 A RU 2018122505A RU 2018122505 A RU2018122505 A RU 2018122505A RU 2018122505 A RU2018122505 A RU 2018122505A
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Юньшэнь ЧЭНЬ
Такер Карран Робертс
Роберт И. Хигучи
Прасуна Параселли
Чжиоюн ЮЙ
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АрКьюИкс ФАРМАСЬЮТИКЭЛС, ИНК.
Дженетек, Инк.
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Claims (51)

1. Соединение формулы (I'):
Figure 00000001
где:
R1 и R2 каждый независимо представляет собой Н, -(С1-С6)алкил, -(С1-С6)алкил-OR23, -CH2CH(OH)CH2NH2, -СН2СН(гетероциклоалкил)CH2NH2, -CH2C(O)NH2, -CH2C(O)N(H)CH2CN, -(С1-С6)алкил-С(O)OR23, -(С1-С6)алкил-NR21R22, -(С1-С6)алкил-C(O)NR25R26, -(С1-С6)алкил-N(R23)С(O)(С1-C6)алкилNR21R22, -(С1-С6)алкил-C(O)N(R23)(C1-С6)алкил, -(C1-C6)алкил-C(O)N(R23)(C1-C6)алкилгетероциклоалкил, (С1-С6)гетероалкил или необязательно замещенный гетероциклоалкил;
R3 представляет собой Н или -(С1-С6)алкил;
R4 представляет собой Н, -(С1-С6)алкил, -(С1-С6)алкил-ОН, -(С3-С6)циклоалкил или -C(O)NH2; или R3 и R4 объединены с образованием гетероциклоалкильного кольца;
R5 представляет собой Н или -(С1-С6)алкил; или R4 и R5 и атом углерода, к которому они присоединены, образуют циклопропильное кольцо;
R6, R7 и R8 каждый независимо представляет собой Н, фтор, гидроксил, амино, необязательно замещенный -(С1-С6)алкил или -(С1-С6)гетероалкил;
R9 представляет собой Н, -(С1-С6)алкил, -(С1-С6)галогеналкил или -(С3-С6)циклоалкил;
R10 представляет собой Н, -(С1-С6)алкил, -(С1-С6)галогеналкил или -(С3-С6)циклоалкил;
или R9 и R10 объединены с образованием гетероциклоалкильного или циклоалкильного кольца;
R11 и R12 каждый независимо представляет собой Н, -NH2, -(С1-С6)алкил, -(C1-C6)алкил-OR23, -(C1-C6)алкил-SR23, -(C1-C6)алкил-C(O)OR23, -(C1-C6)алкил-NR21R22, -(C1-С6)алкил-CN, -(C1-C6)алкил-C(O)NR25R26, -(С1-С6)гетероалкил-CO2H, -(С1-С6)алкил-S(O)-(С1-С6)алкил, -(С1-С6)алкил-N(Н)СН=NH, -(С1-С6)алкил-С(NH2)=NH, -(С1-С6)алкил-N(H)C(NH)NH2, -(C1-C6)алкил-N(H)SO2NR25R26, -(C1-C6)алкил-N(H)-C(O)NR25R26, -(C1-С6)алкилгетероциклоалкил, необязательно замещенный -(С1-С6)алкил-N(Н)гетероциклоалкил или -(С1-С6)алкилгетероарил; или R11 и R18 объединены с образованием необязательно замещенного гетероциклоалкильного кольца и R12 представляет собой Н;
R15, R16, R17 и R18 каждый независимо представляет собой Н, -(С1-С6)алкил, -(С3-С6)циклоалкил, -(C1-C6)алкил-OR23, -(C1-C6)алкил-C(O)OR23 или -(C1-C6)алкил-NR21R22;
X представляет собой необязательно замещенный -(С1-С6)алкил-, -(С2-С6)алкенил-, -(С2-С6)алкинил, -(С3-С7)циклоалкил-, необязательно замещенный гетероциклоалкил, необязательно замещенный арил, необязательно замещенный гетероарил, -O-(C1-С6)алкил-, -N(R24)(С1-С6)алкил-, -N(R24)(C6-C10)арил- или -SO2(С1-С6)алкил-;
Y представляет собой связь, необязательно замещенный -(С1-С6)алкил-, -(С2-С6)алкенил-, -(С2-С6)алкинил, -(C1-C6)алкил-N(R24)(C1-C6)алкил-, -O-(С1-С6)алкил-, -O(С6-С10)арил-, -N(R24)(C1-C6)алкил-, -N(R24)SO2(C1-C6)алкил-, -N(R24)C(O)(C1-C6)алкил-, -С(O)(С1-С6)алкил-, -S(С1-С6)алкил-, -SO2(С1-С6)алкил-, -С(O)NH(С1-С6)алкил-, -(С3-С7)циклоалкил-, необязательно замещенный -С(O)N(R24)арил-, необязательно замещенный -N(R24)C(O)арил-, необязательно замещенный -N(R24)SО2арил-, необязательно замещенный арил или необязательно замещенный гетероарил;
Z представляет собой Н, галоген, -NH2, -CN, -CF3, -CO2H, -(С1-C12)алкил, -(С2-С12)алкенил, -(С2-С12)алкинил, -C(O)NR25R26, -O-(С1-С12)алкил, -N(R24)(C1-C12)алкил, -N(R24)C(O)(C1-C12)алкил, необязательно замещенный -(С3-С7)циклоалкил, -(C1-С6)алкилгетероциклоалкил, необязательно замещенный арил или необязательно замещенный гетероарил;
каждый R21 и R22 независимо представляет собой Н, -(С1-С6)алкил, -(C1-С6)гетероалкил, -(С1-С6)алкил-CO2H, -С(O)(С1-С6)алкил, -С(O)O(С1-С6)алкил, -C(O)O(C1-С6)галогеналкил, -С(=NH)(С1-С6)алкил, -C(=NH)N(R31)2, -C(O)N(R31)2 или -SO2N(R31)2; или R21 и R22 и атом азота, к которому они присоединены, образуют гетероциклоалкильное кольцо;
каждый R31 независимо представляет собой Н или -(С1-С6)алкил; или два R31 и атом азота, к которому они присоединены, образуют гетероциклоалкильное кольцо;
каждый R23 независимо представляет собой Н или -(C1-С6)алкил;
каждый R24 независимо представляет собой Н или -(С1-С6)алкил;
каждый R25 и R26 независимо представляет собой Н или необязательно замещенный -(С1-С6)алкил; или R25 и R26 и атом азота, к которому они присоединены, образуют гетероциклоалкильное кольцо;
каждый R27 независимо представляет собой галоген, -NR23R24, -NC(O)R23, -NC(O)NR23R24), нитро, гидроксил, необязательно замещенный -(С1-С6)алкил, необязательно замещенный -(С1-С6)гетероалкил, -(С1-С6)алкокси, -С(O)(С1-С6)алкил или -S(O)2(С1-С6)алкил;
каждый R28 независимо представляет собой галоген, -NR23R24, -NC(O)R23, -NC(O)NR23R24), нитро, гидроксил, необязательно замещенный -(С1-С6)алкил, необязательно замещенный -(С1-С6)гетероалкил, -(С1-С6)алкокси, -С(O)(С1-С6)алкил или -S(O)2(С1-С6)алкил;
р равно 0, 1 или 2; и
q равно 0, 1 или 2;
или его фармацевтически приемлемая соль, сольват или пролекарство.
2. Соединение по п. 1, характеризующееся структурой формулы (Ia)
Figure 00000002
3. Соединение по п. 1 или 2, характеризующееся структурой формулы (Ib)
Figure 00000003
4. Соединение по любому из пп. 1-3, где R17 представляет собой -СН3 и R18 представляет собой Н.
5. Соединение по любому из пп. 1-4, где R4 представляет собой Н, -(С1-С6)алкил или -(С3-С6)циклоалкил; и R5 представляет собой Н.
6. Соединение по любому из пп. 1-5, где R9 представляет собой -(С1-С6)алкил.
7. Соединение по п. 3, характеризующееся структурой формулы (Ic)
Figure 00000004
8. Соединение по любому из пп. 1-7, где R11 представляет собой -(С1-С6)алкил-OR23, -(С1-С6)алкил или -(С1-С6)алкил-NR21R22.
9. Соединение по любому из пп. 1-8, где R1 и R2 каждый независимо представляет собой Н или -(С1-С6)алкил-NR21R22.
10. Соединение по п. 7, характеризующееся структурой формулы (Id):
Figure 00000005
где R11 представляет собой -CH2CH2NH2 или -CH2CH2CH2NH2.
11. Соединение по любому из пп. 1-10, где X представляет собой необязательно замещенный арил, необязательно замещенный гетероарил или необязательно замещенный -(С1-С6)алкил-.
12. Соединение по любому из пп. 1-11, где Y представляет собой связь, необязательно замещенный арил, необязательно замещенный гетероарил, необязательно замещенный -(С1-С6)алкил-, -O-(С1-С6)алкил- или -N(Н)-(С1-С6)алкил-.
13. Соединение по любому из пп. 1-12, где Z представляет собой -(С1-С6)алкил, необязательно замещенный арил, необязательно замещенный гетероарил, необязательно замещенный -(С3-С7)циклоалкил или галоген.
14. Соединение по любому из пп. 1-13, где -X-Y-Z представляет собой
Figure 00000006
Figure 00000007
Figure 00000008
Figure 00000009
15. Фармацевтическая композиция, содержащая соединение по любому из пп. 1-14 или его фармацевтически приемлемую соль, фармацевтически приемлемый сольват или фармацевтически приемлемое пролекарство и фармацевтически приемлемое вспомогательное вещество.
16. Способ лечения бактериальной инфекции у млекопитающего, включающий в себя введение млекопитающему эффективного количества соединения по любому из пп. 1-14 или его фармацевтически приемлемой соли, фармацевтически приемлемого сольвата или фармацевтически приемлемого пролекарства млекопитающему с частотой и длительностью, достаточных для обеспечения благоприятного эффекта по отношению к млекопитающему.
17. Способ по п. 16, при котором бактериальной инфекцией является инфекция, которая включает в себя Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis или Staphylococcus saccharolyticus.
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