RU2353616C2 - Производные 2-пиридона в качестве ингибиторов эластазы нейтрофилов и их применение - Google Patents

Производные 2-пиридона в качестве ингибиторов эластазы нейтрофилов и их применение Download PDF

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RU2353616C2
RU2353616C2 RU2006112428/04A RU2006112428A RU2353616C2 RU 2353616 C2 RU2353616 C2 RU 2353616C2 RU 2006112428/04 A RU2006112428/04 A RU 2006112428/04A RU 2006112428 A RU2006112428 A RU 2006112428A RU 2353616 C2 RU2353616 C2 RU 2353616C2
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Марьяна АНДЕРССОН (SE)
Марьяна Андерссон
Петер ХАНСЕН (SE)
Петер Хансен
Ханс ЛЁНН (SE)
Ханс Лённ
Антониос НИКИТИДИС (SE)
Антониос Никитидис
Петтер СЬЁЛИН (SE)
Петтер СЬЁЛИН
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Астразенека Аб
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Abstract

Настоящее изобретение относится к соединениям формулы (I), их получению и использованию в качестве ингибиторов эластазы и может быть применено в медицине. ! ! где Y=СН; R1 представляет собой Н или алкил; R2 представляет собой фенил или 5-6-членный гетероарил; G1 представляет собой фенил; R5 представляет собой H, галоген, алкил, CN или фторированный алкил; n=1-3; R4=Н; L представляет собой связь, О, NR29 или алкил; либо R4 и L соединены вместе так, что группа -NR4L- представляет собой 5-7-членное азациклическое кольцо; G2 представляет собой фенил, 5-6-членный гетероарил, циклоалкил, С4-7-гетероцикл, бицикл из двух конденсированных, связанных прямой связью или разделенных атомом О колец, выбранных из фенила, 5-6-членного гетероарила, циклоалкила или С4-7-гетероцикла; или когда L не представляет собой связь, G2 представляет собой Н; s=0-2; R25 представляет собой Н, алкил или циклоалкил; R29 представляет собой Н или алкил. Технический результат - получение новых биологически активных соединений. 6 н. и 4 з.п. ф-лы, 1 табл.

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Figure 00000085

Claims (10)

1. Соединение формулы (I)
Figure 00000086

где Y представляет собой СН;
R1 представляет собой H или С1-6алкил;
R2 представляет собой фенил или пяти- или шестичленное гетероароматическое кольцо, содержащее от 1 до 4 гетероатомов, независимо выбранных из О, S и N; где указанное ароматическое кольцо возможно замещено 1-3 заместителями, выбранными независимо из ОН, С1-6алкила, C1-6алкокси, NR58COR50, COOR51, CONR53R54 и NR47R48; где указанный алкил возможно дополнительно замещен ОН, C1-6алкокси, CN или CO2R49;
R47 и R48 независимо представляют собой Н, С1-6алкил или С2-6алканоил;
G1 представляет собой фенил;
R5 представляет собой Н, галоген, C1-6алкил, CN или C1-3алкил, замещенный одним или более чем одним атомом F;
n представляет собой целое число 1, 2 или 3 и, когда n представляет собой 2 или 3, каждая группа R5 выбрана независимо;
R4 представляет собой Н;
L представляет собой связь, О, NR29 или C1-6алкил;
либо R4 и L соединены вместе так, что группа -NR4L- представляет собой 5-7-членное азациклическое кольцо, возможно включающее один дополнительный гетероатом, выбранный из О, S и NR16;
G2 представляет собой моноциклическую кольцевую систему, выбранную из:
1) фенила,
2) 5- или 6-членного гетероароматического кольца, содержащего от одного до трех гетероатомов, независимо выбранных из О, S и N,
3) С3-6 насыщенного или частично ненасыщенного циклоалкила или
4) С4-7 насыщенного или частично ненасыщенного гетероциклического кольца, содержащего один или два гетероатома, независимо выбраных из О, S и NR17, и, возможно, дополнительно включающего карбонильную группу; или
G2 представляет собой бициклическую кольцевую систему, в которой эти два кольца либо конденсированы вместе, либо связаны вместе прямой связью, либо разделены атомом О, и каждое из двух колец независимо выбрано из:
1) фенила,
2) 5- или 6-членного гетероароматического кольца, содержащего от одного до трех гетероатомов, независимо выбранных из О, S и N,
3) С3-6 насыщенного или частично ненасыщенного циклоалкила или
4) С4-7 насыщенного или частично ненасыщенного гетероциклического кольца, содержащего один или два гетероатома, независимо выбранных из O, S и NR17, и, возможно, дополнительно включающего карбонильную группу;
где указанная моноциклическая или бициклическая кольцевая система возможно дополнительно замещена заместителями в количестве от одного до трех, независимо выбранными из CN, ОН, C1-6алкила, C1-6алкокси, галогена, S(O)sR25, SO2NR26R27 и С1-3алкила, замещенного SO2R39; или когда L не представляет собой связь, G2 может также представлять собой Н;
s представляет собой целое число 0, 1 или 2;
R25 представляет собой Н, C1-6алкил или С3-6циклоалкил;
R16, R17, R26, R27, R29, R39, R49, R50, R51, R53, R54 и R58 независимо представляют собой Н или С1-6алкил;
и его фармацевтически приемлемые соли.
2. Соединение формулы (I) по п.1, где R5 представляет собой Cl, СН3, CN или CF3.
3. Соединение по п.1, которое представляет собой 6-метил-5-(1-метил-1Н-пиразол-5-ил)-N-{[5-(метилсульфонил)пиридин-2-ил]метил}-2-оксо-1-[3-(трифторметил)фенил]-1,2-дигидропиридин-3-карбоксамид или его фармацевтически приемлемую соль.
4. Соединение формулы (I) по п.1 или его фармацевтически приемлемая соль для применения в качестве лекарства.
5. Фармацевтическая композиция, ингибирующая активность эластазы нейтрофилов, содержащая соединение формулы (I), как оно определено в любом из пп.1-3, или его фармацевтически приемлемую соль, в смеси с фармацевтически приемлемым разбавителем или носителем.
6. Применение соединения формулы (I), как оно определено в любом из пп.1-3, или его фармацевтически приемлемой соли в производстве лекарства для лечения или профилактики заболеваний или состояний человека, при которых благотворным является ингибирование активности эластазы нейтрофилов.
7. Применение по п.6 в производстве лекарства для лечения или профилактики воспалительных заболеваний или состояний.
8. Способ получения соединения формулы (I), как оно определено в любом из пп.1-3, и его оптических изомеров, рацематов и таутомеров, а также фармацевтически приемлемых солей, при котором подвергают взаимодействию соединение формулы (II)
Figure 00000087

где R1, R4, R5, Y, G1, G2, L и n являются такими, как определено в формуле (I), и Hal представляет собой атом галогена, предпочтительно бромо или йодо, с нуклеофилом R2-М, где R2 является таким, как определено в формуле (I), a M представляет собой группу оловоорганической или борорганической кислоты, и, если желательно или необходимо, превращают полученное в результате соединение формулы (I) или другую его соль в его фармацевтически приемлемую соль.
9. Способ получения соединения формулы (I), как оно определено в любом из пп.1-3, и его оптических изомеров, рацематов и таутомеров, а также фармацевтически приемлемых солей, при котором:
когда R2 представляет собой кольцо 1,3,4-оксадиазол-2-ил или 1,3,4-тиадиазол-2-ил, подвергают взаимодействию соединение формулы (III)
Figure 00000088

где R1, R4, R5, Y, G1, G2, L и n являются такими, как определено в формуле (I), Z представляет собой О или S, и Х представляет собой C1-6алкил или NR47R48, a R47 и R48 являются такими, как определено в формуле (I), с подходящим дегидратирующим агентом, таким как фосфорилхлорид или триметилсилилполифосфат;
и, если желательно или необходимо, превращают полученное в результате соединение формулы (I) или другую его соль в его фармацевтически приемлемую соль.
10. Способ получения соединения формулы (I), как оно определено в любом из пп.1-3, и его оптических изомеров, рацематов и таутомеров, а также фармацевтически приемлемых солей, при котором:
подвергают взаимодействию соединение формулы (XV)
Figure 00000089

где R1, R2, R5, n, G1 и Y являются такими, как определено в формуле (I), a
L1 представляет собой уходящую группу,
с соединением формулы (IX) или его солью
Figure 00000090

где R4, G2 и L являются такими, как определено в формуле (I);
и, если желательно или необходимо, превращают полученное в результате соединение формулы (I) или другую его соль в его фармацевтически приемлемую соль.
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BRPI0414548A8 (pt) 2018-12-26
CA2538405A1 (en) 2005-03-24
JP4515455B2 (ja) 2010-07-28
AU2004272484B2 (en) 2008-03-13
RU2006112428A (ru) 2007-11-10
KR20060087569A (ko) 2006-08-02
ES2448465T3 (es) 2014-03-14
AU2004272484A1 (en) 2005-03-24
CO5670358A2 (es) 2006-08-31
WO2005026123A1 (en) 2005-03-24
CA2538405C (en) 2012-07-03
EP1663973B1 (en) 2013-12-25
TW200526581A (en) 2005-08-16
ZA200602261B (en) 2007-07-25
BRPI0414548B8 (pt) 2021-05-25
CN1882542B (zh) 2011-11-09
ES2448465T7 (es) 2020-04-29
BRPI0414548B1 (pt) 2019-02-05
CN1882542A (zh) 2006-12-20
AU2004272484C1 (en) 2011-01-20
US8063073B2 (en) 2011-11-22
US8501784B2 (en) 2013-08-06
NO20061660L (no) 2006-04-11
NZ545963A (en) 2009-09-25
SE0302486D0 (sv) 2003-09-18
MY143400A (en) 2011-05-13
IL173990A (en) 2012-01-31
HK1089166A1 (en) 2006-11-24
IS8381A (is) 2006-03-28
US20120035157A1 (en) 2012-02-09
KR101141464B1 (ko) 2012-05-24
SA04250299B1 (ar) 2009-01-31
MXPA06002724A (es) 2006-06-06
US20070203129A1 (en) 2007-08-30

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