RU2328486C2 - Производные 2-пиридона в качестве ингибиторов нейтрофильной эластазы - Google Patents

Производные 2-пиридона в качестве ингибиторов нейтрофильной эластазы Download PDF

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RU2328486C2
RU2328486C2 RU2005113168/04A RU2005113168A RU2328486C2 RU 2328486 C2 RU2328486 C2 RU 2328486C2 RU 2005113168/04 A RU2005113168/04 A RU 2005113168/04A RU 2005113168 A RU2005113168 A RU 2005113168A RU 2328486 C2 RU2328486 C2 RU 2328486C2
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alkyl
formula
compound
independently selected
phenyl
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RU2005113168A (ru
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Хокан БЛАД (SE)
Хокан БЛАД
Томас КЛИНГСТЕДТ (SE)
Томас Клингстедт
Йоаким ЛАРССОН (SE)
Йоаким ЛАРССОН
Каролина ЛАВИЦ (SE)
Каролина Лавиц
Матти ЛЕПИСТЁ (SE)
Матти Лепистё
Ханс ЛЕНН (SE)
Ханс ЛЕНН
Григориос НИКИТИДИС (SE)
Григориос НИКИТИДИС
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Астразенека Аб
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Abstract

Изобретение относится к производным 2-пиридона общей формулы (I)
Figure 00000001
где X, Y1, R1, Y2, G1, R5, R4, L, G2 такие, как указано в формуле изобретения. Также данное изобретение относится к фармацевтическому препарату, ингибирующему активность нейтрофильной эластазы человека, содержащему соединение формулы (I), к применению соединения формулы (I), в производстве лекарства, а также к способу получения соединения формулы (I). Технический результат: получение новых соединений, которые являются ингибиторами активности нейтрофильной эластазы. 5 н. и 3 з.п. ф-лы, 1 табл.

Description

Текст описания приведен в факсимильном виде.
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Claims (8)

1. Соединение формулы (I)
Figure 00000175
где X представляет собой О;
Y1 представляет собой N или CR2; и когда R1 представляет собой ОН, Y1 в таутомерной форме также может представлять собой NR6;
Y2 представляет собой CR3; и когда Y1 представляет собой CR2, тогда Y2 также может представлять собой N;
R1 представляет собой Н или С1-6алкил, причем указанный алкил возможно замещен одним или более чем одним заместителем, независимо выбранным из галогена, CN, CHO, OR7, NR8R9, S(O)mR10 и SO2NR11R12;
и когда Y1 представляет собой N, R1 также может представлять собой ОН;
R7 представляет собой Н или С1-6алкил;
R2 представляет собой Н, галоген или C1-6алкил;
R3 представляет собой Н;
G1 представляет собой фенил или пяти- или шестичленное гетероароматическое кольцо, содержащее от 1 до 3 гетероатомов, независимо выбранных из О, S и N;
R5 представляет собой Н, галоген, С1-6алкил, CN, С1-6алкокси или С1-3алкил, 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 и R6 независимо представляют собой Н или C1-6алкил, причем указанный алкил возможно дополнительно замещен ОН или С1-6алкокси;
или R4 и L соединены вместе так, что группа -NR4L представляет собой 5-7-членное азациклическое кольцо, возможно содержащее один дополнительный гетероатом, выбранный из О, S и NR16;
L представляет собой связь, О, NR29 или C1-6алкил, причем указанный алкил возможно содержит гетероатом, выбранный из О, S и NR16, и указанный алкил возможно дополнительно замещен ОН или ОМе;
G2 представляет собой моноциклическую кольцевую систему, выбранную из:
1) фенила или фенокси,
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 выбранные из О, S(O)p и NR17, и возможно дополнительно содержащего карбонильную группу; или
G2 представляет собой бициклическую кольцевую систему, в которой 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 выбранные из О, S(O)p и NR17, и возможно дополнительно содержащего карбонильную группу;
и эти два кольца либо конденсированы друг с другом, либо связаны непосредственно друг с другом, либо разделены линкерной группой, выбранной из О, S(O)q или СН2,
причем указанная моноциклическая или бициклическая кольцевая система возможно дополнительно замещена одним-тремя заместителями, независимо выбранными из CN, ОН, С1-6алкила, C1-6алкокси, галогена, NR18R19, OSO2R38, CO2R20, S(O)sR25, SO2NR26R27, С1-3алкокси, замещенного одним или более чем одним атомом F, и C1-3алкила, замещенного SO2R39 или одним или более чем одним атомом F; или
когда L не представляет собой связь, тогда G2 также может представлять собой Н;
m, р, q, s и t независимо представляют собой целое число 0, 1 или 2;
R8 и R9 независимо представляют собой Н или C1-6алкил, причем указанный алкил возможно дополнительно замещен фенилом, возможно замещенным SO2R30;
или группа NR8R9 вместе представляет собой 5-7-членное азациклическое кольцо, возможно содержащее один дополнительный гетероатом, выбранный из О, S и NR28;
R18 и R19 независимо представляют собой Н, C1-6алкил, С2-6алканоил, S(O)tR32 или SO2NR33R34, причем указанная алкильная группа возможно дополнительно замещена CN, С1-4алкокси или CONR41R42;
R25 представляет собой Н, C1-6алкил или С3-6циклоалкил, причем указанная алкильная группа возможно дополнительно замещена одним или более чем одним заместителем, независимо выбранным из ОН, CN, CONR35R36, CO2R37, С3-6циклоалкила, C4-7 насыщенного гетероциклического кольца, содержащего один или два гетероатома, независимо выбранные из О и NR43, и фенила или 5-или 6-членного гетероароматического кольца, содержащего от одного до трех гетероатомов, независимо выбранных из О, S и N, причем указанное ароматическое кольцо возможно дополнительно замещено одним или более чем одним заместителем, независимо выбранным из CN, С1-6алкила и NHCOCH3;
R26 и R27 независимо представляют собой Н, C1-6алкил или С2-6алканоил;
R32 представляет собой Н, C1-6алкил или С3-6циклоалкил;
R38 представляет собой С1-6алкил;
R10, R11, R12, R16, R17, R20, R28, R29, R30, R33, R34, R35, R36, R37, R39, R41, R42, и R43 независимо представляют собой Н или С1-6алкил;
и его фармацевтически приемлемые соли, при условии, что следующие соединения исключены:
N-бензил-5,6-диметил-2-оксо-1-фенил-1,2-дигидропиридин-3-карбоксамид,
N-(2-фенэтил)-5,6-диметил-2-оксо-1-фенил-1,2-дигидропиридин-3-карбоксамид,
N-(2-гидроксиэтил)-2,4-диоксо-3-фенил-1,2,3,4-тетрагидропиримидин-5-карбоксамид,
N-[2-(диметиламино)этил]-2,4-диоксо-3-фенил-1,2,3,4-тетрагидропиримидин-5-карбоксамид.
2. Соединение по п.1, где R2 представляет собой Н.
3. Соединение формулы (I) по п.1 или 2, где G1 представляет собой фенил или пиридил.
4. Соединение формулы (I) по п.1 или его фармацевтически приемлемая соль для применения в качестве лекарственного средства.
5. Фармацевтический препарат, ингибирующий активность нейтрофильной эластазы человека, содержащий соединение формулы (I), как оно определено в любом из пп.1-3, или его фармацевтически приемлемую соль, возможно, 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 полезно ингибирование активности нейтрофильной эластазы.
7. 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 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, и его фармацевтически приемлемых солей, включающий взаимодействие соединения формулы (II)
Figure 00000176
где R1,R5, Y1, Y2, X, G1 и n являются такими, как определено в п.1, и L1 представляет собой уходящую группу,
с амином формулы (III) или его солью,
Figure 00000177
где R4, G2 и L являются такими, как определено в п.1, и, если желательно или необходимо, превращение полученного соединения формулы (I) или другой его соли в его фармацевтически приемлемую соль; или превращение одного соединения формулы (I) в другое соединение формулы (I); и, если желательно, превращение полученного соединения формулы (I) в его оптический изомер.
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