RU2345067C2 - Ингибиторы дпп-iv - Google Patents

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RU2345067C2
RU2345067C2 RU2006131597/04A RU2006131597A RU2345067C2 RU 2345067 C2 RU2345067 C2 RU 2345067C2 RU 2006131597/04 A RU2006131597/04 A RU 2006131597/04A RU 2006131597 A RU2006131597 A RU 2006131597A RU 2345067 C2 RU2345067 C2 RU 2345067C2
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Russia
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RU2006131597/04A
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RU2006131597A (ru
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Пол Джон ЕДВАРДС (DE)
Пол Джон ЕДВАРДС
Ахим ФЕУРЕР (DE)
Ахим ФЕУРЕР
Силви СЕРЕЗО-ГАЛВЕЗ (DE)
Силвия СЕРЕЗО-ГАЛВЕЗ
Виктор Гиулио МАТАССА (ES)
Виктор Гиулио МАТАССА
Сон НОРДХОФФ (DE)
Соня НОРДХОФФ
Клауди РОСЕНБАУМ (DE)
Клаудия РОСЕНБАУМ
Стефан БУЛАТ (DE)
Стефан БУЛАТ
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Сантера Фармасьютикалс (Швейц) Гмбх
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Abstract

Настоящее изобретение относится к новым соединениям общей формулы (I)
Figure 00000109
или их фармацевтически приемлемым солям, где Z представляет собой фенил; где Z может быть замещен одним или более R8, где R8 представляет собой галоген; R1, R4 представляют собой Н; R2, R5 представляют собой H; R3 представляет собой Н; Х выбран из группы, состоящей из S(O)2 и С(O); R6, R7 независимо выбраны из группы, состоящей из Н, (C(R29R30))m-X1-Z1 и (C(R31R32))n-X2-X3-Z2 и С1-4алкил, который несет замещение одним или более R29a, где R29a независимо выбран из группы, состоящей из R29b и Z1, при условии, что R6 и R7 выбирают таким образом, чтобы R6 и R7 не были одновременно независимо выбраны из группы, состоящей из Н, СН3, СН2СН3, СН2СН2СН3 и СН(СН3)2; R29, R29b, R30, R31, R32 независимо выбраны из группы, состоящей из Н, C1-6алкила и N(R32a)-C1-6алкила, R32a представляет собой C1-6алкил; m равно 0, 1 или 2; n равно 2; X1 независимо выбран из группы, состоящей из ковалентной связи, -C1-6алкила и -C1-6алкил-N(R33)-; X2 представляет собой -N(R35)-; X3 представляет собой -С(O)-; R33 представляет собой С1-6алкил; R35 представляет собой Н; Z1, Z2 независимо выбраны из группы, состоящей из Z3 и -C(R37a)Z3aZ3b; R37a представляет собой Н; Z3, Z3a, Z3b независимо выбраны из группы, состоящей из Т1, Т2, C1-6алкила, C1-6алкил-Т1 и C1-6алкил-Т2; Т1 представляет собой фенил; где Т1 факультативно несет замещение одним или более R38; причем R38 независимо выбран из группы, состоящей из галогена, CN, R39, C(O)NH2, S(O)2NH2, ОТ3, C(O)N(R40)T3 и Т3, Т2 выбран из группы, состоящей из С3-7циклоалкила, инданила, тетралинила, гетероцикла и гетеробицикла, причем Т2 факультативно несет замещение одним или более R41, где R41 независимо выбран из группы, состоящей из галогена, R42, OH и Т3; R39 выбран из группы, состоящей из C1-6алкила, O-C1-6алкила, S-C1-6алкила, C(O)N(R44)-C1-6алкила, S(O)-С1-6алкила и S(O)2-C1-6алкила, где каждый C1-6алкил факультативно несет замещение одним или более R45, где R45 независимо выбран из группы, состоящей из F, N(R46R47) и Т3; R42 представляет собой C1-6алкил, причем каждый C1-6алкил факультативно несет замещение одним или более R45, где R45 независимо выбран из группы, состоящей из F; R40, R46, R47 независимо выбраны из группы, состоящей из Н и C1-6алкила; R44 представляет собой Н; Т3 выбран из группы, состоящей из Т4 и Т5; Т4 представляет собой фенил, где Т4 факультативно несет замещение одним или более R51, где R51 независимо выбран из группы, состоящей из галогена, OR52, S(O)2N(R52R53), C1-6алкила; R52, R53 независимо выбраны из группы, состоящей из Н и C1-6алкила; Т5 выбран из группы, состоящей из гетероцикла С3-7циклоалкила, где Т5 факультативно несет замещение одним или более R54, где R54 представляет собой C1-6алкил; где гетероцикл обозначает кольцо циклобутана, циклопентана, циклогексана, которое может содержать двойные связи в количестве вплоть до максимального, или ароматическое или неароматическое кольцо, которое является полностью или частично насыщенным, либо ненасыщенным, и в котором по меньшей мере один атом углерода, а максимально до четырех атомов углерода, заменены на гетероатом, выбранный из группы, включающей кислород и азот, и где кольцо связано с остальной частью молекулы через атом углерода или азота; где гетеробицикл обозначает гетероцикл, как определено выше, который конденсирован с фенилом или другим гетероциклом с образованием бициклической системы колец, при условии, что следующее соединение исключено из притязаний: 3-амино-N-циклогексил-4-фенилбутирамид. Также изобретение относится к фармацевтической композиции на основе соединения общей формулы (I) и к применению их для изготовления лекарственного средства для лечения и/или профилактики состояний, при которых желательно ингибирование ДПП-IV. Технический результат: получена новая группа соединений, обладающих полезными биологическими свойствами. 5 н. и 21 з.п. ф-лы, 8 табл.

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Claims (26)

1. Соединение формулы (I)
Figure 00000109

или его фармацевтически приемлемая соль, отличающееся тем, что
Z представляет собой фенил; где Z может быть замещен одним или более
R8, где R8 представляет собой галоген;
R1, R4 представляют собой Н;
R2, R5 представляют собой Н;
R3 представляет собой Н;
Х выбран из группы, состоящей из S(O)2 и С(O);
R6, R7 независимо выбраны из группы, состоящей из Н, (C(R29R30))mX1-Z1 и (C(R31R32))n-X2-X3-Z2 и С1-4алкил, который несет замещение одним или более R29a, где R29a независимо выбран из группы, состоящей из R29b и Z1, при условии, что R6 и R7 выбирают таким образом, чтобы R6 и R7 не были одновременно независимо выбраны из группы, состоящей из Н, СН3, СН2СН3, СН2СН2СН3 и СН(СН3)2;
R29 R29b, R30, R31, R32 независимо выбраны из группы, состоящей из Н, C1-6алкила и N(R32a)-С1-6алкила;
R32a представляет собой C1-6алкил;
m равно 0, 1 или 2;
n равно 2;
X1 независимо выбран из группы, состоящей из ковалентной связи, -C1-6алкила и -С1-6алкил-N(R33)-;
Х представляет собой -N(R35)-;
X3 представляет собой -С(O)-;
R33 представляет собой C1-6алкил;
R35 представляет собой Н;
Z1, Z2 независимо выбраны из группы, состоящей из Z3 и -C(R37a)Z3aZ3b;
R37a представляет собой Н;
Z3, Z3a, Z3b независимо выбраны из группы, состоящей из Т1, Т2, C1-6алкила, C1-6алкил-Т1 и C1-6алкил-Т2;
Т1 представляет собой фенил; где Т1 факультативно несет замещение одним или более R38; причем R38 независимо выбран из группы, состоящей из галогена, CN, R39, C(O)NH2, S(O)2NH2, ОТ3, C(О)N(R40)T3 и Т3, Т2 выбран из группы, состоящей из С3-7циклоалкила, инданила, тетралинила, гетероцикла и гетеробицикла, причем Т2 факультативно несет замещение одним или более R41, где R41 независимо выбран из группы, состоящей из галогена, R42, OH и Т3;
R39 выбран из группы, состоящей из С1-6алкила, O-C1-6алкила, S-C1-6алкила, С(O)N(R44)-С1-6алкила, S(O)-С1-6алкила и S(O)2-С1-6алкила, где каждый C1-6алкил факультативно несет замещение одним или более R45, где R45 независимо выбран из группы, состоящей из F, N(R46R47) и Т3;
R42 представляет собой C1-6алкил, причем каждый C1-6алкил факультативно несет замещение одним или более R45, где R45 независимо выбран из группы, состоящей из F;
R40, R46, R47 независимо выбраны из группы, состоящей из Н и C1-6алкила;
R44 представляет собой Н;
Т3 выбран из группы, состоящей из Т4 и Т5;
Т4 представляет собой фенил, где Т4 факультативно несет замещение одним или более R51, где R51 независимо выбран из группы, состоящей из галогена, OR52, S(O)2N(R52R53), С1-6алкила;
R52, R53 независимо выбраны из группы, состоящей из Н и C1-6алкила;
Т5 выбран из группы, состоящей из гетероцикла С3-7циклоалкила, где Т5 факультативно несет замещение одним или более R54, где R54 представляет собой C1-6алкил;
где гетероцикл обозначает кольцо циклобутана, циклопентана, циклогексана, которое может содержать двойные связи в количестве вплоть до максимального, или ароматическое или неароматическое кольцо, которое является полностью или частично насыщенным либо ненасыщенным, и в котором по меньшей мере один атом углерода, а максимально до четырех атомов углерода, заменены на гетероатом, выбранный из группы, включающей кислород и азот, и где кольцо связано с остальной частью молекулы через атом углерода или азота;
где гетеробицикл обозначает гетероцикл, как определено выше, который конденсирован с фенилом или другим гетероциклом с образованием бициклической системы колец,
при условии, что следующее соединение исключено из притязаний:
3-амино-N-циклогексил-4-фенилбутирамид.
2. Соединение по п.1 формулы (Ia)
Figure 00000110

или его фармацевтически приемлемая соль, отличающееся тем, что Z, R1-R7 и Х имеют значения, указанные в п.1.
3. Соединение по п.1, отличающееся тем, что Z возможно несет замещение 1 или 2 R8, которые могут быть одинаковыми или разными.
4. Соединение по п.1, отличающееся тем, что Z представляет собой 2-фторфенил.
5. Соединение по п.1, отличающееся тем, что R6 выбран из группы, состоящей из Н и СН3.
6. Соединение по п.1, отличающееся тем, что Х1 представляет собой ковалентную связь.
7. Соединение по п.1, отличающееся тем, что R7 представляет собой Z1.
8. Соединение по п.1, отличающееся тем, что R7 представляет собой С1-4алкил, замещенный 1-4 R29a, которые могут быть одинаковыми или разными.
9. Соединение по п.1, отличающееся тем, что R29a выбран из группы, состоящей из R29b и Z1, и где R29b представляет собой N(СН3)2.
10. Соединение по п.1, отличающееся тем, что R29a выбран из группы, состоящей из R29b и Z1, где Z1 выбран из группы, состоящей из Т1 и Т2.
11. Соединение по п.1, отличающееся тем, что Т1 представляет собой фенил, и где Т1 факультативно несет замещение одим-тремя R38, которые могут быть одинаковыми или разными.
12. Соединение по п.1, отличающееся тем, что R38 независимо выбран из группы, состоящей из F, Cl, CN, СН3, С2Н5, СН2CH2СН3, СН(СН3)2, CF3, O-СН3, O-С2Н5. S-СН3, SO2NH2, Т3 и O-Т3.
13. Соединение по п.1, отличающееся тем, что Т2 выбран из группы, состоящей из
Figure 00000111
Figure 00000112
Figure 00000113
Figure 00000114

Figure 00000115
Figure 00000116
Figure 00000117
Figure 00000118

Figure 00000119
Figure 00000120
Figure 00000121
Figure 00000122

Figure 00000123
Figure 00000124
Figure 00000125

и где Т2 возможно несет замещение одним или двумя R41, которые могут быть одинаковыми или разными.
14. Соединение по п.1, отличающееся тем, что R41 выбран из группы, состоящей из ОН, СН3 и Т3;
15. Соединение по п.1, отличающееся тем, что Т3 представляет собой Т4.
16. Соединение по п.1, отличающееся тем, что Т4 представляет собой фенил, где Т4 возможно несет замещение одним-тремя R51, которые могут быть одинаковыми или разными.
17. Соединение по п.1, отличающееся тем, что R51 независимо выбран из группы, состоящей из F, Cl, O-СН3, O-С2Н5.
18. Соединение по п.1, отличающееся тем, что Т3 представляет собой Т5.
19. Соединение по п.1, отличающееся тем, что Т5 представляет собой гетероцикл, где Т5 возможно несет замещение одним или двумя R54, которые могут быть одинаковыми или разными.
20. Соединение по п.1, отличающееся тем, что R54 представляет собой СН3.
21. Соединение по п.1, выбранное из группы, состоящей из
Figure 00000126

Figure 00000127
Figure 00000128
Figure 00000129
Figure 00000130
Figure 00000131
Figure 00000132
22. Фармацевтическая композиция для лечения и/или предупреждения состояний, при которых желательно ингибирование ДПП-IV, содержащая соединение по любому из пп.1-21 или его фармацевтически приемлемую соль совместно с фармацевтически приемлемым носителем.
23. Фармацевтическая композиция по п.22, содержащая одно или более дополнительных соединений или их фармацевтически приемлемых солей, выбранных из группы, состоящей из другого соединения по любому из пп.1-21; другого ингибитора ДПП-IV; сенсибилизаторов к инсулину; агонистов РАПП; бигуанидов; ингибиторов протеин тирозинфосфатазы-1B (РТР-1В); инсулина и миметиков инсулина; производных сульфонилмочевины и других веществ, стимулирующих секрецию инсулина, ингибиторов α-глюкозидазы, антагонистов рецепторов к глюкагону, глюкагоноподобного пептида (GLP-1), миметиков GLP-1 и агонистов рецепторов к GLP-1, гастроингибиторного пептида (ГИП), миметиков ГИП и агонистов рецепторов к ГИП; пептида, активирующего аденилатциклазу гипофиза (РАСАР), миметиков РАСАР и агонистов рецептора 3 к РАСАР; препаратов, снижающих содержание холестерина, ингибиторов HMG-CoA редуктазы (3-гидрокси-3-метилглютарил-коэнзим А-редуктазы); секвестрантов; никотинилового спирта, никотиновой кислоты и ее соли, агонистов РАППα (PPARα); агонистов PPAR-α/γ двойного действия, ингибиторов всасывания холестерина, ингибиторов ацил-СоА-холестерин ацилтрансферазы, антиоксидантов, агонистов РАППδ, соединений для лечения ожирения, ингибитора идеального переносчика желчных кислот и противовоспалительных препаратов.
24. Соединение или его фармацевтически приемлемая соль по любому из пп.1-21 для применения в качестве лекарственного средства для лечения и/или предупреждения состояний, при которых желательно ингибирование ДПП-IV.
25. Применение соединения или его фармацевтически приемлемой соли по любому из пп.1-21 для изготовления лекарственного средства для лечения и профилактики инсулиннезависимого сахарного диабета (Тип II), гипергликемии, ожирения, устойчивости к инсулину, нарушений обмена липидов, дислипидемии, гиперлипидемии, гипертриглицеридемии, гиперхолестеринемии, низких уровней ЛПВП, высоких уровней ЛПНП, атеросклероза, дефицита гормона роста, болезней, связанных с иммунными реакциями, ВИЧ-инфекции, нейтропении, нейрональных заболеваний, метастазирования опухолей, доброкачественной гипертрофии предстательной железы, гингивита, гипертензии, остеопороза, заболеваний, связанных с подвижностью сперматозоидов, низкой толерантности к глюкозе, устойчивости к инсулину, ее последствий, рестеноза сосудов, синдрома раздраженного кишечника, воспалительных заболеваний кишечника, включая болезнь Крона и язвенный колит, других воспалительных заболеваний, панкреатита, абдоминального ожирения, нейродегенеративных заболеваний, тревожности, депрессии, ретинопатии, нефропатии, нейропатии, «синдрома X», гиперандрогенизма яичников (синдром поликистозных яичников), диабета Типа II или дефицита гормона роста.
26. Применение соединения по любому из пп.1-21 в качестве ингибитора ДПП-IV.
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KR20230106651A (ko) 2020-11-12 2023-07-13 알비레오 에이비 진행성 가족성 간내 담즙정체증(pfic)을 치료하기 위한 오데빅시바트
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AU2005229330B2 (en) 2008-12-18
AU2005229330A1 (en) 2005-10-13
WO2005095343A1 (en) 2005-10-13
EP1758861A1 (en) 2007-03-07
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