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RU2013112122A - Новые замещенные хинолиновые соединения как ингибиторы s-нитрозоглутатион-редуктазы - Google Patents

Новые замещенные хинолиновые соединения как ингибиторы s-нитрозоглутатион-редуктазы Download PDF

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RU2013112122A
RU2013112122A RU2013112122/04A RU2013112122A RU2013112122A RU 2013112122 A RU2013112122 A RU 2013112122A RU 2013112122/04 A RU2013112122/04 A RU 2013112122/04A RU 2013112122 A RU2013112122 A RU 2013112122A RU 2013112122 A RU2013112122 A RU 2013112122A
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hydroxyquinolin
benzoic acid
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chloro
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RU2599144C2 (ru
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Сичэн САН
Цзянь ЦЮ
Адам СТАУТ
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Н30 Фармасьютикалз, Инк
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Abstract

1. Соединение Формулы I:гдеm выбран из группы, состоящей из 0, 1, 2 или 3;Rнезависимо выбран из группы, состоящей из хлора, фтора, брома, циано и метокси;Rи Rнезависимо выбраны из группы, состоящей из водорода, галогена, C-Cалкила, фторированного C-Cалкила, циано, C-Cалкокси и N(CH);X выбран из группы, состоящей из,,,,,,; и;n выбран из группы, состоящей из 0, 1 и 2;Rнезависимо выбран из группы, состоящей из галогена, C-Cалкила, фторированного C-Cалкила, циано, C-Cалкокси и NRR, где Rи Rнезависимо выбраны из группы, состоящей из C-Cалкила, или R, взятый вместе с R, образует кольцо из 3-6 членов; иA выбран из группы, состоящей из,,,,,,, и;или его фармацевтически приемлемая соль, стереоизомер или N-оксид.2. Соединение по п.1, отличающееся тем, чтоRнезависимо выбран из группы, состоящей из хлора, фтора и брома;X выбран из группы, состоящей из,,,, и; иRнезависимо выбран из группы, состоящей из галогена, C-Cалкила, фторированного C-Cалкила, циано, C-Cалкокси и NRR, где Rи Rнезависимо выбраны из группы, состоящей из C-Cалкила, или R, взятый вместе с R, образует кольцо из 3-6 членов.3. Соединение по п.1, отличающееся тем, что m выбран из группы, состоящей из 0 и 1; Rи Rнезависимо выбраны из группы, состоящей из водорода, хлора, фтора, метила, трифторметила, циано, метокси и N(CH); n выбран из группы, состоящей из 0 и 1; и Rнезависимо выбран из группы, состоящей из фтора, хлора, брома, метила, трифторметила, циано, метокси и N(CH).4. Соединение по п.3, отличающееся тем, что X является.5. Соединение по п.4, отличающееся тем, что A является COOH.6. Соединение по п.1, выбранное из группы, состоящей из:4-(6-гидрокси-3-метилхинолин-2-ил)бензойной кислоты;2-(4-(1H-тетразол-5-ил)фенил)-3-метилхинолин-6-ола;4-(6-(гидроксихинолин-2-ил)бензойной

Claims (14)

1. Соединение Формулы I:
Figure 00000001
где
m выбран из группы, состоящей из 0, 1, 2 или 3;
R1 независимо выбран из группы, состоящей из хлора, фтора, брома, циано и метокси;
R2b и R2c независимо выбраны из группы, состоящей из водорода, галогена, C1-C3 алкила, фторированного C1-C3 алкила, циано, C1-C3 алкокси и N(CH3)2;
X выбран из группы, состоящей из
Figure 00000002
,
Figure 00000003
,
Figure 00000004
,
Figure 00000005
,
Figure 00000006
,
Figure 00000007
,
Figure 00000008
; и
Figure 00000009
;
n выбран из группы, состоящей из 0, 1 и 2;
R3 независимо выбран из группы, состоящей из галогена, C1-C3 алкила, фторированного C1-C3 алкила, циано, C1-C3 алкокси и NR4R4', где R4 и R4' независимо выбраны из группы, состоящей из C1-C3 алкила, или R4, взятый вместе с R4', образует кольцо из 3-6 членов; и
A выбран из группы, состоящей из
Figure 00000010
,
Figure 00000011
,
Figure 00000012
,
Figure 00000013
,
Figure 00000014
,
Figure 00000015
,
Figure 00000016
, и
Figure 00000017
;
или его фармацевтически приемлемая соль, стереоизомер или N-оксид.
2. Соединение по п.1, отличающееся тем, что
R1 независимо выбран из группы, состоящей из хлора, фтора и брома;
X выбран из группы, состоящей из
Figure 00000018
,
Figure 00000019
,
Figure 00000020
,
Figure 00000021
, и
Figure 00000022
; и
R3 независимо выбран из группы, состоящей из галогена, C1-C3 алкила, фторированного C1-C3 алкила, циано, C1-C3 алкокси и NR4R4', где R4 и R4' независимо выбраны из группы, состоящей из C1-C3 алкила, или R4, взятый вместе с R4', образует кольцо из 3-6 членов.
3. Соединение по п.1, отличающееся тем, что m выбран из группы, состоящей из 0 и 1; R2b и R2c независимо выбраны из группы, состоящей из водорода, хлора, фтора, метила, трифторметила, циано, метокси и N(CH3)2; n выбран из группы, состоящей из 0 и 1; и R3 независимо выбран из группы, состоящей из фтора, хлора, брома, метила, трифторметила, циано, метокси и N(CH3)2.
4. Соединение по п.3, отличающееся тем, что X является
Figure 00000020
.
5. Соединение по п.4, отличающееся тем, что A является COOH.
6. Соединение по п.1, выбранное из группы, состоящей из:
4-(6-гидрокси-3-метилхинолин-2-ил)бензойной кислоты;
2-(4-(1H-тетразол-5-ил)фенил)-3-метилхинолин-6-ола;
4-(6-(гидроксихинолин-2-ил)бензойной кислоты;
2-(4-(1H-тетразол-5-ил)фенил)хинолин-6-ола;
1-(6-гидроксихинолин-2-ил)пиперидин-4-карбоновой кислоты;
(1r,4r)-4-(6-гидроксихинолин-2-ил)циклогексанкарбоновой кислоты;
(1s,4s)-4-(6-гидроксихинолин-2-ил)циклогексанкарбоновой кислоты;
3-хлор-4-(6-гидроксихинолин-2-ил)бензойной кислоты;
2-хлор-4-(6-гидроксихинолин-2-ил)бензойной кислоты;
2-фтор-4-(6-гидроксихинолин-2-ил)бензойной кислоты;
2-(4-(2H-тетразол-5-ил)фенил)-4-хлорхинолин-6-ола;
3-(4-(6-гидроксихинолин-2-ил)фенил)-1,2,4-оксадиазол-5-(2H)-она;
3-фтор-4-(6-гидроксихинолин-2-ил)бензойной кислоты;
4-(6-гидроксихинолин-2-ил)-3-метоксибензойной кислоты;
5-(6-гидроксихинолин-2-ил)тиофен-2-карбоновой кислоты;
4-(6-гидроксихинолин-2-ил)циклогекс-3-енкарбоновой кислоты;
4-(3-фтор-6-гидроксихинолин-2-ил)бензойной кислоты;
4-(4-хлор-3-фтор-6-гидроксихинолин-2-ил)бензойной кислоты;
4-(3-хлор-6-гидроксихинолин-2-ил)бензойной кислоты;
3-(2-фтор-4-(6-гидроксихинолин-2-ил)фенил)-1,2,4-оксадиазол-5(4H)-она;
3-(3-фтор-4-(6-гидроксихинолин-2-ил)фенил)-1,2,4-оксадиазол-5(4H)-она;
4-(4-хлор-6-гидроксихинолин-2-ил)бензойной кислоты;
2-(2-хлор-4-(2H-тетразол-5-ил)фенил)хинолин-6-ола;
5-(4-(6-гидроксихинолин-2-ил)фенил)-1,3,4-оксадиазол-2(3H)-она;
3-(диметиламино)-4-(6-гидроксихинолин-2-ил)бензойной кислоты;
4-(4-фтор-6-гидроксихинолин-2-ил)бензойной кислоты;
4-(6-гидроксихинолин-2-ил)-3-метилбензойной кислоты;
4-(3-хлор-6-гидроксихинолин-2-ил)-3-фторбензойной кислоты;
3-(4-(6-гидроксихинолин-2-ил)фенил)-1,2,4-тиадиазол-5(2H)-она;
4-(6-гидроксихииолин-2-ил)-3-(трифторметил)бензойной кислоты;
4-(6-гидрокси-3-(трифторметил)хинолин-2-ил)бензойной кислоты;
2-(4-карбоксифенил)-6-гидроксихинолин 1-оксида;
5-(4-(6-гидроксихинолин-2-ил)фенил)-1,3,4-тиадиазол-2(3H)-она;
5-(4-(6-гидроксихинолин-2-ил)фенил)-1,2,4-оксадиазол-3(2H)-она;
(1r,4r)-4-(3-хлор-6-гидроксихинолин-2-ил)циклогексанкарбоновой кислоты;
(1s,4s)-4-(3-хлор-6-гидроксихинолин-2-ил)циклогексанкарбоновой кислоты;
3-хлор-4-(4-фтор-6-гидроксихинолин-2-ил)бензойной кислоты;
2-(5-(2H-тетразол-5-ил)тиофен-2-ил)хииолин-6-ола;
5-(4-(6-гидроксихинолин-2-ил)фенил)-1,2,4-тиадиазол-3(2H)-она;
3-фтор-4-(4-фтор-6-гидроксихинолин-2-ил)бензойной кислоты;
1-(6-гидрокси-3-(трифторметил)хинолин-2-ил)пиперидин-4-карбоновой кислоты;
4-(5-хлор-6-гидроксихинолин-2-ил)бензойной кислоты;
(1r,4r)-4-(6-гидрокси-3-(трифторметил)хинолин-2-ил)циклогексанкарбоновой кислоты;
(1s,4s)-4-(6-гидрокси-3-(трифторметил)хинолин-2-ил)циклогексанкарбоновой кислоты;
4-(5-бром-6-гидроксихинолин-2-ил)бензойной кислоты;
3-бром-4-(6-гидроксихинолин-2-ил)бензойной кислоты;
4-(4-(диметиламино)-6-гидроксихинолин-2-ил)бензойной кислоты;
4-(4-фтор-6-гидроксихинолин-2-ил)-3-метоксибензойной кислоты;
3-циано-4-(6-гидроксихинолин-2-ил)бензойной кислоты;
2-(4-карбокси-2-хлорфенил)-6-гидроксихинолин 1-оксида;
4-(4-амино-6-гидроксихинолин-2-ил)бензойной кислоты;
4-(3-циано-6-гидроксихинолин-2-ил)бензойной кислоты;
4-(5-фтор-6-гидроксихинолин-2-ил)бензойной кислоты;
4-(8-фтор-6-гидроксихинолин-2-ил)бензойной кислоты;
3-фтор-4-(5-фтор-6-гидроксихинолин-2-ил)бензойной кислоты.
7. Соединение по п.6, отличающееся тем, что соединением является 3-хлор-4-(6-гидроксихинолин-2-ил)бензойная кислота.
8. Соединение по п.6, отличающееся тем, что соединением является 3-фтор-4-(6-гидроксихинолин-2-ил)бензойная кислота.
9. Соединение по п.6, отличающееся тем, что соединением является 4-(6-гидроксихинолин-2-ил)-3-метилбензойная кислота.
10. Применение соединения Формулы I, определенного по п.1, или его фармацевтически приемлемой соли в качестве ингибитора GSNOR.
11. Применение соединений по п.6 в качестве ингибиторов GSNOR.
12. Фармацевтическая композиция, включающая терапевтически эффективное количество соединения по п.1 вместе с фармацевтически приемлемым носителем или формообразующим средством.
13. Способ лечения заболевания или состояния, который включает введение терапевтически эффективного количества соединения Формулы I, определенного по п.1, пациенту, нуждающемуся в таком лечении.
14. Способ получения фармацевтической композиции по п.12, включающий объединение соединения Формулы I, определенного по п.1, с фармацевтически приемлемым носителем или формообразующим средством.
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