EA026578B1 - Вещества, связывающие ядерные рецепторы - Google Patents

Вещества, связывающие ядерные рецепторы Download PDF

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EA026578B1
EA026578B1 EA201400056A EA201400056A EA026578B1 EA 026578 B1 EA026578 B1 EA 026578B1 EA 201400056 A EA201400056 A EA 201400056A EA 201400056 A EA201400056 A EA 201400056A EA 026578 B1 EA026578 B1 EA 026578B1
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Eurasian Patent Office
Prior art keywords
hydroxyphenyl
dihydroxy
isoquinolin
hydroxy
represents hydrogen
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EA201400056A
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EA201400056A1 (ru
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Джеймс Т. Далтон
Дуэйн Д. Миллер
Майкл Л. Молер
Чжунчжи У
Сеоунг-Соо Хонг
Девеш Сривастава
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ДЖиТиЭкс, ИНК.
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Publication of EA026578B1 publication Critical patent/EA026578B1/ru

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Abstract

Изобретение относится к применению соединения, или его фармацевтически оптического изомера, или его фармацевтически приемлемой соли, представленного структурной формулой VIгде определения радикалов даны в формуле изобретения, для получения лекарственного средства для лечения, предотвращения, подавления или ингибирования повреждения печени, вызванного жировыми отложениями, у пациента, причем заболеванием печени, обусловленным жировыми отложениями, является неалкогольный стеатогепатит.

Description

(54) ВЕЩЕСТВА, СВЯЗЫВАЮЩИЕ ЯДЕРНЫЕ РЕЦЕПТОРЫ (31) 60/881,476; 60/907,754 (32) 2007.01.22; 2007.04.16 (33) и§ (43) 2014.04.30 (62) 200970707; 2008.01.22 (71) (73) Заявитель и патентовладелец:
ДжиТиЭкс, ИНК. (ϋδ) (72) Изобретатель:
Далтон Джеймс Т., Миллер Дуэйн Д., Молер Майкл Л., У Чжунчжи, Хонг Сеоунг-Соо, Сривастава Девеш (ϋδ) (74) Представитель:
Медведев В.Н. (Κϋ) (56) \¥0-А1-2006108107 υδ-Α-2848356 υδ-Α1-20040138244
ΌΙΑΜΑΝΤΙ-ΚΑΝΌΑΚΑΚΙδ е! а1. ТНс ЕГГсс! οί а Риге Аий-аийтодеи РсссрЮг В1оскег. Е1и1апис1с. оп Иге υρίάΡτοίϊΙε ίη (Нс Ро1усу8Йс О\ ;ну 8упс1готс. 1оитпа1 οί СЬшса1 Епс1осппо1оду апс1 МеШЬоНкт, 1998, 83:2699-2705; екр. аЬкйас!; рд., со1. 1, рага 3
РК1СЕ с1 а1. ТогспиГспс ίοτ (Нс Ρτενεηίίοη οί Рго81а1е Сапсет ίη Меп \νί11ι ЕПдН Сгас1с РгоЯаОс 1п1таерНЬеНа1 ΝεορΙιΑι: КевиНк οί а ОоиЫе-ΒΙίηά, ИасеЬо СоШгоПсс! РЬаке ПВ СНшса1 Тпа1. ТЬе 1оитпа1 οί иго1оду, 2006, 176:965-971, аЬкйас! оп1у
ΚΕΜΜΕΚδ с1 а1. Те81о81егопе гсссрЮг ЫоскаДс айег йашиа-ЬепюггЬаде ίπιρτονθδ сагсЬас апс1 Ьерайс ГипсОопх ίη та1е8. Ат. 1 РЬу8ю1 - Неай Саге РЬу8ю1, 1997, 273:2919-2925, екр аЪкйас!, рд. Н2924,сок 1
ΜΟίΙΝΝΟΝ с1 а1. СНаисота: оси1аг АМгсппсгА сНзеаке? Ρτοηίίετδ ίη Βίοδοίεηοε, 2003, 8:81140-1156, екр. аЬккас!; р. 1141, сок 2, рага 2; р. 1150, со1. 1, рага 2
ΡΙΝΤΗυδ с1 а1. Апскодсп Мисс 5 Ас1ар1аОоп 1о О.\1с1а0\ с δίτεδδ Ιη Рго81а1е Сапсег: 1трНсайоп8 ίοτ ТгсаОпсШ \νίΐ1ι РасЬаОоп ТЬегару. ΝεορΙιΜ. ауаПаЫе οηίίηε 10 1апиату 2007, Уо1. 9:68-80, екр. аЬзкас!; р. 70, сок 1, рага 6; р. 71, сок 1, рага 2
026578 В1
026578 Β1

Claims (4)

  1. ФОРМУЛА ИЗОБРЕТЕНИЯ
    1. Применение соединения, или его оптического изомера, или фармацевтически приемлемой соли, представленного структурной формулой VI
    Κ2 представляет собой водород, СООН, -Ο(=ΝΗ)-ΘΗ, гидроксил, цианогруппу, ОСОР, С2-6алкенил или О8О2СР3;
    Κ3, Κ8 и Κ9 представляют собой водород;
    Κ10 представляет собой водород, галоген, СН=СНСО2Н, СН=СНСО2Р, циано, фенил, 4-метоксифенил, 4-гидроксифенил, С2-6алкенил, С1-6алкил или С1-6галогеналкил;
    Κ11 представляет собой водород, галоген, циано или §О2ГС ГС представляет собой водород, галоген или С1-С6-алкил;
    Κ7 представляет собой водород или галоген;
    Κ' представляет собой водород, Α11< или СОГС Κ представляет собой водород, Α11< или СОГС
    Κ представляет собой С1-6алкил, С1-6галогеналкил, С1-6дигалогеналкил, С1-6тригалогеналкил, фенил, бензил, галоген, С2-6алкенил, СN или NО2;
    Α11< представляет собой линейную алкильную группу с 1-7 атомами углерода, разветвленную алкильную группу с 1-7 атомами углерода или циклоалкильную группу с 3-8 атомами углерода, для получения лекарственного средства для лечения, предотвращения, подавления или ингибирования повреждения печени, вызванного жировыми отложениями, у пациента.
  2. 2. Применение по п.1, где указанное соединение представляет собой 4-бром-2-(3-фтор-4-гидроксифенил)-6-гидроксиизохинолин-1(2Н)-он; 4-хлор-6-гидрокси-2-(4-гидроксифенил)изохинолин-1(2Н)-он; 4-хлор-2-(3-фтор-4-гидроксифенил)-6-гидроксиизохинолин-1(2Н)-он; 6-гидрокси-2-(4-гидроксифенил)-4-йодизохинолин-1(2Н)-он;
    6.8- дигидрокси-2-(4-гидроксифенил)изохинолин-1(2Н)-он; 2-(3-фтор-4-гидроксифенил)-6-гидрокси-4-йодизохинолин-1(2Н)-он; 2-(3-фтор-4-гидроксифенил)-6,8-дигидроксиизохинолин-1(2Н)-он; 4-бром-6,8-дигидрокси-2-(4-гидроксифенил)изохинолин-1(2Н)-он; 4-бром-8-гидрокси-2-(4-гидроксифенил)-6-метоксиизохинолин-1(2Н)-он; 4-хлор-6,8-дигидрокси-2-(4-гидроксифенил)изохинолин-1(2Н)-он; 4-бром-6,8-дигидрокси-2-(3-фтор-4-гидроксифенил)изохинолин-1(2Н)-он;
    4- бром-6-гидрокси-2-(4-гидроксифенил)-1-оксо-1,2-дигидроизохинолин-8-карбонитрил;
    6.8- дигидрокси-2-(4-гидроксифенил)-4-винилизохинолин-1(2Н)-он;
    6.8- дигидрокси-2-(4-гидроксифенил)-1-оксо-1,2-дигидроизохинолин-4-карбонитрил; 6-гидрокси-2-(4-гидроксифенил)-4-фенилизохинолин-1(2Н)-он; 6-гидрокси-2-(4-гидроксифенил)-4-(4-метоксифенил)изохинолин-1(2Н)-он; 2-(3-фтор-4-гидроксифенил)-6,8-дигидрокси-4-винилизохинолин-1(2Н)-он;
    6.8- дигидрокси-2-(4-гидроксифенил)-4-(4-метоксифенил)изохинолин-1(2Н)-он;
    6.8- дигидрокси-2-(4-гидроксифенил)-4-фенилизохинолин-1(2Н)-он; (Е)-6,8-дигидрокси-2-(4-гидроксифенил)-4-(проп-1-енил)изохинолин-1(2Н)-он;
    5- бром-6,8-дигидрокси-2-(4-гидроксифенил)изохинолин-1(2Н)-он или 8-гидрокси-2-(4-гидроксифенил)-6-метокси-1-оксо-1,2-дигидроизохинолин-5-карбонитрил.
  3. 3. Применение по п.1 или 2, где повреждение печени, вызванное жировыми отложениями, представляет собой неалкогольный стеатогепатит.
  4. 4. Применение по любому из пп.1-3, где пациент страдает от диабета.
    Влияние 12Ь и 12и на пролиферацию клеток ЬХСаР
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    Влияние 12Ь и 12и на пролиферацию клеток С-26
    Фиг. 2
    Фиг. 3
    - 48 026578
    Влияние 12у на адгезию макрофагов к клеткам эндотелия
    Фиг. 4
    - 49 026578
    - 50 026578
    Фиг. 5А-5Н нМ - 1 0.1 1 10 1001000 - 1 0.1 1 101001000
    Е2 _____——— Е2 Фиг. 6
    - 51 026578
    Фиг. 8
    Фиг. 9
    100 НМ РЕ
    3’20 мин. Равновесие I 3'20 мин. 10 нгМ I Равновесие АСН 1 2 часа инкубации ЗЕНЫ Кумулятивная кривая доза - ответ для РЕ г...... Ί Г“1'4 I 1
    Фиг. 10
    Фиг. 11
    Смена буфера г---П СменаСуфера, инкубация зии нм 1 зо мкм, 141 е течение 15=16 | ΝΕ Ц ч. при Э7*С 300 нм ΝΕ ООО ИМ ΝΕ π I 1 , 1
    Влияние 141 на сократимость кольца аорты у крыс (* = р< 0.05 νβ носитель) лис <п=5)
    Фиг. 12
    - 52 026578
    Пролиферация ГМ КАК под действием 141
    Флуооесиентное летектигювание АФК
    Фиг. 14
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