UA73553C2 - Piperazine derivatives - Google Patents

Piperazine derivatives Download PDF

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Publication number
UA73553C2
UA73553C2 UA2002097590A UA2002097590A UA73553C2 UA 73553 C2 UA73553 C2 UA 73553C2 UA 2002097590 A UA2002097590 A UA 2002097590A UA 2002097590 A UA2002097590 A UA 2002097590A UA 73553 C2 UA73553 C2 UA 73553C2
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UA
Ukraine
Prior art keywords
piperazine derivatives
receptor
inflammatory
acute
chronic
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UA2002097590A
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English (en)
Inventor
Laura Cook Blumberg
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Pfizer Prod Inc
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Publication of UA73553C2 publication Critical patent/UA73553C2/uk

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Description

Опис винаходу
Представлений винахід стосується нових похідних піперазину, способів використання і фармацевтичних 2 композицій, що їх містять.
Сполуки винаходу є сильними і селективними інгібіторами хемокіну, завдяки зв'язуванню його рецептора
ССКІ, який знаходиться в запальних і імуномодулюючих клітинах (переважно лейкоцитах і лімфоцитах).
Рецептор ССКІ1 також іноді відносять до СС-СККІ рецептора. Ці сполуки також інгібують МІР-1сс (і подібні хемокіни взаємодіють з ССК1 (наприклад, КАМТЕ5 і МСР-3)) викликаючи хемотаксис ТНР-1 клітин і лейкоцитів 70 людини і є потенційно корисними для лікування або запобігання аутоїмунних захворювань (таких як ревматоїдний артрит, діабет типу | (нещодавній приступ), вовчанки, запального захворювання кишки, очного нейриту, псоріазу, розсіяного склерозу, ревматичної поліміалгії, увеїту і васкуліту), гострих і хронічних станів запалення (таких як остеоартрит, респіраторний дистрессиндром повнолітніх, респіраторний дистрессиндром неповнолітніх, ішемічне реперфузивне ушкодження і гломеронефрит), алергічних станів (такі як 12 астма і атопічний дерматит), запалення обумовленого інфекцією (таке як вірусне запалення (включаючи грип і гепатит) і хвороба Джилліана-Барра), хронічного бронхіту, ксенотрансплантації, відторгнення трансплантованих тканин (хронічного і гострого), відторгнення трасплантованого органу (хронічного і гострого), атеросклерозу, рестенозу, ВІЛ інфекції (використання корецепторів) і грануломатозних захворювань (включаючи саркоідоз, проказа і туберкульоз) і ускладнень обумовлених деякими злоякісними пухлинами, такими як множинна мієлома. 20 Сполуки цього ряду можуть також обмежувати продукування цитокінів в місцях запалення, включаючи але не обмежуючись, ТМЕ і 1-1, як наслідок зменшення інфільтрації клітини, забезпечення полегшення захворювання зв'язаного з ТМЕ і 1-1, включаючи ушкодження серця в наслідок закупорювання, легенева емфізема або задуха в наслідок неї, емфізема; ВІЛ-1, ВІЛ-2, ВІЛ-3; цитомегаловірус (ЦМВ), аденовірус, вірус герпесу (Негрев5 208іег і Негрез зітріех). Вони також можуть забезпечувати полегшення захворювань обумовлених інфекцією, с 25 коли така інфекція викликає продукування детриментальних запальних цитокінів, таких як ТМЕ, наприклад, Ге) грибковий менінгіт, руйнування тканин суглобів, гіперплазія, утворення панусу, ресорбція кісток, псоріатичний артрит, ушкодження печінки, бактеріальний менінгіт, синдром Кавасакі, інфаркт міокарду, гостре ушкодження печінки, хвороба Ліма, септичний шок, рак, травма і малярія.
МІР-їа і КАМТЕ5Б є розчинними хемотактичними пептидами (хемокіни), які продукуються запальними о 30 клітинами, зокрема, СО8я- лімфоцитами, поліморфоядерними лейкоцитами (ПМЯ) і макрофагами, .-). Віої. Спет., ю 270 (30) 29671-29675 (1995). Дія цих хемокінів індукується міграцією і активуванням ключа запалення і імуномодуляторними клітинами. Підвищення рівнів хемокінів було виявлено в синовіальній рідині пацієнтів о хворих на ревматоїдний артрит, пацієнтів з хронічним і гострим відторгненням трансплантату і в назальних со секретах пацієнтів, що страждають на алергічний риніт після дії алергену (Тегап, еї аї., 9. Іттипо).. 35 1806-1812 (1996), і Кипа еї аї., 9. АМПегду Сіїп. Іттипої. 321 (1994)). Антитіла які перешкоджають взаємодії в хемокін/рецептор шляхом нейтралізації МІРІ А або гену руйнування забезпечують безпосереднє підтвердження ролі МІР-ТА і КАМТЕЗ у хворобі шляхом обмеження чисельності моноцитів і СОвя- лімфоцитів (Зтіїпй егаї.,..
Іттипої, 153. 4704 (1994) і Соок еї аї.. Зсіепсе. 269, 1583 (1995)). Разом з цими даними було показано, що « антагоністи ССКІ рецептора будуть ефективними при лікуванні деяких імунних захворювань. Описані тут З 50 сполуки є сильними і селективними антагоністами ССК1 рецептора. с Короткий опис винаходу Представлений винахід також стосується сполуки формули . и ання ль ях, що жк уч | . -1 1: Й або її фармацевтично прийнятної солі; в якій
Мн а є 1, 2, 3, 4 або 5;, БО, 1, 2, З або; с сєбабої1; сл 50 деї, 2, З, 4 або 5; є є 0 або 1; се» )| є 1,2, 3, або 4;
Х є С(О), С(5) або СН»;
У є СН», або якщо є є 0, У є СН», де Р є воднем, (Се-Сід)арилом або МАУВ 9; 7 є киснем, МЕ? або СВ" В,
Ф) іме) 60 б5
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