JP2014521647A - アルファ2アドレナリン作動性受容体のモジュレーターとしてのn−(イミダゾリジン−2−イリデン)キノリン誘導体 - Google Patents
アルファ2アドレナリン作動性受容体のモジュレーターとしてのn−(イミダゾリジン−2−イリデン)キノリン誘導体 Download PDFInfo
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- JP2014521647A JP2014521647A JP2014522900A JP2014522900A JP2014521647A JP 2014521647 A JP2014521647 A JP 2014521647A JP 2014522900 A JP2014522900 A JP 2014522900A JP 2014522900 A JP2014522900 A JP 2014522900A JP 2014521647 A JP2014521647 A JP 2014521647A
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- Prior art keywords
- imidazolidin
- ylidene
- amine
- compound
- quinolin
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Abstract
Description
本出願は、2011年、7月25日に出願された、米国特許仮出願番号第61/511,298号の利益を主張し、その開示は、参照によりその全体が本明細書に組み入れられる。
(式中:
R1は、水素、置換もしくは非置換のC1-8アルキルまたはハロゲンであり;
YはCHまたはNであり;
XはCHまたはNである)
の化合物、そのエナンチオマー、ジアステレオマー、水和物、溶媒和化合物、結晶形態および互変異性体、またはその薬剤的に許容される塩、ならびに
化合物N−(4,5−ジヒドロ−1H−イミダゾール−2−イル)−3−キノリンアミンを除く、化合物N−(イミダゾリジン−2−イリデン)キノリン−4−アミンを提供する。
R1が水素、メチル、臭素または塩素であり;
YがCHまたはNであり;および
XがCHまたはNであり、
化合物N−(4,5−ジヒドロ−1H−イミダゾール−2−イル)−3−キノリンアミンを除く、
式Iの化合物を提供する。
R1がメチル、臭素または塩素であり;
YがCHまたはNであり;および
XがCHまたはNである、
式Iの化合物を提供する。
R1がメチル、臭素または塩素であり;
YがCHまたはNであり;および
XがCHまたはNである、
式Iの化合物を提供する。
R1がメチルであり;
YがCHまたはNであり;および
XがCHまたはNである、
式Iの化合物を提供する。
R1が臭素であり;
YがCHまたはNであり;および
XがCHまたはNである、
式Iの化合物を提供する。
R1が塩素であり;
YがCHまたはNであり;および
XがCHまたはNである、
式Iの化合物を提供する。
R1が塩素であり;
YがCHまたはNであり;および
XがCHである、
式Iの化合物を提供する。
R1は塩素であり;
YはCHであり;および
XはCHまたはNである、
式Iの化合物を提供する。
N−(イミダゾリジン−2−イリデン)キノリン−4−アミン;
N−(イミダゾリジン−2−イリデン)−4−メチルキノリン−3−アミン;
4−クロロ−N−(イミダゾリジン−2−イリデン)キノリン−3−アミン;
4−ブロモ−N−(イミダゾリジン−2−イリデン)キノリン−3−アミン;
N−(イミダゾリジン−2−イリデン)ピリド[2,3−b]ピラジン−7−アミン;
N−(イミダゾリジン−2−イリデン)−8−メチルピリド[2,3−b]ピラジン−7−アミン;
4−クロロ−N−(イミダゾリジン−2−イリデン)−1,5−ナフチリジン−3−アミン;
である。
DCM ジクロロメタン
EtOH エタノール
MeOH メタノール
NH3 アンモニア
EtOAc エチルアセテート
TEA トリエチルアミン
CSCl2 チオホスゲン
THF テトラヒドロフラン
中間体1
1−(2−アミノエチル)−3−(キノリン−4−イル)チオ尿素
中間体2
4−クロロ−3−イソチオシアナト−1,5−ナフチリジン
中間体3
1−(2−アミノエチル)−3−(4−クロロ−1,5−ナフチリジン−3−イル)チオ尿素
化合物1
N−(イミダゾリジン−2−イリデン)キノリン−4−アミン
1H NMR(メタノール−d6) δ:8.54(d、J=5.0Hz、1H)、8.23(d、J=7.9Hz、1H)、7.88(d、J=8.5Hz、1H)、7.61−7.72(m、1H)、7.41−7.53(m、1H)、7.05(d、J=5.3Hz、1H)、3.56(s、4H)。
化合物2
4−クロロ−N−(イミダゾリジン−2−イリデン)−1,5−ナフチリジン−3−アミン
1H NMR (メタノール−d4) δ:8.90(dd、J=4.1、1.5Hz、5H)、8.68(s、1H)、8.36(dd、J=8.2、1.5Hz、1H)、7.66(dd、J=8.5、4.4Hz、1H)、3.56(s、4H)。
RSAT化合物スクリーニング
新規な化合物を合成し、受容体選択および増幅技術(RSAT)アッセイ(Messier et. al., 1995, Pharmacol. Toxicol. 76, pp. 308-311)を使用して、アルファアドレナリン作動活性について試験した。アルファ2アドレナリン作動性受容体のそれぞれを単独で発現している細胞を、種々の化合物とともに培養し、受容体に媒介される増殖応答を測定した。化合物の活性を、標準的な完全アゴニストと比較した、相対的有効性として表した(表2を参照のこと)。本発明の化合物は、アルファ2受容体を活性化する。
Claims (15)
- R1が水素、メチル、臭素または塩素であり;
YがCHまたはNであり;
XがCHまたはNであり;かつ
化合物N−(4,5−ジヒドロ−1H−イミダゾール−2−イル)−3−キノリンアミンを除く、請求項1に記載の化合物。 - R1がメチル、臭素または塩素であり;
YがCHまたはNであり;および
XがCHまたはNである、
請求項1に記載の化合物。 - R1がメチルであり;
YがCHまたはNであり;および
XがCHまたはNである、
請求項1に記載の化合物。 - R1が臭素であり;
YがCHまたはNであり;および
XがCHまたはNである、
請求項1に記載の化合物。 - R1が塩素であり;
YがCHまたはNであり;および
XがCHまたはNである、
請求項1に記載の化合物。 - R1が塩素であり;
YがCHまたはNであり;および
XがCHである、
請求項1に記載の化合物。 - R1が塩素であり;
YがCHあり;および
XがCHまたはNである、
請求項1に記載の化合物。 - N−(イミダゾリジン−2−イリデン)キノリン−4−アミン;
N−(イミダゾリジン−2−イリデン)−4−メチルキノリン−3−アミン;
4−クロロ−N−(イミダゾリジン−2−イリデン)キノリン−3−アミン;
4−ブロモ−N−(イミダゾリジン−2−イリデン)キノリン−3−アミン;
N−(イミダゾリジン−2−イリデン)ピリド[2,3−b]ピラジン−7−アミン;
N−(イミダゾリジン−2−イリデン)−8−メチルピリド[2,3−b]ピラジン−7−アミン;および
4−クロロ−N−(イミダゾリジン−2−イリデン)−1,5−ナフチリジン−3−アミン;
から選択される、請求項1に記載の化合物。 - 有効成分として、治療的有効量の請求項1に記載の化合物、および薬剤的に許容されるアジュバント、希釈剤または担体を含む、医薬組成物。
- 前記化合物が:
N−(イミダゾリジン−2−イリデン)キノリン−4−アミン;
N−(イミダゾリジン−2−イリデン)−4−メチルキノリン−3−アミン;
4−クロロ−N−(イミダゾリジン−2−イリデン)キノリン−3−アミン;
4−ブロモ−N−(イミダゾリジン−2−イリデン)キノリン−3−アミン;
N−(イミダゾリジン−2−イリデン)ピリド[2,3−b]ピラジン−7−アミン;
N−(イミダゾリジン−2−イリデン)−8−メチルピリド[2,3−b]ピラジン−7−アミン;および
4−クロロ−N−(イミダゾリジン−2−イリデン)−1,5−ナフチリジン−3−アミン;
から選択される、請求項10に記載の医薬組成物。 - 前記状態が、加齢黄斑変性、滲出型黄斑変性、乾燥型黄斑変性、地図状萎縮、糖尿病性網膜症、糖尿病性黄斑浮腫、腫瘍、網膜静脈閉塞、高眼圧症、緑内障、網膜色素変性症、および多発性硬化症に続発する神経炎、から選択される、請求項12に記載の方法。
- 前記障害が、酒さ、日焼け、乾癬、酒さ性ざ瘡、閉経に伴う顔面紅潮、精巣摘出術により生じる顔面紅潮、アトピー性皮膚炎、光老化、脂漏性皮膚炎、座瘡、アレルギー性皮膚炎、皮膚の発赤、顔面の毛細血管拡張症、鼻瘤、酒さ鼻(red bulbous nose)、座瘡様皮疹、顔面の灼熱感または刺痛感(stinging sensation)、眼の刺激症状および充血および涙目、皮膚の紅斑、皮膚血管の拡張による皮膚機能亢進、ライエル症候群、スティーブンス・ジョンソン症候群、軽症多形紅斑、重症多形紅斑およびまたは他の炎症性皮膚疾患、から選択される皮膚状態である、請求項12に記載の方法。
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US9199989B2 (en) | 2015-12-01 |
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BR112014001938A2 (pt) | 2017-02-21 |
WO2013016178A1 (en) | 2013-01-31 |
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US20160045489A1 (en) | 2016-02-18 |
JP6031719B2 (ja) | 2016-11-24 |
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CN103827107A (zh) | 2014-05-28 |
US20140329852A1 (en) | 2014-11-06 |
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