JP6052685B2 - α2アドレナリン受容体の調節因子としてのN−(イミダゾリジン−2−イリデン)−ヘテロシクロペンタ[b]ピリジン誘導体 - Google Patents
α2アドレナリン受容体の調節因子としてのN−(イミダゾリジン−2−イリデン)−ヘテロシクロペンタ[b]ピリジン誘導体 Download PDFInfo
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- JP6052685B2 JP6052685B2 JP2014522853A JP2014522853A JP6052685B2 JP 6052685 B2 JP6052685 B2 JP 6052685B2 JP 2014522853 A JP2014522853 A JP 2014522853A JP 2014522853 A JP2014522853 A JP 2014522853A JP 6052685 B2 JP6052685 B2 JP 6052685B2
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- ylidene
- pyridin
- amine
- imidazolidin
- hydrogen
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Description
本出願は、2011年7月25に出願された、米国仮特許出願第61/511,372号(その開示はその10の全体として、本明細書に参照により組み込まれる)の恩典を主張する。
本発明は、α2アドレナリン調節因子としての新規N−(イミダゾリジン−2−イリデン)−ヘテロシクロペンタ[b]ピリジン誘導体に関する。α1A、α1B、α2A、α2Bおよびα2Cを含むα2アドレナリン受容体は、分子および薬理学的方法により特徴付けられている。これらのα受容体の活性化は生理応答を誘起する。この発明において記載されるアドレナリン調節因子は、α2受容体を活性化し、有用な治療作用を有する。
式中:
R1は水素、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O、S、NRであり;かつ
Rは水素またはC1-3アルキルである。
ここで:
R1は水素、メチル、臭素または塩素であり;
YはCHまたはNであり;
XはO、S、NRであり;かつ
Rは水素またはメチルである。
ここで:
R1は水素であり;
YはCHであり;
XはO、NRであり;かつ
Rは水素またはメチルである。
ここで:
R1は水素であり;
YはCHであり;
XはNRであり;かつ
Rは水素またはメチルである。
ここで:
R1はメチルであり;
YはCHであり;
XはNRであり;かつ
Rはメチルである。
ここで:
R1は臭素または塩素であり;
YはCHであり;
XはNRであり;かつ
Rは水素である。
ここで:
R1は水素であり;
YはNであり;
XはO、S、NRであり;かつ
Rは水素またはメチルである。
ここで:
R1は水素であり;
YはNであり;
XはS、NRであり;かつ
Rは水素またはメチルである。
ここで:
R1は水素であり;
YはNであり;かつ
XはSである。
ここで:
R1は水素であり;
YはNであり;
XはNRであり;かつ
Rは水素またはメチルである。
N−(イミダゾリジン−2−イリデン)−1H−ピロロ[2,3−b]ピリジン−5−アミン;
N−(イミダゾリジン−2−イリデン)−4−メチル−1H−ピロロ[2,3−b]ピリジン−5−アミン;
4−クロロ−N−(イミダゾリジン−2−イリデン)−1H−ピロロ[2,3−b]ピリジン−5−アミン;
4−ブロモ−N−(イミダゾリジン−2−イリデン)−1H−ピロロ[2,3−b]ピリジン−5−アミン;
N−(イミダゾリジン−2−イリデン)−1−メチル−1H−ピロロ[2,3−b]ピリジン−5−アミン;
N−(イミダゾリジン−2−イリデン)フロ[2,3−b]ピリジン−5−アミン;
N−(イミダゾリジン−2−イリデン)−3H−イミダゾ[4,5−b]ピリジン−6−アミン;
N−(イミダゾリジン−2−イリデン)チアゾロ[5,4−b]ピリジン−6−アミン。
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
NaOH 水酸化ナトリウム
MgSO4 硫酸マグネシウム
EtOAc 酢酸エチル
MPLC 中圧液体クロマトグラフィー
DMF ジメチルホルムアミド
THF テトラヒドロフラン
Na2CO3 炭酸ナトリウム
PdCl2(PPh3)2 ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド
Pd/C パラジウム炭素
中間体1
4−メチル−1−(フェニルスルホニル)−1H−ピロロ[2,3−b]ピリジン
中間体2
4−メチル−5−ニトロ−1−(フェニルスルホニル)−1H−ピロロ[2,3−b]ピリジン
中間体3
4−メチル−1−(フェニルスルホニル)−1H−ピロロ[2,3−b]ピリジン−5−アミン
中間体4
エチル2−((4−メチル−1−(フェニルスルホニル)−1H−ピロロ[2,3−b]ピリジン−5−イル)アミノ)−4,5−ジヒドロ−1H−イミダゾール−1−カルボキシレート
中間体5
2−((4−メチル−1−(フェニルスルホニル)−1H−ピロロ[2,3−b]ピリジン−5−イル)アミノ)−4,5−ジヒドロ−1H−イミダゾール
化合物1
N−(4,5−ジヒドロ−1H−イミダゾール−2−イル)−4−メチル−1H−ピロロ[2,3−b]ピリジン−5−アミン
中間体5(380mg、0.89mmol)を含むMeOH(10mL)の混合物に、5N NaOH(1.5mL)水溶液を添加し、混合物を80℃で4h加熱した。室温まで冷却した時点で、白色固体沈殿物が形成し、これを濾過して除去した。シリカゲルを濾液に添加し、濃縮した。この材料をMPLCによりアミンカラムを使用して、10%MeOH:DCMを用いて精製し、化合物1(26mg)を得た。
1H NMR (メタノール-d4) δ: 7.77 (s、1H)、7.27 (d、J = 3.2 Hz、1H)、6.45 (d、J = 3.5 Hz、1H)、3.46 (s、4H)、2.39 (s、3H)。
化合物6
N−(4,5−ジヒドロ−1H−イミダゾール−2−イル)チアゾロ[5,4−b]ピリジン−6−アミン
1H NMR (メタノール-d4) δ: 9.28 (s、1H)、8.30 (d、J = 2.1 Hz、1H)、7.95 (d、J = 2.1 Hz、1H)、3.52 (s、4H)、3.47 (s、1H)、3.27 - 3.37 (m、3H)。
RSAT化合物スクリーニング
本発明の新規化合物を合成し、受容体選択および増幅技術(Receptor Selection and Amplification Technology)(RSAT)アッセイ(Messier et. al., 1995, Pharmacol. Toxicol. 76, pp. 308-311)を使用してαアドレナリン活性に対して試験した。α2アドレナリン受容体の各々のみを発現する細胞を様々な化合物と共にインキュベートし、受容体介在性増殖応答を測定した。化合物の活性を、標準完全アゴニストと比較したその相対効力として表す(表3を参照されたい)。この発明の化合物はα2受容体を活性化する。
Claims (18)
- R1は水素、メチル、臭素または塩素であり;
YはCHまたはNであり;
XはO、S、NRであり;かつ
Rは水素またはメチルである、請求項1に記載の化合物。 - R1は水素であり;
YはCHであり;
XはO、NRであり;かつ
Rは水素またはメチルである、請求項1に記載の化合物。 - R1はメチルであり;
YはCHであり;
XはNRであり;かつ
Rはメチルである、請求項1に記載の化合物。 - R1は臭素または塩素であり;
YはCHであり;
XはNRであり;かつ
Rは水素である、請求項1に記載の化合物。 - R1は水素であり;
YはNであり;
XはO、S、NRであり;かつ
Rは水素またはメチルである、請求項1に記載の化合物。 - R1は水素であり;
YはNであり;
XはS、NRであり;かつ
Rは水素またはメチルである、請求項1に記載の化合物。 - 下記から選択される、請求項1に記載の化合物:
N−(イミダゾリジン−2−イリデン)−1H−ピロロ[2,3−b]ピリジン−5−アミン;
N−(イミダゾリジン−2−イリデン)−4−メチル−1H−ピロロ[2,3−b]ピリジン−5−アミン;
4−クロロ−N−(イミダゾリジン−2−イリデン)−1H−ピロロ[2,3−b]ピリジン−5−アミン;
4−ブロモ−N−(イミダゾリジン−2−イリデン)−1H−ピロロ[2,3−b]ピリジン−5−アミン;
N−(イミダゾリジン−2−イリデン)−1−メチル−1H−ピロロ[2,3−b]ピリジン−5−アミン;
N−(イミダゾリジン−2−イリデン)フロ[2,3−b]ピリジン−5−アミン;
N−(イミダゾリジン−2−イリデン)−3H−イミダゾ[4,5−b]ピリジン−6−アミン;
N−(イミダゾリジン−2−イリデン)チアゾロ[5,4−b]ピリジン−6−アミン。 - 前記化合物がN−(イミダゾリジン−2−イリデン)−4−メチル−1H−ピロロ[2,3−b]ピリジン−5−アミンである、請求項1に記載の化合物。
- 活性成分として治療有効量の請求項1に記載の化合物を含み、且つ薬学的に許容されるアジュバント、希釈剤または担体を含んでいてもよい、医薬組成物。
- 前記化合物は下記から選択される、請求項10に記載の医薬組成物:
N−(イミダゾリジン−2−イリデン)−1H−ピロロ[2,3−b]ピリジン−5−アミン;
N−(イミダゾリジン−2−イリデン)−4−メチル−1H−ピロロ[2,3−b]ピリジン−5−アミン;
4−クロロ−N−(イミダゾリジン−2−イリデン)−1H−ピロロ[2,3−b]ピリジン−5−アミン;
4−ブロモ−N−(イミダゾリジン−2−イリデン)−1H−ピロロ[2,3−b]ピリジン−5−アミン;
N−(イミダゾリジン−2−イリデン)−1−メチル−1H−ピロロ[2,3−b]ピリジン−5−アミン;
N−(イミダゾリジン−2−イリデン)フロ[2,3−b]ピリジン−5−アミン;
N−(イミダゾリジン−2−イリデン)−3H−イミダゾ[4,5−b]ピリジン−6−アミン;
N−(イミダゾリジン−2−イリデン)チアゾロ[5,4−b]ピリジン−6−アミン。 - 前記化合物がN−(イミダゾリジン−2−イリデン)−4−メチル−1H−ピロロ[2,3−b]ピリジン−5−アミンである、請求項10に記載の医薬組成物。
- 前記障害は下記から選択される網膜疾患である、請求項13に記載の医薬組成物:加齢黄斑変性、滲出型黄斑変性、萎縮型黄斑変性、地図状萎縮、糖尿病性網膜症、糖尿病黄斑浮腫、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。
- 前記障害は下記:酒さ、日焼け、乾癬、酒さ性ざ瘡、更年期関連のぼせ、精巣摘出に起因するのぼせ、アトピー性皮膚炎、光老化、脂漏性皮膚炎、ざ瘡、アレルギー性皮膚炎、皮膚の発赤、顔の毛細血管拡張症(以前から存在していた微小血管の拡張)、鼻瘤(濾胞性拡張を有する鼻の肥大)、赤色球状鼻、ざ瘡様皮疹(滲出または痂皮となり得る)、顔の焼けるまたは刺すような感じ、皮膚の紅斑、皮膚の血管の拡張を伴う皮膚機能亢進、Lyell症候群、スティーブンス・ジョンソン症候群、多形性紅斑マイナー、多形性紅斑メジャーおよび他の炎症性皮膚疾患から選択される皮膚状態であるか、或いはひりひりして充血した涙ぐんだ目である、請求項13に記載の医薬組成物。
- 前記障害は緑内障、眼圧亢進、虚血性ニューロパチー、視神経症、疼痛、内臓痛、角膜痛、頭痛、片頭痛、癌性疼痛、背部痛、過敏性腸症候群痛、筋肉痛および糖尿病性ニューロパチーと関連する疼痛、糖尿病性網膜症、他の網膜変性状態、脳卒中、認知障害、精神神経状態、薬物依存および嗜癖、離脱症状、強迫性障害、肥満、インスリン抵抗性、ストレス関連状態、下痢、利尿、鼻閉、痙縮、注意欠陥障害、精神病、不安、うつ病、自己免疫疾患、クローン病、胃炎、アルツハイマー病、パーキンソンALS、神経変性疾患である、請求項13に記載の医薬組成物。
- 治療有効量のN−(イミダゾリジン−2−イリデン)−4−メチル−1H−ピロロ[2,3−b]ピリジン−5−アミンを含む、請求項13〜16のいずれか1項に記載の医薬組成物。
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US4166452A (en) | 1976-05-03 | 1979-09-04 | Generales Constantine D J Jr | Apparatus for testing human responses to stimuli |
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US4265874A (en) | 1980-04-25 | 1981-05-05 | Alza Corporation | Method of delivering drug with aid of effervescent activity generated in environment of use |
US5478858A (en) * | 1993-12-17 | 1995-12-26 | The Procter & Gamble Company | 5-(2-imidazolinylamino) benzimidazole compounds useful as alpha-2 adrenoceptor agonists |
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US5677321A (en) * | 1996-02-29 | 1997-10-14 | Synaptic Pharmaceutical Corporation | 5- and 6-(2-imidazolin-2-ylamino) and -(2-thiazolin-2-ylamino)-benzothiazoles as alpha-2 adrenergic ligands |
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MX336578B (es) | 2016-01-25 |
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JP2014521642A (ja) | 2014-08-28 |
US20140228395A1 (en) | 2014-08-14 |
US20130030014A1 (en) | 2013-01-31 |
AU2012287338A1 (en) | 2014-02-27 |
IL230653A0 (en) | 2014-03-31 |
EP2736906A1 (en) | 2014-06-04 |
CN103781785A (zh) | 2014-05-07 |
US8741921B2 (en) | 2014-06-03 |
BR112014001951A2 (pt) | 2017-02-21 |
RU2014106367A (ru) | 2015-08-27 |
US8513419B2 (en) | 2013-08-20 |
US9034896B2 (en) | 2015-05-19 |
IL230653A (en) | 2016-04-21 |
HK1198763A1 (en) | 2015-06-05 |
KR20140082643A (ko) | 2014-07-02 |
US20130324571A1 (en) | 2013-12-05 |
WO2013015984A1 (en) | 2013-01-31 |
CA2843245A1 (en) | 2013-01-31 |
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