JP2012526827A - (S)−7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリンの結晶形態およびその使用 - Google Patents
(S)−7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリンの結晶形態およびその使用 Download PDFInfo
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- JP2012526827A JP2012526827A JP2012510952A JP2012510952A JP2012526827A JP 2012526827 A JP2012526827 A JP 2012526827A JP 2012510952 A JP2012510952 A JP 2012510952A JP 2012510952 A JP2012510952 A JP 2012510952A JP 2012526827 A JP2012526827 A JP 2012526827A
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Abstract
Description
本発明は、様々な神経疾患および精神疾患を治療するための化合物、結晶形態、組成物、および方法、ならびに複合療法における化合物および結晶形態の使用に関する。特に、本発明は、そのような化合物、結晶形態、組成物、および方法に関し、化合物は、新規の[1,2,4]トリアゾロ[1,5−a]ピリジニル−6−イル置換テトラヒドロイソキノリン誘導体である。これらの化合物および結晶形態SA−1およびN−2を形成する方法も、本発明において説明される。
モノアミン再取り込み阻害薬は、再取り込みに関与する輸送体、つまり、セロトニン輸送体(SERT)、ノルエピネフリン輸送体(NET)、およびドーパミン輸送体(DAT)のうちの1つまたは複数に結合することによって、脳内のセロトニン(5−HT)、ノルエピネフリン(NE)、および/またはドーパミン(DA)の細胞外レベルを上昇させ、それによって、シナプス間隙からの神経伝達物質の再取り込みを遮断する。モノアミン再取り込み阻害薬は、多数のCNS疾患、特に、大鬱病性障害(MDD)の治療に対する有用性が証明されている、既知の薬物群である。
セル寸法:
a=11.0668(9)Å
b=7.3750(6)Å
c=15.3927(14)Å
α=90°
β=100.594(7)°
γ=90°
空間群:単斜晶系、P21
体積:1234.90(18)Å3
Z、算出密度:2、1.363Mg/m3
セル寸法:
a=7.1183(2)Å
b=21.2160(7)Å
c=26.3602(9)Å
α=90°
β=90°
γ=90°
空間群:斜方晶系、P212121
体積:3981.0(2)Å3
Z、算出密度:8、1.441Mg/m3
3−ホルミルフェニルボロン酸および6−ブロモ−[1,2,4]トリアゾロ[1,5−a]ピリジンの鈴木カップリングは、3−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)ベンズアルデヒドを生じる。このアルデヒドは、還元的アミノ化を経て、2−(3−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)ベンジルアミノ)−1−(3,4−ジクロロフェニル)エタノールを生じ、次に、硫酸媒介環化に供されて、7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリンを提供する。
ステップA:メタノール(1L)中の3−メトキシベンズアルデヒド(180g、1.32mol)溶液に、メチルアミンの40%水溶液(113mL、1.31mol)を添加し、続いて1時間、0℃で攪拌した。ホウ化水素ナトリウム(75g、1.98mol)を、0℃で何度かに分けて添加し、反応混合液を1時間攪拌した。溶液を少量に濃縮し、次に、水(200mL)で希釈して、得られる溶液を塩化メチレン(3x500mL)で抽出した。複合有機抽出物を硫酸ナトリウム上で乾燥させ、ろ過して、減圧下で濃縮し、粗N−メチルベンジルアミン(220g、定量的)を透明な油として得て、これをさらなる精製なしに次のステップで使用した。
望ましくない5−メトキシ異性体も単離された(1.20g、3ステップ後10%)。
ステップA:ジメチルスルホキシド(200mL)中の実施例1のステップGからのトリフラート(9.5g、21.6mmol)およびビス(ピナコラート)ジボロン(6.6g、25.9mmol)の溶液に、酢酸カリウム(6.4g、64.8mmol)を添加した。溶液をアルゴンで5分間脱気した後、ジクロロ[1,1′−ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)(1.6g、2.2mmol)をそれに添加した。反応混合液をアルゴンで5分間脱気し、80℃で1時間加熱した後、室温に冷却した。この溶液に、6−ブロモ−[1,2,4]トリアゾロ[1,5−α]ピリジン(4.8g、23.8mmol)および炭酸セシウム(21.1g、87mLの水中64.8mmol)水溶液を添加した。得られる溶液をアルゴンで脱気した後、ジクロロ[1,1′−ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)(0.8g、1.1mmol)をそれに添加した。反応混合液をアルゴンで脱気し、80℃で1時間加熱した。反応中に、暗色の粘性油が形成された。暗色の上澄み溶液を注ぎ出し、水で希釈して、酢酸エチル(3x)で抽出し、これを硫酸ナトリウム上で乾燥させ、真空で濃縮した。残った油をジクロロメタンに溶解し、得られる溶液を水で洗浄し、硫酸ナトリウム上で乾燥させて、真空で濃縮した。複合粗生成物を、フラッシュカラムクロマトグラフィ(100%酢酸エチル〜92:7.2:0.8酢酸エチル/メタノール/水酸化アンモニウム)によって精製し、7−([1,2,4]トリアゾロ[1,5−α]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−2−メチル−1,2,3,4−テトラヒドロイソキノリン(7.7g、87%、AUC HPLC 97.6%)を茶色の泡として得た。
ステップA:1Lの丸底フラスコに、2−アミノ−5−ブロモピリジン(100g、578mmol)、DMF−DMA(101mL、751mmol)および2−プロパノール(200mL)を添加した。混合液を加熱し、3時間還流させて、透明な暗色溶液を得た。次に、50℃に冷却し、塩酸ヒドロキシルアミン(52.2g、751mmol)を添加した。混合液を50℃で一晩攪拌し、黄色の懸濁液を得た。沈殿物をろ過によって収集した。黒いろ液を濃縮し、残渣をEtOH(20mL)中で20分間攪拌した。固体をろ過によって収集した。複合固体をオーブンで乾燥させて、N−(5−ブロモピリジン−2−イル)−N′−ヒドロキシホルムイミドアミドを、砂色の固体として得た(94g、収率75%)。
膜の調製
hSERT、hDAT、またはhNETタンパク質のいずれかを発現する組み換えHEK−293細胞は、T−175フラスコから以下のように採取した。培地をフラスコから除去し、細胞をCaおよびMgを含まないHBSSで洗浄した。次に、ピペッティングおよび剥離の組み合わせで引き上げる前に、必要に応じて、細胞を5〜10分間、10mM Tris−Cl、pH 7.5、5mM EDTA中でインキュベートした。細胞懸濁液を、遠心分離ボトルに収集し、30秒間Polytronホモジナイザで均質化した。懸濁液を、30分間、32,000×g、4℃で遠心分離した。上澄みを移し、ペレットを50mM Tris−Cl、pH 7.5、1mM EDTA中で10秒間、再懸濁および均質化した。次に、懸濁液を再度30分間、32,000xg、4℃で遠心分離した。上澄みを移し、ペレットを50mM Tris−Cl、pH7.5、1mM EDTA中で再懸濁し、短時間均質化した。ブラッドフォード分析(Bio−rad)を行い、50mM Tris−Cl、pH 7.5、1mM EDTAで膜調製物を2mg/mLに希釈した。アリコートを調製した後、凍結させて、−80℃で保管した。
化合物を、所望の最高分析濃度の100倍の濃度で100% DMSOに溶解し、100% DMSO中で1:3に連続希釈し、各溶液の0.4μL/ウェルをNuncポリプロピレン、丸底384ウェルプレートに分注した。100%阻害は、DMSOに溶解された0.4μL/ウェルの1mM フルオキセチンで定義される。20μL/ウェルの2x膜調製物(50mM Tris−Cl、pH7.5、120mM NaCl、5mM KCl中の15μg/mL)および20μL/ウェルの2x放射性リガンド溶液(50mM Tris−Cl、pH7.5、120mM NaCl、5mM KCl中の520pM [125I]RTI−55)を、各ウェルに添加し、反応液を1時間、室温でインキュベートした。次に、分析プレートの内容物を、0.5% PEIで少なくとも1時間事前処理したMillipore MultiscreenHTS GF/Bフィルタープレートに移した。プレートを真空ろ過し、4℃に冷却された100μL/ウェル 50mM Tris−Cl、pH7.5、120mM NaCl、5mM KClの7回洗浄で洗浄した。ろ過および洗浄は、90秒未満で完了した。プレートを一晩空気乾燥し、12μL/ウェルのMicroScintシンチレーション液を添加し、プレートをTriluxにおいてカウントした。
化合物を所望の最高分析濃度の100倍の濃度で100% DMSOに溶解し、100% DMSO中で1:3に連続希釈し、各溶液の0.4μL/ウェルをNuncポリプロピレン、丸底384ウェルプレートに分注した。100%阻害は、DMSOに溶解された0.4μL/ウェルの1mM GBR−12935で定義される。20μL/ウェルの2x膜調製物(30mM リン酸ナトリウム緩衝液、pH7.9、4℃中12.5μg/mL)および20μL/ウェルの2x放射性リガンド溶液(30mM リン酸ナトリウム緩衝液、pH7.9、4℃中250pM [125I]RTI−55)を、各ウェルに添加し、反応液を1時間、室温でインキュベートした。次に、分析プレートの内容物を、0.5% PEIで少なくとも1時間事前処理したMillipore MultiscreenHTS GF/Bフィルタープレートに移した。プレートを真空ろ過し、4℃に冷却された100μL/ウェル 50mM Tris−Cl、pH7.5、120mM NaCl、5mM KClの7回洗浄で洗浄した。ろ過および洗浄は、90秒未満で完了した。プレートを一晩空気乾燥し、12μL/ウェルのMicroScintシンチレーション液を添加し、プレートをTriluxにおいてカウントした。
化合物を所望の最高分析濃度の100倍の濃度で100% DMSOに溶解し、100% DMSO中で1:3に連続希釈し、各溶液の1.0μL/ウェルをNuncポリプロピレン、丸底384ウェルプレートに分注した。100%阻害は、DMSOに溶解された1.0μL/ウェルの10mM デシプラミンで定義される。50μL/ウェルの2x膜調製物(50mM Tris−Cl、pH7.5、120mM NaCl、5mM KCl中0.4mg/mL)および50μL/ウェルの2x放射性リガンド溶液(50mM Tris−Cl、pH7.5、120mM NaCl、5mM KCl中の4nM [3H]ニソキセチン)を、ウェルに添加し、反応液を1時間、室温でインキュベートした。次に、分析プレートの内容物を、0.5% PEIで少なくとも1時間事前処理したMillipore MultiscreenHTS GF/Bフィルタープレートに移した。プレートを真空ろ過し、4℃に冷却された100μL/ウェルの50mM Tris−Cl、pH7.5、120mM NaCl、5mM KClの7回洗浄で洗浄した。ろ過および洗浄は、90秒未満で完了した。プレートを一晩空気乾燥し、12μL/ウェルのMicroScintシンチレーション液を添加し、プレートをTriluxにおいてカウントした。
原データを、各プレートで実行される0%(DMSOのみ)および100%(選択的阻害薬)阻害薬を定義する対照ウェルを使用して、阻害%に標準化した。各プレートは、3重複で行い、それによって生成された濃度反応曲線は、各化合物のIC50値を決定するために、4つのパラメータ用量反応等式Y=Bottom+(Top−Bottom)/(1+10^((LogIC50−X)*HillSlope))を使用して適合させた。各分析に選択される放射性リガンド濃度は、各分析に対して、飽和結合分析によって決定されるKd濃度に対応する。
脳組織収集および輸送体占有率評価のための一般的な手順は、以下のように端的に説明される。マウスはCO2中の窒息によって、ラットは断頭術によって、およびイヌは安楽死溶液のIV注入によって犠牲死させた。マウスおよびラットの場合、脳を頭蓋骨から除去した後、前脳組織(脳幹および小脳の除去)を、SERT、NET、およびDAT占有率評価に使用した。イヌにおいて、線条体をDAT占有率について分析し、残りの前脳組織(線条体、脳幹、および小脳を含まない)を、SERTおよびNET占有率評価に使用した。脳組織を冷却したイソペンタン中で凍結させ、均質化するまで−80℃で保管した。
全試験
すべての動物を、参照によりそれら全体が本明細書に組み込まれる、Committee on Animals of the Bristol−Myers Squibb CompanyのガイドラインおよびGuide for Care and Use of Laboratory Animals,Institute of Animal Laboratory Resources,1996に従って維持した。研究プロトコルは、Bristol−Myers Squibb Company Institutional Animal Care and Use Committeeによって承認された。
雄のスイスウェブスターマウスを、一定温度(21〜23℃)および湿度(50±10%)、12時間の明暗周期で維持された室内で、ケージ当り3〜4匹収容した。研究を通して、動物は、水および食糧に自由にアクセスした。試験の日に、動物を試験室に入れ、1時間順応させた。試験を開始するために、尾部に一片のテープを取り付け、次に、それを防音室の天井のフックに取り付けた。Med Associatesソフトウェアを使用して、不動性を自動的に記録した。化合物は、セッション前の固定された前処理間隔で、急性投与した。
雄のスプラーグドーリーラットを、一定温度(21〜23℃)および湿度(50±10%)、12時間の明暗周期で維持された室内で、対で収容した。研究を通して、動物は、水および食糧に自由にアクセスした。実験を開始する2日前に、それぞれ2分間、動物を処理する。試験の初日に、ラットを水泳タンク(Pyrexシリンダ 高さ46cmx直径21cm、24〜26℃の範囲の水を30cm入れた)に、15分間入れた(水泳前セッション)。15分のセッションの最後に、ラットを乾かし、それらのホームケージに移した。2回目の試験水泳前に、次の24時間の3つの時点(23.5、5、および1時間)で、化合物を投与する。この水泳試験の期間は5分であり、動物の動作をビデオ撮影し、活発な動作(不動性、水泳、登坂)を採点する。5分の試験セッション中、各5秒期間の最後に、ラットの動作を以下のうちの1つとして採点する。不動性(ラットは、もがくことなく水中に浮遊したままであり、頭部を水上に維持するために必要な運動のみを行った)、水泳(ラットは、頭部を水上に維持するために必要な程度以上に、活発な水泳動作を行った、例えば、シリンダ内を動き回った)、または登坂(ラットは、通常、シリンダ壁に向けて、前足を水から出し入れして活発に運動した)。化合物は、既定のコードによってのみ識別され、実験者は、実験を通して(ビデオテープの採点中を含む)、盲検状態である。
2つの種に関して上述される条件に従って、動物を収容する。試験装置は、8つのフォトビームの中断を検出する、Digiscan活動モニタを備えたPlexiglas室(Omnitech Electronics,Columbus,Ohio)で構成される。水平活動は、計60分間、5分間隔で記録し、網羅される総距離として表す(cm)。化合物は、試験前に固定された規定間隔で急性投与する。
(S)−7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリンL−酒石酸塩(20mg)を、バイアル中で加熱しながら、メタノール(8mL)に溶解した。次に、蒸留水(2mL)を、上記の透明な溶液に添加した。得られる溶液に蓋をし、室温で放置した。(S)−7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリンL−酒石酸塩の針状結晶は、数日以内に、空気中にゆっくり蒸発した後に得られた。
(S)−7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリン一塩酸塩(20mg)を、バイアル中で加熱しながら、イソプロパノール(10mL)に溶解した。次に、蒸留水(2mL)を、上記の透明な溶液に添加した。得られる溶液に蓋をし、室温で放置した。(S)−7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリン一塩酸塩一イソプロパノール酸塩一水和物塩の長い針状結晶は、数日以内に、空気中にゆっくり蒸発した後に得られた。針状結晶は、ろ過によって母液から分離し、湿式ケーキを、45℃および100mmHgの条件下で、16時間オーブンで乾燥させた。
(S)−7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリン一塩酸塩(20mg)を、バイアル中で加熱しながら、メタノール(8mL)に溶解した。次に、蒸留水(2mL)を、上記の透明な溶液に添加した。得られる溶液に蓋をし、室温で放置した。(S)−7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリン一塩酸塩の針状単結晶は、数日以内に、空気中にゆっくり蒸発した後に得られた。
(S)−7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリンL−酒石酸(L−酒石酸塩)および(S)−7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリン一塩酸塩(HCl塩、形態N−2)結晶のデータは、グラファイト単色化Cu Kα放射線(λ=1.54178Å)を備えるSMART CCD回折計上で、225Kおよび室温でそれぞれ収集した。(S)−7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリン一塩酸塩一イソプロパノール酸塩一水和物(HCl塩、形態SA−1)のデータは、グラファイト単色化Cu Kα放射線(λ=1.54178Å)を備えるX8−ApexII回折計上で、室温で収集した(APEX−II 1.0−28、Bruker CCDデバイス用データ収集ソフトウェアBruker AXS Inc.,Madison,Wisconsin,US. SAINT PLUS、Bruker CCDデバイス用処理ソフトウェア、Bruker AXS Inc.,Madison,Wisconsin,US)。最終単位セルパラメータは、全体データセットを使用して決定した。
実験式 C40 H40 Cl2 N8 O8
式重量 831.70
温度 225(1) K
波長 1.54178 Å
結晶系、空間基 斜方晶系、C2221
単位セル寸法 a = 7.6264(10) Å α = 90°
b = 38.942(5) Å β = 90°
c = 24.449(3) Å γ = 90°
体積 7261.1(16) Å3
Z, 算出密度 8, 1.522 Mg/m3
吸収係数 2.195 mm-1
F(000) 3472
データ収集のθ範囲 2.27〜66.20°
限界指数 -8<=h<=8, -45<=k<=42, -22<=l<=28
収集された/固有の反射 24815 / 6156 [R(int) = 0.1027]
精密化法 F^2に関する全マトリクス最小二乗
データ/拘束/パラメータ 6156 / 2 / 323
F^2に関する適合度 2.340
最終R指数[I>2sigma(I)] R1 = 0.2345, wR2 = 0.4418
R指数(全データ) R1 = 0.3127, wR2 = 0.4595
絶対構造パラメータ 0.00(11)
減衰係数 0.0075(9)
最大差ピークおよびホール 0.991および-0.773 e. Å-3
実験式 C24 H26 Cl3 N4 O2
式重量 508.84
温度 298(2) K
波長 1.54178 Å
結晶系、空間基 単斜晶系、P21
単位セル寸法 a = 11.0668(9) Å α = 90°
b = 7.3750(6) Å β = 100.594(7)°
c = 15.3927(14) Å γ = 90°
体積 1234.90(18) Å3
Z, 算出密度 2, 1.363 Mg/m3
吸収係数 3.595 mm-1
F(000) 530
データ収集のθ範囲 4.06〜61.98°
限界指数 -12<=h<=12, -7<=k<=6, -17<=l<=15
収集された/固有の反射 3911 / 2687 [R(int) = 0.0253]
θに対する完全性 = 61.98 89.5 %
精密化法 F^2に関する全マトリクス最小二乗
データ/拘束/パラメータ 2687 / 1 / 306
F^2に関する適合度 1.035
最終R指数[I>2sigma(I)] R1 = 0.0382, wR2 = 0.0994
R指数(全データ) R1 = 0.0423, wR2 = 0.1027
絶対構造パラメータ 0.02(2)
最大差ピークおよびホール 0.270および-0.201 e. Å-3
実験式 C21 H17 Cl3 N4
式重量 431.74
温度 298(2) K
波長 1.54178 Å
結晶系、空間基 斜方晶系, P212121
単位セル寸法 a = 7.1183(2) Å α = 90°
b = 21.2160(7) Å β = 90°
c = 26.3602(9) Å γ = 90°
体積 3981.0(2) Å3
Z, 算出密度 8, 1.441 Mg/m3
吸収係数 4.283 mm-1
F(000) 1776
結晶サイズ 0.16 x 0.07 x 0.06 mm
データ収集のθ範囲 2.67〜44.53°
限界指数 -6<=h<=5, -19<=k<=18, -23<=l<=23
収集された/固有の反射 9626 / 2985 [R(int) = 0.0700]
θに対する完全性 = 44.53 95.3 %
データ/拘束/パラメータ 2985 / 0 / 505
F^2に関する適合度 1.031
最終R指数[I>2sigma(I)] R1 = 0.0580, wR2 = 0.1446
R指数(全データ) R1 = 0.0780, wR2 = 0.1669
絶対構造パラメータ 0.10(4)
最大差ピークおよびホール 0.260および-0.278 e. Å-3
X線粉末回折(PXRD)データは、Bruker C2 GADDSを使用して得た。放射線は、Cu Kα(40KV、40MA)であった。試料検出器距離は、15cmであった。粉末試料を、直径1mm以下の密閉ガラス毛細管に入れ、毛細管をデータ収集中に回転させた。少なくとも1000秒の試料曝露時間で、3<20<35°のデータを収集した。得られる二次元回折アークを統合して、従来の一次元PXRDを形成した。形態SA−1の単結晶データから算出されたPXRDパターンおよび模擬パターンの結果は、図1に示される。
示差走査熱量測定(DSC)実験は、TA Instruments(商標)モデルQ1000または2920において行った。試料(約2〜6mg)を、針を刺した密閉したアルミ皿に計量し、1/100ミリグラムまで正確に記録して、DSCに移した。装置は、窒素ガス50mL/分でパージした。データは、室温〜300℃、10℃/分の加熱率で収集した。下方を指している吸熱ピークでプロットを形成した。結果が図2に示される。
結果が図3に示される。
Claims (44)
- 前記形態SA−1が、少なくとも98重量%の純度を有する、請求項6に記載の結晶形態。
- 前記形態SA−1が、少なくとも99重量%の純度を有する、請求項6に記載の結晶形態。
- 薬学的に許容される担体と、治療上有効量の請求項1に記載の結晶形態とを含む、薬学的組成物。
- ノルエピネフリン、ドーパミン、またはセロトニンの利用能の減少によって形成されるか、またはそれに依存する疾患を治療する方法であって、請求項1に記載の治療上有効量の結晶形態、またはその薬学的に許容される塩を、そのような治療を必要とする患者に投与することを含む、方法。
- 前記疾患が、注意欠陥多動性障害(ADHD)、認知障害、不安障害、全般性不安障害(GAD)、パニック障害、双極性障害もしくは躁鬱病または躁鬱性障害、強迫神経症(OCD)、心的外傷後ストレス障害(PTSD)、急性ストレス障害、社会恐怖症、単純恐怖症、月経前不快気分障害(PMDD)、社会不安障害(SAD)、大鬱病性障害(MDD)、産後鬱、気分変調、アルツハイマー病、パーキンソン病、または精神病に関連する鬱、核上麻痺、摂食障害、肥満、神経性食欲不振、神経性過食症、むちゃ食い障害、糖尿病、虚血性疾患、疼痛、薬物乱用障害、薬物依存、ニコチン中毒、コカイン中毒、アンフェタミン中毒、アルコール中毒、レッシュナイハン症候群、神経変性病、パーキンソン病、黄体期後期症候群またはナルコレプシー、精神科的症状、怒り、拒絶過敏症、運動障害、錐体外路症候群、チック障害、下肢静止不能症候群(RLS)、遅発性ジスキネジー、核上麻痺、睡眠関連摂食障害(SRED)、夜食症候群(NES)、腹圧性尿失禁(SUI)、偏頭痛、神経障害性疼痛、糖尿病性神経障害、腰痛、線維筋痛症候群(FS)、変形性関節炎痛、関節炎痛、慢性疲労症候群(CFS)、性機能障害、早漏、男性性的不能、体温調節障害(例えば、更年期障害に関連する火照り)、および過敏性腸症候群(IBS)から成る群から選択される、請求項10に記載の方法。
- 治療上有効量のセロトニン1A受容体拮抗薬、またはその薬学的に許容される塩を投与することをさらに含む、請求項10に記載の方法。
- 前記セロトニン1A受容体拮抗薬が、WAY100135およびスピペロンから成る群から選択される、請求項12に記載の方法。
- 治療上有効量の選択的ニューロキニン−1受容体拮抗薬、またはその薬学的に許容される塩を投与することをさらに含む、請求項10に記載の方法。
- 治療上有効量のノルエピネフリン前駆体、またはその薬学的に許容される塩を投与することをさらに含む、請求項10に記載の方法。
- 前記ノルエピネフリン前駆体が、L−チロシンおよびL−フェニルアラニンから成る群から選択される、請求項15に記載の方法。
- 患者において、シナプスのノルエピネフリン取り込みを阻害する方法であって、治療上有効な阻害量の請求項1に記載の結晶形態、またはその薬学的に許容される塩を、前記患者に投与することを含む、方法。
- 患者において、シナプスのセロトニン取り込みを阻害する方法であって、治療上有効な阻害量の請求項1に記載の結晶形態、またはその薬学的に許容される塩を、前記患者に投与することを含む、方法。
- 患者において、シナプスのドーパミン取り込みを阻害する方法であって、治療上有効な阻害量の請求項1に記載の結晶形態、またはその薬学的に許容される塩を、前記患者に投与することを含む、方法。
- ヒトの喫煙欲求を抑制する方法であって、喫煙欲求を軽減するために、有効量の請求項1に記載の結晶形態、またはその薬学的に許容される塩を、そのような抑制を必要とするヒトに投与することを含む、方法。
- ヒトのアルコール消費欲求を抑制する方法であって、アルコール消費欲求を軽減するために、有効量の請求項1に記載の結晶形態、またはその薬学的に許容される塩を、そのような抑制を必要とするヒトに投与することを含む、方法。
- 前記形態N−2が、少なくとも98重量%の純度を有する、請求項27に記載の結晶形態。
- 前記形態N−2が、少なくとも99重量%の純度を有する、請求項27に記載の結晶形態。
- 薬学的に許容される担体と、治療上有効量の請求項22に記載の結晶形態とを含む、薬学的組成物。
- ノルエピネフリン、ドーパミン、またはセロトニンの利用能の減少によって形成されるか、またはそれに依存する疾患を治療する方法であって、治療上有効量の請求項22に記載の結晶形態、またはその薬学的に許容される塩を、そのような治療を必要とする患者に投与することを含む、方法。
- 前記疾患が、注意欠陥多動性障害(ADHD)、認知障害、不安障害、全般性不安障害(GAD)、パニック障害、双極性障害もしくは躁鬱病または躁鬱性障害、強迫神経症(OCD)、心的外傷後ストレス障害(PTSD)、急性ストレス障害、社会恐怖症、単純恐怖症、月経前不快気分障害(PMDD)、社会不安障害(SAD)、大鬱病性障害(MDD)、産後鬱、気分変調、アルツハイマー病、パーキンソン病、または精神病に関連する鬱、核上麻痺、摂食障害、肥満、神経性食欲不振、神経性過食症、むちゃ食い障害、糖尿病、虚血性疾患、疼痛、薬物乱用障害、薬物依存、ニコチン中毒、コカイン中毒、アンフェタミン中毒、アルコール中毒、レッシュナイハン症候群、神経変性病、パーキンソン病、黄体期後期症候群またはナルコレプシー、精神科的症状、怒り、拒絶過敏症、運動障害、錐体外路症候群、チック障害、下肢静止不能症候群(RLS)、遅発性ジスキネジー、核上麻痺、睡眠関連摂食障害(SRED)、夜食症候群(NES)、腹圧性尿失禁(SUI)、偏頭痛、神経障害性疼痛、糖尿病性神経障害、腰痛、線維筋痛症候群(FS)、変形性関節炎痛、関節炎痛、慢性疲労症候群(CFS)、性機能障害、早漏、男性性的不能、体温調節障害(例えば、更年期障害に関連する火照り)、および過敏性腸症候群(IBS)から成る群から選択される、請求項31に記載の方法。
- 治療上有効量のセロトニン1A受容体拮抗薬、またはその薬学的に許容される塩を投与することをさらに含む、請求項31に記載の方法。
- 前記セロトニン1A受容体拮抗薬が、WAY100135およびスピペロンから成る群から選択される、請求項33に記載の方法。
- 治療上有効量の選択的ニューロキニン−1受容体拮抗薬、またはその薬学的に許容される塩を投与することをさらに含む、請求項31に記載の方法。
- 治療上有効量のノルエピネフリン前駆体、またはその薬学的に許容される塩を投与することをさらに含む、請求項31に記載の方法。
- 前記ノルエピネフリン前駆体が、L−チロシンおよびL−フェニルアラニンから成る群から選択される、請求項36に記載の方法。
- 患者において、シナプスのノルエピネフリン取り込みを阻害する方法であって、治療上有効な阻害量の請求項22に記載の結晶形態、またはその薬学的に許容される塩を、前記患者に投与することを含む、方法。
- 患者において、シナプスのセロトニン取り込みを阻害する方法であって、治療上有効な阻害量の請求項22に記載の結晶形態、またはその薬学的に許容される塩を、前記患者に投与することを含む、方法。
- 患者において、シナプスのドーパミン取り込みを阻害する方法であって、治療上有効な阻害量の請求項22に記載の結晶形態、またはその薬学的に許容される塩を、前記患者に投与することを含む、方法。
- ヒトの喫煙欲求を抑制する方法であって、喫煙欲求を軽減するために、有効量の請求項22に記載の結晶形態、またはその薬学的に許容される塩を、そのような抑制を必要とするヒトに投与することを含む、方法。
- ヒトのアルコール消費欲求を抑制する方法であって、アルコール消費欲求を軽減するために、有効量の請求項22に記載の結晶形態、またはその薬学的に許容される塩を、そのような抑制を必要とするヒトに投与することを含む、方法。
- 前記酸が、硫酸、メタンスルホン酸、リン酸、およびL−酒石酸から成る群から選択される、請求項43に記載のプロセス。
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JP2012510952A Active JP5739415B2 (ja) | 2009-05-12 | 2010-05-11 | (S)−7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリンの結晶形態およびその使用 |
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EP (1) | EP2429293B1 (ja) |
JP (1) | JP5739415B2 (ja) |
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CN (1) | CN102638982B (ja) |
AU (1) | AU2010247735B2 (ja) |
ES (1) | ES2528404T3 (ja) |
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Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006020049A2 (en) | 2004-07-15 | 2006-02-23 | Amr Technology, Inc. | Aryl-and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
US9156812B2 (en) | 2008-06-04 | 2015-10-13 | Bristol-Myers Squibb Company | Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine |
KR20120034644A (ko) | 2009-05-12 | 2012-04-12 | 알바니 몰레큘라 리써치, 인크. | 아릴, 헤테로아릴, 및 헤테로사이클 치환된 테트라하이드로이소퀴놀린 및 이의 용도 |
CA2760837C (en) * | 2009-05-12 | 2018-04-03 | Albany Molecular Research, Inc. | 7-([1,2,4]triazolo[1,5-.alpha.]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof |
EP2429293B1 (en) | 2009-05-12 | 2014-10-29 | Bristol-Myers Squibb Company | CRYSTALLINE FORMS OF (S)-7-([1,2,4]TRIAZOLO[1,5-a]PYRIDIN-6-YL)-4-(3,4-DICHLOROHPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE AND USE THEREOF |
EP2606049A4 (en) | 2010-08-17 | 2014-01-08 | Albany Molecular Res Inc | 2,5-METHANO- AND 2,5-ETHANO-TETRAHYDROBENZAZEPINE DERIVATIVES AND USES THEREOF FOR BLOCKING NOREPINEPHRINE, DOPAMINE, AND SEROTONIN REUPTAKE |
GB201315846D0 (en) | 2013-09-05 | 2013-10-23 | Imp Innovations Ltd | Method for treating or preventing hot flushes |
FI3268379T3 (fi) * | 2015-03-09 | 2023-12-15 | Grace W R & Co | Nikotiiniamidiribosidin kiteinen muoto |
US11414407B2 (en) | 2017-12-22 | 2022-08-16 | Elysium Health, Inc. | Crystalline forms of nicotinamide riboside chloride |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003513074A (ja) * | 1999-11-03 | 2003-04-08 | アルバニー モレキュラー リサーチ インコーポレーティッド | アリールおよびヘテロアリール置換テトラヒドロイソキノリン、ならびにノルエピネフリン、ドーパミンおよびセロトニンの再取り込みを阻止するためのそれらの使用 |
JP2008520720A (ja) * | 2004-11-22 | 2008-06-19 | エーエムアール テクノロジー インコーポレイテッド | 4−フェニル置換テトラヒドロイソキノリン、ならびにそのノルエンピネフリン、ドーパミンおよびセロトニン再取り込み遮断のための使用 |
JP2008524118A (ja) * | 2004-11-22 | 2008-07-10 | エーエムアール テクノロジー インコーポレイテッド | ノルエピネフリン、ドーパミンおよびセロトニンの再取り込み遮断のためのアリール置換テトラヒドロイソキノリンおよびヘテロアリール置 |
JP2011522827A (ja) * | 2008-06-04 | 2011-08-04 | ブリストル−マイヤーズ スクイブ カンパニー | 6−[(4s)−2−メチル−4−(2−ナフチル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]ピリダジン−3−アミンの結晶形 |
JP2012526825A (ja) * | 2009-05-12 | 2012-11-01 | アルバニー モレキュラー リサーチ, インコーポレイテッド | 7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリンおよびその使用 |
JP2012526823A (ja) * | 2009-05-12 | 2012-11-01 | アルバニー モレキュラー リサーチ, インコーポレイテッド | アリール、ヘテロアリール、および複素環置換テトラヒドロイソキノリンならびにそれらの使用 |
Family Cites Families (299)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3155670A (en) | 1962-06-22 | 1964-11-03 | Res Lab Dr C Janssen N V | 1-oxo-2, 4, 8, triaza-spiro (4, 5) decanes |
US3155669A (en) | 1962-06-22 | 1964-11-03 | Res Lab Dr C Janssen N V | 2, 4, 8-triaza-spiro (4, 5) dec-2-enes |
US3947456A (en) * | 1970-01-06 | 1976-03-30 | Hoffman-La Roche Inc. | Substituted 4-phenyl isoquinolines |
US3666763A (en) * | 1970-01-06 | 1972-05-30 | Hoffmann La Roche | 4-phenyl isoquinolines and process for preparing same |
CH538477A (de) | 1970-01-06 | 1973-06-30 | Hoffmann La Roche | Verfahren zur Herstellung von Isochinolin-Derivaten |
GB1504424A (en) * | 1975-08-09 | 1978-03-22 | Beecham Group Ltd | Isoquinoline-derived aminoethers |
US4340600A (en) * | 1980-05-22 | 1982-07-20 | Smithkline Corporation | Renal dilating methods and compositions using 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines |
US4535186A (en) | 1983-04-19 | 1985-08-13 | American Home Products Corporation | 2-Phenyl-2-(1-hydroxycycloalkyl or 1-hydroxycycloalk-2-enyl)ethylamine derivatives |
DE3333994A1 (de) | 1983-09-21 | 1985-04-04 | Troponwerke GmbH & Co KG, 5000 Köln | Neue pyridoindolderivate, verfahren zu ihrer herstellung und ihre verwendung |
US4843071A (en) * | 1986-12-05 | 1989-06-27 | Serotonin Industries Of Charleston | Method and composition for treating obesity, drug abuse, and narcolepsy |
KR880007433A (ko) | 1986-12-22 | 1988-08-27 | 메리 앤 터커 | 3-아릴옥시-3-치환된 프로판아민 |
ZA885824B (en) * | 1987-08-14 | 1989-04-26 | Merrell Dow Pharma | Novel antidepressants |
EP0360390A1 (en) | 1988-07-25 | 1990-03-28 | Glaxo Group Limited | Spirolactam derivatives |
MX18467A (es) | 1988-11-23 | 1993-07-01 | Pfizer | Agentes terapeuticos de quinuclidinas |
FI895821A0 (fi) | 1988-12-07 | 1989-12-05 | Wellcome Found | Farmaceutiskt aktiva cns foereningar. |
US4902710A (en) * | 1988-12-14 | 1990-02-20 | Eli Lilly And Company | Serotonin and norepinephrine uptake inhibitors |
US5114976A (en) * | 1989-01-06 | 1992-05-19 | Norden Michael J | Method for treating certain psychiatric disorders and certain psychiatric symptoms |
GB8909209D0 (en) | 1989-04-22 | 1989-06-07 | Wyeth John & Brother Ltd | Piperazine derivatives |
EP0380223A1 (en) | 1989-01-17 | 1990-08-01 | Konica Corporation | Colour filter and process for producing the same |
BG49761A1 (en) | 1989-04-24 | 1992-02-14 | Vissh Khim T I | 4- (4'- chalophenyl)- 2- methyl- 1, 2, 3, 4- tetrahydroisohinolines and method for its preparation |
US5164372A (en) | 1989-04-28 | 1992-11-17 | Fujisawa Pharmaceutical Company, Ltd. | Peptide compounds having substance p antagonism, processes for preparation thereof and pharmaceutical composition comprising the same |
AU6368090A (en) | 1989-10-03 | 1991-04-11 | Warner-Lambert Company | Substituted carboxytetrahydroisoquinolines and derivatives thereof having pharmaceutical activity |
FI97540C (fi) | 1989-11-06 | 1997-01-10 | Sanofi Sa | Menetelmä terapeuttisesti käyttökelpoisten, aromaattisesti substituoitujen piperidiini- ja piperatsiinijohdannaisten valmistamiseksi |
FR2654725B1 (fr) | 1989-11-23 | 1992-02-14 | Rhone Poulenc Sante | Nouveaux derives de l'isoindolone, leur preparation et les compositions pharmaceutiques qui les contiennent. |
FR2654726B1 (fr) | 1989-11-23 | 1992-02-14 | Rhone Poulenc Sante | Nouveaux derives de l'isoindolone et leur preparation. |
GB8929070D0 (en) | 1989-12-22 | 1990-02-28 | Fujisawa Pharmaceutical Co | Peptide compounds,processes for preparation thereof and pharmaceutical composition comprising the same |
UA41251C2 (uk) | 1990-01-04 | 2001-09-17 | Пфайзер, Інк. | Гідровані азотвмісні гетероциклічні сполуки, похідні піперидину, фармацевтична композиція та спосіб пригнічення активності речовини р в організмі |
US5232929A (en) | 1990-11-28 | 1993-08-03 | Pfizer Inc. | 3-aminopiperidine derivatives and related nitrogen containing heterocycles and pharmaceutical compositions and use |
EP0515681A4 (en) | 1990-02-15 | 1993-12-29 | Fujisawa Pharmaceutical Co., Ltd. | Peptide compound |
US5447947A (en) * | 1990-02-26 | 1995-09-05 | Arc 1 | Compositions and methods of treatment of sympathetically maintained pain |
CA2084193C (en) | 1990-06-01 | 1998-04-07 | John A. Lowe, Iii | 3-amino-2-aryl quinuclidines |
EP0540526B1 (en) | 1990-07-23 | 1994-12-28 | Pfizer Inc. | Quinuclidine derivatives |
CA2089736A1 (en) | 1990-09-28 | 1992-03-29 | Manoj C. Desai | Fused ring analogs of nitrogen containing nonaromatic heterocycles |
GB9023116D0 (en) | 1990-10-24 | 1990-12-05 | Fujisawa Pharmaceutical Co | Peptide compounds,processes for preparation thereof and pharmaceutical composition comprising the same |
JPH04193867A (ja) | 1990-11-23 | 1992-07-13 | Nippon Shinyaku Co Ltd | イソキノリノール誘導体及び医薬 |
ATE129409T1 (de) | 1990-12-21 | 1995-11-15 | Fujisawa Pharmaceutical Co | Neue verwendung von peptidderivat. |
EP0566589A1 (en) | 1991-01-10 | 1993-10-27 | Pfizer Inc. | N-alkyl quinuclidinium salts as substance p antagonists |
ATE154354T1 (de) | 1991-02-11 | 1997-06-15 | Merck Sharp & Dohme | Azabicyclische verbindungen, diese enthaltende pharmazeutische zubereitungen und ihre therapeutische verwendung |
US5373003A (en) | 1991-03-01 | 1994-12-13 | Pfizer Inc. | 1-azabicyclo[3.2.2]nonan-3-amine derivatives |
KR0145432B1 (ko) | 1991-03-26 | 1998-07-15 | 알렌 제이. 스피겔 | 치환된 피페리딘의 입체선택적 제조 방법 |
FR2677361A1 (fr) | 1991-06-04 | 1992-12-11 | Adir | Nouveaux peptides et pseudopeptides, derives de tachykinines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
FR2676055B1 (fr) | 1991-05-03 | 1993-09-03 | Sanofi Elf | Composes polycycliques amines et leurs enantiomeres, procede pour leur preparation et compositions pharmaceutiques les contenant. |
FR2676053B1 (fr) | 1991-05-03 | 1993-08-27 | Sanofi Elf | Nouveaux composes dialkylenepiperidino et leurs enantiomeres, procede pour leur preparation et compositions pharmaceutiques les contenant. |
FR2676447B1 (fr) | 1991-05-17 | 1993-08-06 | Rhone Poulenc Rorer Sa | Nouveaux derives du thiopyranopyrrole et leur preparation. |
FR2676442B1 (fr) | 1991-05-17 | 1993-08-06 | Rhone Poulenc Rorer Sa | Nouveau derives de perhydroisoindole, leur preparation et les compositions pharmaceutiques qui les contiennent. |
FR2676443B1 (fr) | 1991-05-17 | 1993-08-06 | Rhone Poulenc Rorer Sa | Nouveaux derives de perhydroisoindole et leur preparation. |
FR2676446B1 (fr) | 1991-05-17 | 1993-08-06 | Rhone Poulenc Rorer Sa | Nouveaux derives du thiopyranopyrrole, leur preparation et les compositions pharmaceutiques qui les contiennent. |
EP0585328B1 (en) | 1991-05-22 | 2002-01-09 | Pfizer Inc. | Substituted 3-aminoquinuclidines |
WO1992020661A1 (en) | 1991-05-22 | 1992-11-26 | Merck & Co., Inc. | N, n-diacylpiperazines |
WO1992021677A1 (en) | 1991-05-31 | 1992-12-10 | Pfizer Inc. | bibNUCLIDINE DERIVATIVES |
GB9113219D0 (en) | 1991-06-19 | 1991-08-07 | Fujisawa Pharmaceutical Co | Peptide compound,processes for preparation thereof and pharmaceutical composition comprising the same |
ES2092113T3 (es) | 1991-06-20 | 1996-11-16 | Pfizer | Derivados fluoroalcoxibencilamino de heterociclos que contienen nitrogeno. |
TW202432B (ja) | 1991-06-21 | 1993-03-21 | Pfizer | |
US5288730A (en) | 1991-06-24 | 1994-02-22 | Merck Sharp & Dohme Limited | Azabicyclic compounds, pharmaceutical compositions containing them and their use in therapy |
EP0536817A1 (en) | 1991-07-05 | 1993-04-14 | MERCK SHARP & DOHME LTD. | Azabicyclic compounds as tachykinin antagonists |
US5472978A (en) | 1991-07-05 | 1995-12-05 | Merck Sharp & Dohme Ltd. | Aromatic compounds, pharmaceutical compositions containing them and their use in therapy |
US5629347A (en) | 1991-07-05 | 1997-05-13 | Merck Sharp & Dohme Ltd. | Aromatic compounds, pharmaceutical compositions containing them and their use in therapy |
US5495047A (en) | 1991-07-10 | 1996-02-27 | Merck, Sharp & Dohme (Ltd.) | Fused tricyclic compounds, pharmaceutical compositions containing them and their use in therapy |
WO1993001165A2 (en) | 1991-07-10 | 1993-01-21 | Merck Sharp & Dohme Limited | Aromatic compounds, compositions containing them and their use in therapy |
MY110227A (en) | 1991-08-12 | 1998-03-31 | Ciba Geigy Ag | 1-acylpiperindine compounds. |
US5459270A (en) | 1991-08-20 | 1995-10-17 | Merck Sharp & Dohme Limited | Azacyclic compounds, processes for their preparation and pharmaceutical compositions containing them |
JP2535134B2 (ja) | 1991-09-16 | 1996-09-18 | ファイザー・インコーポレーテッド | 縮合三環式窒素含有複素環 |
EP1082959A1 (en) | 1991-09-20 | 2001-03-14 | Glaxo Group Limited | NK1 Antagonists for the treatment of depression |
JP2553020B2 (ja) | 1991-11-07 | 1996-11-13 | 吉富製薬株式会社 | キヌクリジン化合物およびその医薬用途 |
ES2111650T3 (es) | 1991-11-12 | 1998-03-16 | Pfizer | Derivados aciclicos de etilenodiamina como antagonistas de receptores de la sustancia p. |
EP0545478A1 (en) | 1991-12-03 | 1993-06-09 | MERCK SHARP & DOHME LTD. | Heterocyclic compounds as tachykinin antagonists |
GB9200535D0 (en) | 1992-01-10 | 1992-02-26 | Fujisawa Pharmaceutical Co | New compound |
GB9201179D0 (en) | 1992-01-21 | 1992-03-11 | Glaxo Group Ltd | Chemical compounds |
US5241065A (en) * | 1992-02-25 | 1993-08-31 | Schering Corporation | 2,3,4,5-tetrahydro-1h-3-benzazepines having anti-psychotic activity |
US5328927A (en) | 1992-03-03 | 1994-07-12 | Merck Sharpe & Dohme, Ltd. | Hetercyclic compounds, processes for their preparation and pharmaceutical compositions containing them |
US5595872A (en) * | 1992-03-06 | 1997-01-21 | Bristol-Myers Squibb Company | Nucleic acids encoding microsomal trigyceride transfer protein |
JP2656702B2 (ja) | 1992-03-23 | 1997-09-24 | ファイザー製薬株式会社 | ペプチド性キヌクリジン |
FR2689888B1 (fr) | 1992-04-10 | 1994-06-10 | Rhone Poulenc Rorer Sa | Nouveaux derives de perhydroisoindole, leur preparation et les compositions pharmaceutiques qui les contiennent. |
AU675786B2 (en) | 1992-04-15 | 1997-02-20 | Merck Sharp & Dohme Limited | Azacyclic compounds |
GB2266529A (en) | 1992-05-01 | 1993-11-03 | Merck Sharp & Dohme | Tetrahydroisoquinoline derivatives |
WO1993023380A1 (en) | 1992-05-18 | 1993-11-25 | Pfizer Inc. | Bridged aza-bicyclic derivatives as substance p antagonists |
GB9211193D0 (en) | 1992-05-27 | 1992-07-08 | Merck Sharp & Dohme | Therapeutic agents |
IL106142A (en) | 1992-06-29 | 1997-03-18 | Merck & Co Inc | Morpholine and thiomorpholine tachykinin receptor antagonists, their preparation and pharmaceutical compositions containing them |
US5637699A (en) | 1992-06-29 | 1997-06-10 | Merck & Co., Inc. | Process for preparing morpholine tachykinin receptor antagonists |
WO1994001402A1 (en) | 1992-07-13 | 1994-01-20 | Merck Sharp & Dohme Limited | Heterocyclic amide derivatives as tachykinin derivatives |
AU4769893A (en) | 1992-07-17 | 1994-02-14 | Ribozyme Pharmaceuticals, Inc. | Method and reagent for treatment of animal diseases |
GB2268931A (en) | 1992-07-22 | 1994-01-26 | Merck Sharp & Dohme | Azabicyclic tachykinin-receptor antagonists |
ES2124318T3 (es) | 1992-07-28 | 1999-02-01 | Merck Sharp & Dohme | Compuestos azaciclicos. |
GB2269170A (en) | 1992-07-29 | 1994-02-02 | Merck Sharp & Dohme | Azatricyclic tachykinin antagonists |
AU4718093A (en) | 1992-07-31 | 1994-03-03 | Merck Sharp & Dohme Limited | Substituted amines as tachykinin receptor antagonists |
US5688804A (en) | 1992-08-04 | 1997-11-18 | Pfizer Inc. | 3-Benzylamino-2-phenyl-piperidine derivatives as substance P receptor antagonists |
GB9216911D0 (en) | 1992-08-10 | 1992-09-23 | Merck Sharp & Dohme | Therapeutic agents |
EP1000930A3 (en) | 1992-08-13 | 2003-10-29 | Warner-Lambert Company | Tachykinin antagonists |
US5212185A (en) * | 1992-08-14 | 1993-05-18 | G. D. Searle & Co. | Piperidinyl-terminated alkylamino ethynyl alanine amino diol compounds for treatment of hypertension |
ATE208376T1 (de) | 1992-08-19 | 2001-11-15 | Pfizer | Substituierte benzylamin-stickstoff enthaltende nichtaromatische heterocyclen |
US5387595A (en) | 1992-08-26 | 1995-02-07 | Merck & Co., Inc. | Alicyclic compounds as tachykinin receptor antagonists |
DE69315920T2 (de) | 1992-09-04 | 1998-06-10 | Takeda Chemical Industries Ltd | Kondensierte heterozyklische Verbindungen, deren Herstellung und Verwendung |
US5563161A (en) | 1992-09-10 | 1996-10-08 | Merck Sharp & Dohme Ltd. | Alcohols and ethers with aromatic substituents as tachykinin-antagonists |
GB9220286D0 (en) | 1992-09-25 | 1992-11-11 | Merck Sharp & Dohme | Therapeutic agents |
GB2271566A (en) | 1992-10-14 | 1994-04-20 | Merck & Co Inc | HIV integrase inhibitors |
JP2656699B2 (ja) | 1992-10-21 | 1997-09-24 | ファイザー製薬株式会社 | 置換ベンジルアミノキヌクリジン |
GB9222262D0 (en) | 1992-10-23 | 1992-12-09 | Merck Sharp & Dohme | Therapeutic agents |
GB9222486D0 (en) | 1992-10-26 | 1992-12-09 | Merck Sharp & Dohme | Therapeutic agents |
JP2656700B2 (ja) | 1992-10-28 | 1997-09-24 | ファイザー製薬株式会社 | 置換キヌクリジン誘導体 |
US5620989A (en) | 1992-10-28 | 1997-04-15 | Merck Sharp & Dohme Limited | 4-Arylmethyloxymethyl piperidines as tachykinin antagonsits |
US5554627A (en) | 1992-10-30 | 1996-09-10 | Merck, Sharp & Dohme Ltd. | Tachykinin antagonists |
EP0668863B1 (en) | 1992-11-12 | 1997-01-08 | Pfizer Inc. | Quinuclidine derivative as substance p antagonist |
US5261188A (en) | 1992-11-23 | 1993-11-16 | The Standard Products Company | Belt weatherstrip with bulb |
JPH06153997A (ja) | 1992-11-27 | 1994-06-03 | Canon Inc | 検出信号増幅による標的核酸の検出方法 |
ES2147759T3 (es) | 1992-12-10 | 2000-10-01 | Pfizer | Heterociclos no aromaticos sustituidos con aminometileno y uso como antagonistas de la sustancia p. |
CA2150951A1 (en) | 1992-12-14 | 1994-06-23 | Angus Murray Macleod | 4-aminomethyl/thiomethyl/sulfonylmethyl-4-phenylpiperidines as tachykinin receptor antagonists |
GB9226581D0 (en) | 1992-12-21 | 1993-02-17 | Merck Sharp & Dohme | Therapeutic agents |
DK154192D0 (da) * | 1992-12-23 | 1992-12-23 | Neurosearch As | Heterocycliske forbindelser |
GB9300051D0 (en) | 1993-01-04 | 1993-03-03 | Merck Sharp & Dohme | Therapeutic agents |
US5466689A (en) | 1993-02-08 | 1995-11-14 | Takeda Chemical Industries, Ltd. | Morpholine derivatives and their use |
AU679207B2 (en) | 1993-02-18 | 1997-06-26 | Merck Sharp & Dohme Limited | Azacyclic compounds, compositions containing them and their use as tachykinin antagonists |
US5674889A (en) | 1993-02-22 | 1997-10-07 | Merck, Sharp & Dohme, Ltd. | Aromatic compounds, compositions containing them and their use in therapy |
ATE166650T1 (de) | 1993-03-04 | 1998-06-15 | Pfizer | Spiroazacyclischderivate als substanz p antagonisten |
US5656642A (en) * | 1993-04-07 | 1997-08-12 | Otsuka Pharmaceutical Co., Ltd. | Peripheral vasodilating agent containing piperidine derivative as active ingredient |
US5496833A (en) | 1993-04-13 | 1996-03-05 | Merck Sharp & Dohme Limited | Piperidine tachykinin receptor antagonists |
DK0696280T3 (da) | 1993-05-06 | 1998-01-12 | Merrell Pharma Inc | Substituerede pyrrolidin-3-yl-alkyl-piperidiner anvendelige som tachykinin-antagonister |
IL109646A0 (en) | 1993-05-19 | 1994-08-26 | Pfizer | Heteroatom substituted alkyl benzylamino-quinuclidines |
JPH08511522A (ja) | 1993-06-07 | 1996-12-03 | メルク エンド カンパニー インコーポレーテッド | ニューロキニンアンタゴニストとしてのスピロ置換アザ環 |
EP0634402A1 (en) | 1993-07-14 | 1995-01-18 | Takeda Chemical Industries, Ltd. | Isochinolinone derivatives, their production and use |
US5869499A (en) | 1993-07-15 | 1999-02-09 | Pfizer Inc | Benzyloxyquinuclidines as substance P antagonists |
TW365603B (en) | 1993-07-30 | 1999-08-01 | Rhone Poulenc Rorer Sa | Novel perhydroisoindole derivatives, their preparation and pharmaceutical compositions which contain them |
GB9315808D0 (en) | 1993-07-30 | 1993-09-15 | Merck Sharp & Dohme | Therapeutic agents |
GB9317987D0 (en) | 1993-08-26 | 1993-10-13 | Glaxo Group Ltd | Chemical compounds |
EP0719266A1 (en) | 1993-09-17 | 1996-07-03 | Pfizer Inc. | Heteroarylamino and heteroarylsulfonamido substituted 3-benzylaminomethyl piperidines and related compounds |
CA2171637C (en) | 1993-09-17 | 2000-05-23 | Masaya Ikunaka | Substituted azaheterocyclecarboxylic acids |
IL111002A (en) | 1993-09-22 | 1998-09-24 | Glaxo Group Ltd | History of piperidine, their preparation and the pharmaceutical preparations containing them |
AU7947594A (en) | 1993-10-27 | 1995-05-22 | Merck Sharp & Dohme Limited | Substituted amides as tachykinin antagonists |
US6403577B1 (en) | 1993-11-17 | 2002-06-11 | Eli Lilly And Company | Hexamethyleneiminyl tachykinin receptor antagonists |
IT1271462B (it) | 1993-12-03 | 1997-05-28 | Menarini Farma Ind | Antagonisti delle tachichinine,procedimento per la loro preparazione e loro impiego in formulazioni farmaceutiche. |
IL111960A (en) | 1993-12-17 | 1999-12-22 | Merck & Co Inc | Morpholines and thiomorpholines their preparation and pharmaceutical compositions containing them |
AU1339795A (en) | 1993-12-21 | 1995-07-10 | Eli Lilly And Company | Non-peptide tachykinin receptor antagonists |
US5612337A (en) | 1993-12-29 | 1997-03-18 | Merck Sharp & Dohme Limited | Substituted morpholine derivatives and their use as therapeutic agents |
DE69416869T2 (de) | 1993-12-29 | 1999-07-01 | Pfizer | Diazabicyclische neurokinin antagonisten |
WO1995019344A1 (en) | 1994-01-13 | 1995-07-20 | Merck Sharp & Dohme Limited | Gem-disubstituted azacyclic tachykinin antagonists |
EP0741704A1 (en) | 1994-01-28 | 1996-11-13 | MERCK SHARP & DOHME LTD. | Aralkylamino substituted azacyclic therapeutic agents |
GB9402688D0 (en) | 1994-02-11 | 1994-04-06 | Merck Sharp & Dohme | Therapeutic agents |
US5610165A (en) | 1994-02-17 | 1997-03-11 | Merck & Co., Inc. | N-acylpiperidine tachykinin antagonists |
TW385308B (en) | 1994-03-04 | 2000-03-21 | Merck & Co Inc | Prodrugs of morpholine tachykinin receptor antagonists |
FR2718136B1 (fr) | 1994-03-29 | 1996-06-21 | Sanofi Sa | Composés aromatiques aminés, procédé pour leur obtention et compositions pharmaceutiques les contenant. |
US5610145A (en) | 1994-04-15 | 1997-03-11 | Warner-Lambert Company | Tachykinin antagonists |
US5607939A (en) * | 1994-04-28 | 1997-03-04 | Takeda Chemical Industries, Ltd. | Condensed heterocyclic compounds, their production and use |
NZ270985A (en) | 1994-04-29 | 1997-06-24 | Lilly Co Eli | Substituted benzimidazole derivatives; medicaments and preparation of medicaments |
EP0758329A1 (en) | 1994-05-05 | 1997-02-19 | MERCK SHARP & DOHME LTD. | Morpholine derivatives and their use as antagonists of tachikinins |
EE9600186A (et) | 1994-05-07 | 1997-08-15 | Boehringer Ingelheim Kg | Neurokiniini (tahhüülkiniini) antagonistid |
DE69523154T2 (de) | 1994-06-06 | 2002-06-06 | Warner Lambert Co | Tachykinin (nk1) rezeptor antagonisten |
EP0686629A3 (en) | 1994-06-10 | 1999-02-10 | Eli Lilly And Company | Cyclohexyl tachykinine receptor antagonists |
CA2134038C (en) * | 1994-06-16 | 1997-06-03 | David Taiwai Wong | Potentiation of drug response |
BR9508375A (pt) | 1994-07-12 | 1997-10-28 | Lilly Co Eli | Antagonista de receptor de taquicinina heterociclica |
HUT76639A (en) * | 1994-07-20 | 1997-10-28 | Byk Gulden Lomberg Chem Fab | Pyridyl-thio-compounds, process for producing them and their use |
CA2154116A1 (en) | 1994-07-22 | 1996-01-23 | Philip Arthur Hipskind | 1-aryl-2-acetamidopentanone derivatives for use as tachykinin receptor antagonists |
GB9415996D0 (en) | 1994-08-08 | 1994-09-28 | Merck Sharp & Dohme | Therapeutic agents |
GB9415997D0 (en) | 1994-08-08 | 1994-09-28 | Merck Sharp & Dohme | Therapeutic agents |
TW432061B (en) | 1994-08-09 | 2001-05-01 | Pfizer Res & Dev | Lactams |
US5824678A (en) | 1994-08-15 | 1998-10-20 | Merck Sharp & Dohme Ltd. | Morpholine derivatives and their use as therapeutic agents |
CA2198084C (en) | 1994-08-25 | 2000-03-28 | Timothy P. Burkholder | Novel substituted piperidines useful for the treatment of allergic diseases |
ATE158568T1 (de) | 1994-08-29 | 1997-10-15 | Akzo Nobel Nv | Verfahren zur herstellung von quaternären diestern |
GB9417956D0 (en) | 1994-09-02 | 1994-10-26 | Merck Sharp & Dohme | Therapeutic agents |
GB9418545D0 (en) | 1994-09-15 | 1994-11-02 | Merck Sharp & Dohme | Therapeutic agents |
US5457107A (en) | 1994-09-16 | 1995-10-10 | Merck & Co., Inc. | Polymorphic form of a tachykinin receptor antagonist |
ATE212981T1 (de) | 1994-09-30 | 2002-02-15 | Novartis Erfind Verwalt Gmbh | 1-acyl-4-aliphatische aminopiperidin verbindungen |
TW397825B (en) | 1994-10-14 | 2000-07-11 | Novartis Ag | Aroyl-piperidine derivatives |
FR2725986B1 (fr) | 1994-10-21 | 1996-11-29 | Adir | Nouveaux derives de piperidine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
EP0709375B1 (en) | 1994-10-25 | 2005-05-18 | AstraZeneca AB | Therapeutic heterocycles |
GB9421709D0 (en) | 1994-10-27 | 1994-12-14 | Zeneca Ltd | Therapeutic compounds |
CA2162786A1 (en) | 1994-11-22 | 1996-05-23 | Philip Arthur Hipskind | Heterocyclic tachykinin receptor antagonists |
FR2727411B1 (fr) | 1994-11-30 | 1997-01-03 | Rhone Poulenc Rorer Sa | Nouveaux derives de perhydroisoindole, leur preparation et les compositions pharmaceutiques qui les contiennent |
IL116323A0 (en) | 1994-12-13 | 1996-03-31 | Sandoz Ag | Tachykinin antagonists their preparation and pharmaceutical compositions containing them |
GB9426103D0 (en) | 1994-12-23 | 1995-02-22 | Merck Sharp & Dohme | Therapeutic agents |
ATE279406T1 (de) | 1995-01-12 | 2004-10-15 | Glaxo Group Ltd | Piperidinderivate mit tachykinin-antagonistischer wirkung |
FR2729951B1 (fr) | 1995-01-30 | 1997-04-18 | Sanofi Sa | Nouveaux composes heterocycliques, procede pour leur preparation et compositions pharmaceutiques en contenant |
GB9505492D0 (en) | 1995-03-18 | 1995-05-03 | Merck Sharp & Dohme | Therapeutic agents |
GB9505491D0 (en) | 1995-03-18 | 1995-05-03 | Merck Sharp & Dohme | Therapeutic agents |
US5554641A (en) | 1995-03-20 | 1996-09-10 | Horwell; David C. | Nonpeptides as tachykinin antagonists |
GB9505692D0 (en) | 1995-03-21 | 1995-05-10 | Glaxo Group Ltd | Chemical compounds |
ES2194937T3 (es) | 1995-03-24 | 2003-12-01 | Takeda Chemical Industries Ltd | Compuestos ciclicos, su produccion y uso como antagonistas de los receptores de taquiquinina. |
US5565568A (en) | 1995-04-06 | 1996-10-15 | Eli Lilly And Company | 2-acylaminopropanamides as tachykinin receptor antagonists |
JP3950170B2 (ja) | 1995-04-13 | 2007-07-25 | アベンティス・ファーマスーティカルズ・インコーポレイテッド | タキキニン受容体アンタゴニスト活性を有する新規な置換されたピペラジン誘導体 |
JP3071829B2 (ja) | 1995-05-25 | 2000-07-31 | 藤沢薬品工業株式会社 | ニューロキニン受容体拮抗剤としての1−ベンゾイル−2−(インドリル−3−アルキル)−ピペラジン誘導体 |
US5654316A (en) * | 1995-06-06 | 1997-08-05 | Schering Corporation | Piperidine derivatives as neurokinin antagonists |
DE19520964A1 (de) | 1995-06-08 | 1996-12-12 | Inst Neue Mat Gemein Gmbh | Beschichtete anorganische Pigmente, Verfahren zu deren Herstellung und deren Verwendung |
US5817832A (en) * | 1995-06-22 | 1998-10-06 | Ciba Specialty Chemicals Corporation | Blue diketopyrrolopyrrole pigments |
GB9513118D0 (en) | 1995-06-28 | 1995-08-30 | Merck Sharp & Dohme | Therapeutic agents |
GB9513121D0 (en) | 1995-06-28 | 1995-08-30 | Merck Sharp & Dohme | Therapeutic agents |
GB9513117D0 (en) | 1995-06-28 | 1995-08-30 | Merck Sharp & Dohme | Therapeutic agents |
DE69612003T2 (de) | 1995-07-07 | 2001-06-21 | Pfizer | Substituierte benzolaktamverbindungen als substanz-p-antagonisten |
TW340842B (en) | 1995-08-24 | 1998-09-21 | Pfizer | Substituted benzylaminopiperidine compounds |
WO1997014671A1 (en) | 1995-10-18 | 1997-04-24 | Merck & Co., Inc. | Cyclopentyl tachykinin receptor antagonists |
DE19541283A1 (de) | 1995-11-06 | 1997-05-07 | Boehringer Ingelheim Kg | Neue Aminosäurederivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen |
GB9523244D0 (en) | 1995-11-14 | 1996-01-17 | Merck Sharp & Dohme | Therapeutic agents |
JP2000500760A (ja) | 1995-11-23 | 2000-01-25 | メルク シヤープ エンド ドーム リミテツド | スピロピペリジン誘導体およびタキキニン拮抗薬としてのその使用 |
GB9524157D0 (en) | 1995-11-25 | 1996-01-24 | Pfizer Ltd | Therapeutic agents |
HU224225B1 (hu) | 1995-12-01 | 2005-06-28 | Sankyo Co. Ltd. | Tachikinin receptor antagonista hatású heterociklusos vegyületek, ezek előállítási eljárása és alkalmazásuk gyógyszerkészítmények előállítására |
GB9525296D0 (en) | 1995-12-11 | 1996-02-07 | Merck Sharp & Dohme | Therapeutic agents |
ZA9610738B (en) | 1995-12-22 | 1997-06-24 | Warner Lambert Co | Subtype selective nmda receptor ligands and the use thereof |
US6025355A (en) * | 1997-05-19 | 2000-02-15 | Cambridge Neuroscience, Inc. | Pharmaceutically active compounds and methods of use |
AU720358B2 (en) | 1996-02-22 | 2000-06-01 | Neurosearch A/S | Tropane-derivatives, their preparation and use |
AU715658B2 (en) | 1996-04-03 | 2000-02-10 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
US5885983A (en) * | 1996-05-10 | 1999-03-23 | Bristol-Myers Squibb Company | Inhibitors of microsomal triglyceride transfer protein and method |
US5827875A (en) * | 1996-05-10 | 1998-10-27 | Bristol-Myers Squibb Company | Inhibitors of microsomal triglyceride transfer protein and method |
EP0906315A1 (en) | 1996-06-21 | 1999-04-07 | MERCK SHARP & DOHME LTD. | Spiro-piperidine derivatives and their use as therapeutic agents |
DE19638484A1 (de) * | 1996-09-20 | 1998-03-26 | Basf Ag | Hetaroylderivate |
DE19638486A1 (de) * | 1996-09-20 | 1998-03-26 | Basf Ag | Hetaroylderivate |
WO1998035939A1 (fr) | 1997-02-18 | 1998-08-20 | Sanwa Kagaku Kenkyusho Co., Ltd. | Derives de diamide malonique et utilisation de ces derniers |
US5907041A (en) | 1997-03-12 | 1999-05-25 | Rhone-Poulenc Inc. | Process for preparing pyrazole derivatives |
JPH10292008A (ja) | 1997-04-21 | 1998-11-04 | Grand Polymer:Kk | α−オレフィンの重合方法 |
DE69810651T2 (de) * | 1997-10-07 | 2003-08-21 | Boehringer Ingelheim Ca Ltd | Azetidinonderivate zur behandlung von hcmv entzündungen |
JP2001519330A (ja) * | 1997-10-07 | 2001-10-23 | ベーリンガー インゲルハイム (カナダ) リミテッド | Hcmv感染の治療に用いるアゼチジノン誘導体 |
US7041702B1 (en) * | 1997-10-21 | 2006-05-09 | Scion Pharmaceuticals, Inc. | Pharmaceutically active compounds and methods of use |
US6121261A (en) | 1997-11-19 | 2000-09-19 | Merck & Co., Inc. | Method for treating attention deficit disorder |
US6943159B1 (en) * | 1998-02-18 | 2005-09-13 | Neurosearch A/S | Compounds and their use as positive AMPA receptor modulators |
US6043253A (en) * | 1998-03-03 | 2000-03-28 | Merck & Co., Inc. | Fused piperidine substituted arylsulfonamides as β3-agonists |
CN1301164A (zh) | 1998-04-09 | 2001-06-27 | 法玛西雅厄普约翰美国公司 | 神经病症的新疗法 |
WO2000014076A1 (en) | 1998-09-04 | 2000-03-16 | Ciba Specialty Chemicals Holding Inc. | Process for making 2,4-dihydroxyphenyl and 2-hydroxy-4-alkoxyphenyl substituted triazine compounds |
JP2000186110A (ja) | 1998-12-21 | 2000-07-04 | Ube Ind Ltd | エチレン共重合体の製造方法 |
US6664293B2 (en) * | 1999-02-26 | 2003-12-16 | Fujiwawa Pharmaceutical Co., Ltd. | Amide compounds for the potentiation of cholinergic activity |
US6586447B1 (en) * | 1999-04-01 | 2003-07-01 | Pfizer Inc | 3,3-disubstituted-oxindole derivatives useful as anticancer agents |
JP2001026580A (ja) | 1999-05-10 | 2001-01-30 | Sumitomo Chem Co Ltd | 光学活性1−アリール−1,2,3,4−テトラヒドロイソキノリン類の製造法 |
US6562836B1 (en) * | 1999-05-24 | 2003-05-13 | Queen's University Of Kingston | Methods and compounds for inhibiting amyloid deposits |
US6642228B1 (en) * | 1999-06-24 | 2003-11-04 | Toray Industries, Inc. | α1b-adrenergic receptor antagonists |
WO2001003680A2 (en) * | 1999-07-09 | 2001-01-18 | Isis Innovation Limited | Compounds for inhibiting diseases and preparing cells for transplantation |
US6340681B1 (en) * | 1999-07-16 | 2002-01-22 | Pfizer Inc | 2-benzimidazolylamine compounds as ORL-1-receptor agonists |
US6410736B1 (en) | 1999-11-29 | 2002-06-25 | Pfizer Inc. | Biaryl ether derivatives useful as monoamine reuptake inhibitors |
JP4907817B2 (ja) | 1999-11-03 | 2012-04-04 | エーエムアール テクノロジー インコーポレイテッド | ノルエピネフリン、ドーパミンおよびセロトニンの再取り込みを遮断するための、4−フェニル置換テトラヒドロイソキノリン類およびその利用 |
US7163949B1 (en) * | 1999-11-03 | 2007-01-16 | Amr Technology, Inc. | 4-phenyl substituted tetrahydroisoquinolines and use thereof |
WO2001070728A1 (en) | 2000-03-23 | 2001-09-27 | Sanofi-Synthelabo | 2-[nitrogen-heterocyclic]pyrimidone derivatives |
EP1292576A1 (en) * | 2000-05-15 | 2003-03-19 | Darwin Discovery Limited | Hydroxamic and carboxylic acid derivatives having mmp and tnf inhibitory activity |
CN100430401C (zh) | 2000-07-11 | 2008-11-05 | Amr科技公司 | 新的4-苯基取代的四氢异喹啉类化合物及其治疗用途 |
WO2002046164A1 (en) * | 2000-12-07 | 2002-06-13 | Astrazeneca Ab | Therapeutic compounds |
US6506772B1 (en) * | 2000-12-15 | 2003-01-14 | Hoffmann-La Roche Inc. | Substituted [1,2,4]triazolo[1,5a]pyridine derivatives with activity as adenosine receptor ligands |
US6900220B2 (en) * | 2001-01-02 | 2005-05-31 | Syntex (U.S.A.) Llc | Quinazolone derivatives as alpha 1A/B adrenergic receptor antagonists |
JP2002281203A (ja) | 2001-03-19 | 2002-09-27 | Canon Inc | 蓋付き電子機器 |
US6635675B2 (en) | 2001-11-05 | 2003-10-21 | Cypress Bioscience, Inc. | Method of treating chronic fatigue syndrome |
US6911453B2 (en) * | 2001-12-05 | 2005-06-28 | Aventis Pharma Deutschland Gmbh | Substituted 4-phenyltetrahydroisoquinolinium, process for their preparation, their use as a medicament, and medicament containing them |
US6974803B2 (en) * | 2001-12-06 | 2005-12-13 | Pfizer Inc | Pharmaceutical combination |
AU2002360561A1 (en) | 2001-12-11 | 2003-06-23 | Sepracor, Inc. | 4-substituted piperidines, and methods of use thereof |
US6703405B2 (en) * | 2001-12-22 | 2004-03-09 | Aventis Pharma Deutschland Gmbh | Substituted 4-phenyltetrahydroisoquinolinium salts, process for their preparation, their use as a medicament, and medicament containing them |
US20050113283A1 (en) * | 2002-01-18 | 2005-05-26 | David Solow-Cordero | Methods of treating conditions associated with an EDG-4 receptor |
US20050261298A1 (en) * | 2002-01-18 | 2005-11-24 | David Solow-Cordero | Methods of treating conditions associated with an Edg-7 receptor |
EP1676844A1 (en) * | 2004-12-28 | 2006-07-05 | Laboratorios Del Dr. Esteve, S.A. | 5-HT7 receptor antagonists |
US7241774B2 (en) * | 2002-03-13 | 2007-07-10 | University Of Tennessee Research Foundation | Substituted tetrahydroisoquinoline compounds, methods of making, and their use |
MXPA04011859A (es) | 2002-05-30 | 2005-03-31 | Neurosearch As | Inhibidores de la receptacion de monoamina triple para el tratamiento de dolor cronico. |
MXPA05001786A (es) * | 2002-08-13 | 2005-04-25 | Warner Lambert Co | Derivados de azaisoquinolina como inhibidores de la metaloproteinasa de matriz. |
AU2003250469A1 (en) * | 2002-08-13 | 2004-02-25 | Warner-Lambert Company Llc | Isoquinoline derivatives as matrix metalloproteinase inhibitors |
AU2002357644A1 (en) * | 2002-09-20 | 2004-04-08 | Medisyn Technologies, Inc. | Therapeutic agents and corresponding treatments |
PL376770A1 (pl) * | 2002-10-16 | 2006-01-09 | Isis Innovation Limited | Hydroksylazy asparaginylowe i ich modulatory |
GB0224557D0 (en) * | 2002-10-22 | 2002-11-27 | Glaxo Group Ltd | Novel compounds |
WO2004050628A1 (en) * | 2002-12-02 | 2004-06-17 | Pharmacia & Upjohn Company Llc | The use of 4-phenyl-substituted tetrahydroisoquinolines in the treatment of pain, migraine headaches and urinary incontinence |
WO2004050630A1 (en) * | 2002-12-02 | 2004-06-17 | Pharmacia & Upjohn Company Llc | The use of aryl- and heteroaryl-substituted tetrahydroisoquinolines in the treatment of chronic and neuropathic pain, migraine headaches, and urge, stress and mixed urinary incontinence |
DE10303254B3 (de) | 2003-01-28 | 2004-09-23 | Johannes-Gutenberg-Universität Mainz | 3,3-Dimethyl-8-oxoisochinoline, Verfahren zu ihrer Herstellung, sie enthaltende pharmazeutische Zusammensetzungen und deren Verwendung |
WO2004069162A2 (en) * | 2003-01-31 | 2004-08-19 | Merck & Co., Inc. | 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
US7241775B2 (en) * | 2003-03-24 | 2007-07-10 | Sanofi-Aventis Deutschland Gmbh | Composition, process of making, and medical use of substituted 4-phenyltetrahydroisoquinolines |
WO2004096774A1 (en) | 2003-05-01 | 2004-11-11 | Glaxo Group Limited | Acyl isoindoline derivatives and acyl isoquinoline derivatives as anti-viral agents |
US7459460B2 (en) * | 2003-05-28 | 2008-12-02 | Bristol-Myers Squibb Company | Trisubstituted heteroaromatic compounds as calcium sensing receptor modulators |
EP2236131A3 (en) | 2003-07-01 | 2011-03-02 | President and Fellows of Harvard College | Sirt1 modulators for manipulating cell/organism lifespan/stress response |
US7501538B2 (en) * | 2003-08-08 | 2009-03-10 | Transtech Pharma, Inc. | Aryl and heteroaryl compounds, compositions and methods of use |
JP4943845B2 (ja) | 2003-09-17 | 2012-05-30 | ザ ガバメント オブ ザ ユナイテッド ステイツ オブ アメリカ アズ リプレゼンティッド バイ ザ セクレタリー オブ ザ デパートメント オブ ヘルス アンド ヒューマン サービシーズ | サリドマイド類似体 |
US7491794B2 (en) * | 2003-10-14 | 2009-02-17 | Intermune, Inc. | Macrocyclic compounds as inhibitors of viral replication |
JP2007008816A (ja) | 2003-10-15 | 2007-01-18 | Ube Ind Ltd | 新規イソキノリン誘導体 |
CA2547212A1 (en) * | 2003-11-25 | 2005-06-16 | Eli Lilly And Company | Peroxisome proliferator activated receptor modulators |
EP1708689A2 (en) * | 2003-12-29 | 2006-10-11 | The President and Fellows of Harvard College | Compositions for treating or preventing obesity and insulin resistance disorders |
CA2556413A1 (en) * | 2004-02-18 | 2005-09-09 | Pfizer Products Inc. | Tetrahydroisoquinolinyl derivatives of quinazoline and isoquinoline |
CN1942186B (zh) | 2004-03-09 | 2010-10-06 | 国家卫生研究院 | 吡咯烷化合物 |
NZ549697A (en) | 2004-03-30 | 2009-12-24 | Intermune Inc | Macrocyclic compounds as inhibitors of viral replication |
CA2568622C (en) | 2004-06-01 | 2016-01-26 | University Of Virginia Patent Foundation | Dual small molecule inhibitors of cancer and angiogenesis |
US20060014705A1 (en) * | 2004-06-30 | 2006-01-19 | Howitz Konrad T | Compositions and methods for selectively activating human sirtuins |
WO2006020049A2 (en) * | 2004-07-15 | 2006-02-23 | Amr Technology, Inc. | Aryl-and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
US20090054358A1 (en) | 2004-07-19 | 2009-02-26 | The John Hopkins University | Flt3 inhibitors for immune suppression |
US7211584B2 (en) * | 2004-08-18 | 2007-05-01 | Laboratorios Del Dr. Esteve, S.A. | 5-HT7 receptor ligands |
US7211585B2 (en) * | 2004-08-18 | 2007-05-01 | Laboratorios Del Dr. Esteve, S.A. | 5-HT7 receptor antagonists |
DE102004046492A1 (de) | 2004-09-23 | 2006-03-30 | Sanofi-Aventis Deutschland Gmbh | Substituierte 4-Phenyltetrahydroisochinoline, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, sowie sie enthaltendes Medikament |
US20060111385A1 (en) | 2004-11-22 | 2006-05-25 | Molino Bruce F | Novel 4-phenyl substituted tetrahydroisoquinolines and therapeutic use thereof |
CN101128432A (zh) * | 2004-12-17 | 2008-02-20 | 詹森药业有限公司 | 用于治疗中枢神经系统疾病的四氢异喹啉化合物 |
US20070060589A1 (en) * | 2004-12-21 | 2007-03-15 | Purandare Ashok V | Inhibitors of protein arginine methyl transferases |
AU2006206274A1 (en) * | 2005-01-20 | 2006-07-27 | Sirtris Pharmaceuticals, Inc. | Use of sirtuin-activating compounds for treating flushing and drug induced weight gain |
RU2007128987A (ru) | 2005-02-15 | 2009-03-27 | Ново Нордиск А/С (DK) | 3,4-дигидро-1н-изохинолин-2-карбоновой кислоты 5-аминопиридин-2-2-иловые эфиры |
WO2006105440A2 (en) * | 2005-03-30 | 2006-10-05 | Sirtris Pharmaceuticals, Inc. | Nicotinamide riboside and analogues thereof |
DE102005025625A1 (de) | 2005-06-01 | 2006-12-07 | Friedrich-Schiller-Universität Jena | Neue hochaffine Dopaminantagonisten zur Behandlung der Schizophrenie und Verfahren zu ihrer Herstellung |
KR101589551B1 (ko) * | 2005-07-15 | 2016-02-02 | 알바니 몰레큘라 리써치, 인크. | 아릴- 및 헤테로아릴-치환된 테트라히드로벤자제핀, 및 노르에피네프린, 도파민 및 세로토닌의 재흡수를 차단하기 위한 용도 |
US7425633B2 (en) * | 2005-08-26 | 2008-09-16 | National Health Research Institutes | Pyrrolidine compounds |
WO2007033002A1 (en) | 2005-09-14 | 2007-03-22 | Amgen Inc. | Conformationally constrained 3- (4-hydroxy-phenyl) - substituted-propanoic acids useful for treating metabolic disorders |
JP2009510073A (ja) | 2005-09-27 | 2009-03-12 | ノバルティス アクチエンゲゼルシャフト | カルボキシアミン化合物およびその使用方法 |
CN101346353B (zh) | 2005-10-26 | 2012-01-11 | 默克雪兰诺有限公司 | 磺酰胺衍生物及其在调节金属蛋白酶中的用途 |
WO2007054453A2 (en) * | 2005-11-11 | 2007-05-18 | F. Hoffmann-La Roche Ag | Carbocyclic fused cyclic amines as inhibitors of the coagulation factor xa |
WO2007098608A1 (en) | 2006-03-02 | 2007-09-07 | Chao-Jun Li | Chiral ligands, their preparation and uses thereof in assymetric reactions |
ES2442347T3 (es) | 2006-03-29 | 2014-02-11 | Novartis Ag | Imidazoles como inhibidores de aldosterona sintasa |
US7919598B2 (en) * | 2006-06-28 | 2011-04-05 | Bristol-Myers Squibb Company | Crystal structures of SGLT2 inhibitors and processes for preparing same |
WO2008019356A2 (en) | 2006-08-07 | 2008-02-14 | Janssen Pharmaceutica, N.V. | Process for the preparation of substituted-1,2,3,4-tetrahydroisoquinoline derivates |
CA2661462C (en) | 2006-08-23 | 2015-09-29 | Valeant Pharmaceuticals International | Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators |
DE102006046922B3 (de) | 2006-09-27 | 2007-11-15 | Julius-Maximilians-Universität Würzburg | Biofilm-hemmende Wirkung sowie anti-infektive Aktivität N,C-verknüpfter Arylisochinoline, deren pharmazeutischen Zusammensetzung und deren Verwendung |
BRPI0808525A2 (pt) * | 2007-03-01 | 2014-08-19 | Janssen Pharmaceutica Nv | Compostos de tetraidroisoquinolina como moduladors do receptor de histamina h3 |
EA017308B1 (ru) | 2007-05-10 | 2012-11-30 | Олбани Молекьюлар Рисерч, Инк. | Арилокси- и гетероарилоксизамещенные тетрагидробензазепины и их применение для блокировки обратного захвата норэпинефрина, допамина и серотонина |
EP2146722A4 (en) | 2007-05-10 | 2011-08-03 | Amr Technology Inc | ARYL AND HETEROARYL SUBSTITUTED TETRAHYDROBENZO-1,4-DIAZEPINES AND THEIR USE FOR BLOCKING THE RECOVERY OF NOREPINEPHRIN, DOPAMINE AND SEROTONINE |
US7846930B2 (en) * | 2007-05-18 | 2010-12-07 | Janssen Pharmaceutica Nv | Diaryl-substituted tetrahydroisoquinolines as histamine H3 receptor and serotonin transporter modulators |
EP2167083B1 (en) * | 2007-06-06 | 2015-10-28 | Euthymics Bioscience, Inc. | 1- heteroaryl-3-azabicyclo[3.1.0]hexanes, methods for their preparation and their use as medicaments |
BRPI0909945A2 (pt) | 2008-06-20 | 2015-07-28 | Genentech Inc | "composto, composição farmacêutica, método para tratar ou atenuar a gravidade de uma doença ou condição responsiva à inibição da atividade jak2 quinase em um paciente, kit para o tratamento de uma doença ou distúrbio responsivo à inibição da jak quinase" |
TWI453207B (zh) | 2008-09-08 | 2014-09-21 | Signal Pharm Llc | 胺基三唑并吡啶,其組合物及使用其之治療方法 |
TWI396689B (zh) | 2008-11-14 | 2013-05-21 | Amgen Inc | 作為磷酸二酯酶10抑制劑之吡衍生物 |
EP2429293B1 (en) | 2009-05-12 | 2014-10-29 | Bristol-Myers Squibb Company | CRYSTALLINE FORMS OF (S)-7-([1,2,4]TRIAZOLO[1,5-a]PYRIDIN-6-YL)-4-(3,4-DICHLOROHPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE AND USE THEREOF |
EP2606049A4 (en) | 2010-08-17 | 2014-01-08 | Albany Molecular Res Inc | 2,5-METHANO- AND 2,5-ETHANO-TETRAHYDROBENZAZEPINE DERIVATIVES AND USES THEREOF FOR BLOCKING NOREPINEPHRINE, DOPAMINE, AND SEROTONIN REUPTAKE |
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003513074A (ja) * | 1999-11-03 | 2003-04-08 | アルバニー モレキュラー リサーチ インコーポレーティッド | アリールおよびヘテロアリール置換テトラヒドロイソキノリン、ならびにノルエピネフリン、ドーパミンおよびセロトニンの再取り込みを阻止するためのそれらの使用 |
JP2008520720A (ja) * | 2004-11-22 | 2008-06-19 | エーエムアール テクノロジー インコーポレイテッド | 4−フェニル置換テトラヒドロイソキノリン、ならびにそのノルエンピネフリン、ドーパミンおよびセロトニン再取り込み遮断のための使用 |
JP2008524118A (ja) * | 2004-11-22 | 2008-07-10 | エーエムアール テクノロジー インコーポレイテッド | ノルエピネフリン、ドーパミンおよびセロトニンの再取り込み遮断のためのアリール置換テトラヒドロイソキノリンおよびヘテロアリール置 |
JP2011522827A (ja) * | 2008-06-04 | 2011-08-04 | ブリストル−マイヤーズ スクイブ カンパニー | 6−[(4s)−2−メチル−4−(2−ナフチル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]ピリダジン−3−アミンの結晶形 |
JP2011524346A (ja) * | 2008-06-04 | 2011-09-01 | ブリストル−マイヤーズ スクイブ カンパニー | テトラヒドロイソキノリンの製造方法 |
JP2012526825A (ja) * | 2009-05-12 | 2012-11-01 | アルバニー モレキュラー リサーチ, インコーポレイテッド | 7−([1,2,4]トリアゾロ[1,5−a]ピリジン−6−イル)−4−(3,4−ジクロロフェニル)−1,2,3,4−テトラヒドロイソキノリンおよびその使用 |
JP2012526823A (ja) * | 2009-05-12 | 2012-11-01 | アルバニー モレキュラー リサーチ, インコーポレイテッド | アリール、ヘテロアリール、および複素環置換テトラヒドロイソキノリンならびにそれらの使用 |
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MX2011011900A (es) | 2012-01-20 |
US20140364441A1 (en) | 2014-12-11 |
JP5739415B2 (ja) | 2015-06-24 |
CN102638982B (zh) | 2015-07-08 |
EP2429293A1 (en) | 2012-03-21 |
AU2010247735B2 (en) | 2015-07-16 |
CN102638982A (zh) | 2012-08-15 |
WO2010132487A1 (en) | 2010-11-18 |
EP2429293B1 (en) | 2014-10-29 |
KR20120023072A (ko) | 2012-03-12 |
AU2010247735A1 (en) | 2011-12-01 |
ES2528404T3 (es) | 2015-02-10 |
US20100292250A1 (en) | 2010-11-18 |
US8815894B2 (en) | 2014-08-26 |
EP2429293A4 (en) | 2013-01-23 |
US9173879B2 (en) | 2015-11-03 |
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