JP6449277B2 - イミダゾールカルボキサミドおよびfaah阻害剤としてのそれらの使用 - Google Patents
イミダゾールカルボキサミドおよびfaah阻害剤としてのそれらの使用 Download PDFInfo
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- JP6449277B2 JP6449277B2 JP2016529739A JP2016529739A JP6449277B2 JP 6449277 B2 JP6449277 B2 JP 6449277B2 JP 2016529739 A JP2016529739 A JP 2016529739A JP 2016529739 A JP2016529739 A JP 2016529739A JP 6449277 B2 JP6449277 B2 JP 6449277B2
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- imidazole
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- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- PRXNKYBFWAWBNZ-UHFFFAOYSA-N trimethylphenylammonium tribromide Chemical compound Br[Br-]Br.C[N+](C)(C)C1=CC=CC=C1 PRXNKYBFWAWBNZ-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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Description
本発明は、化合物及びその使用に関し、特に化合物及び脂肪酸アミドヒドロラーゼ (fatty acid amide hydrolase)(FAAH)酵素によって分解される基質、例えば神経伝達物質であるアナンダミドと関連する症状の処置又は予防におけるその化合物の治療用途に関する。
FAAH酵素は、アナンダミド(N−アラキドノイルエタノールアミン)、N−オレイルエタノールアミン(OEA)、N−パルミトイルエタノールアミン(PEA)、及びオレアミドなどの脂肪酸アミドを分解する。アナンダミドは、N−アラキドノイルエタノールアミン、又はAEAとしても知られ、動物及びヒトの臓器内、特に脳内に見出される内因性のカンナビノイド神経伝達物質である。アナンダミドが、バニロイド受容体に結合することも見出されている。アナンダミドは、脂肪酸アミドヒドロラーゼ(FAAH)酵素により、エタノールアミン及びアラキドン酸に分解される。従って、FAAHの阻害剤は、アナンダミドのレベル上昇を引き起こす。
第1の態様では、本発明は、以下:
(i)疼痛、特に急性又は慢性の神経原性の疼痛(neurogenic pain)、例えば偏頭痛(migraine)及び神経障害性の疼痛(例えば代謝性神経障害性の疼痛、ヘルペス後神経痛(post-herpetic neuralgia)、三叉神経痛(trigeminal neuralgia));偏頭痛;急性又は慢性炎症性疼痛、炎症性疾患、例えば関節炎、リウマチ性関節炎(rheumatoid arthritis)、骨関節炎(osteoarthritis)、骨粗しょう症、脊椎炎(spondylitis)、痛風(gout)、血管炎(vasculitis)、クローン病、及び過敏性腸症候群に関連するもの等;急性又は慢性の末梢疼痛;癌疼痛;
から選択されてもよい。
本発明は、以下でさらに詳細に、例としてのみ記載される:
1. 合成の方法論
本発明の化合物の合成に使用した方法を、以下の一般的なスキーム及び具体的な合成により例示する。すべての化合物及び中間体は、核磁気共鳴法(NMR)により特性評価した。これらの化合物を調製するのに使用した出発物質及び試薬は、市販品の供給元から入手可能である、又は当業者に自明の方法により調製することができる。これらの一般的なスキーム及び具体的な合成は、本発明の化合物を合成することができる方法を単に例示するだけのものであって、これらのスキーム及び合成に様々な修正を行うことは可能であり、本開示を参照した当業者に提案されることになるであろう。
1H : 9.54 (1H, s), 8.14 (1H, s), 7.94 (1H, s), 7.64 (1H, s), 7.44 (1H, d, J = 7.7 Hz), 7.27 (1H, t, J = 7.6 Hz), 7.15 (2H, s), 7.05 (1H, d, J = 8.2 Hz), 4.10 (1H, m), 3.93 (2H, dd, J = 4.0, 11.3 Hz), 3.36 (2H, m), 2.95 (3H, s), 1.86 (2H, dq, J = 4.1, 12.3 Hz), 1.70 (2H, d, J = 12.0 Hz).
13C : 151, 140.6, 139.9, 137.5, 134, 129, 118.6, 116.9, 114.6, 114.4, 66.3, 54.2, 31.6, 29.1.
1H : 9.34 (1H, s), 8.06 (1H, d, J = 1.2 Hz), 7.77 (1H, d, J = 1.2 Hz), 7.55 (1H, d, J = 1.6 Hz), 7.47 (1H, dd, J = 2, 8.3 Hz), 6.77 (1H, d, J = 8.3 Hz), 4.53 (1H, d, J = 12.5 Hz), 4.10 (1H, m), 3.95 (1H, d, J = 13.5 Hz), 3.06 (1H, mt, J = 13.0 Hz), 2.91 (3H, s), 2.56 (1H, mt, J = 12.8 Hz), 2.34 (2H, q, J = 7.5 Hz), 2.14 (3H, s), 1.76 (3H, m), 1.60 (1H, dq, J = 4.3, 12.3 Hz), 0.98 (3H, t, J = 7.5 Hz).
13C : 171.1, 154.8, 151.1, 141.1, 137.3, 127.3, 124.2, 123.8, 123.4, 114.6, 112.3, 55.1, 43.9, 40.3, 31.6, 28.6, 28, 25.5, 16.1, 9.5.
1H : 9.32 (1H, s), 8.06 (1H, d, J = 1.2 Hz), 7.76 (1H, d, J = 1.2 Hz), 7.55 (1H, d, J = 1.6 Hz), 7.47 (1H, dd, J = 2, 8.2 Hz), 6.77 (1H, d, J = 8.2 Hz), 4.51 (1H, d, J = 12.0 Hz), 4.37 (1H, d, J = 13.0 Hz), 4.13 (1H, m), 3.15 (1H, t, J = 13.0 Hz), 2.92 (3H, s), 2.61 (1H, mt, J = 13.0 Hz), 2.14 (3H, s), 2.0 (1H, m), 1.85 (1H, md), 1.77 (2H, m), 1.63 (1H, mq), 0.8-0.66 (4H, m).
13C : 170.8, 154.8, 151.2, 141.1, 137.3, 127.3, 124.2, 123.8, 123.4, 114.6, 112.4, 55.2, 44, 40.8, 31.7, 28.9, 28, 16.1, 10.3, 7, 6.9.
すべての動物手順は、実験及びその他の科学的目的に使用される脊椎動物の保護に向けた欧州の指導(European Directive for Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes(86/609CEE)、及びポルトガルの立法(Decreto-Lei 129/92, Portarias 1005/92 e 1131/97)に厳密に沿って実行した。使用した動物の数は、現状の規制及び科学的完全性に従って、最小限とした。
マウスにおける実験
動物の処置
実験に使用した動物は、インテルファウナ・イベリカ(Interfauna Iberica(スペイン))から入手した雄のNMRIマウス(体重27〜44g)であった。マウスは、管理された環境条件(12時間の明/暗周期、及び室温22±1℃)下、1ケージ当たり5匹を維持した。餌及び水道水は不断に与え、実験すべて日中の時間に実行した。
アナンダミド[エタノールアミン−1−3H−](40〜60Ci/mmol)を、アメリカンラジオケミカルズ社(American Radiochemicals)から入手した。その他すべての試薬は、シグマアルドリッチ社(Sigma-Aldrich)から入手した。Optiphase Supermixをパーキンエルマー社(Perkin Elmer)から入手し、活性炭をシグマアルドリッチ社から入手した。
組織を氷上で解凍し、10体積量の膜緩衝液(3mMのMgCl2、1mMのEDTA、50mMのTris HCl pH7.4)中で、Potter−Elvejhem(脳−500rpmで8ストローク)、又はHeidolph Diax(肝臓−30秒の休止を入れて20秒間、5の位置で2ストローク)のいずれかを用いてホモジネートした。
反応混合物(200μlの全体積)は:1mMのEDTA、10mMのTris pH7.6中、2μMのAEA(2μMのAEA+5nMの3H−AEA)、脂肪酸を含まない0.1%のBSA、15μg(脳)又は5μg(肝臓)のタンパク質を含有していた。37℃での15分のプレインキュベーション期の後、基質溶液(冷AEA+放射標識されたAEA+BSA)の添加により反応が開始した。反応は、10分間(脳)、又は7分間(肝臓)実行したのち、400μlの活性炭懸濁液(連続して強く攪拌した状態で32ml、0.5MのHCl中、8gの炭)の添加により停止させた。室温で強く攪拌して30分のインキュベーション時間の後、炭を、微量遠心管中で遠心分離(13000rpmで10分)により沈降させた。200μlの上清を、24ウェルプレートに事前に分配されたOptiphase Supermixシンチレーション反応混液800μlに加えた。カウント毎分(cpm)を、MicrobetaTriLuxシンチレーションカウンター中で定量した。
動物の処置
雄のウィスターラット(体重範囲:190〜230g)は、ハーラン(Harlan(スペイン))から入手した。ラットは、管理された環境条件(12時間の明/暗周期、及び室温22±1℃)下、1ケージ当たり5匹を維持した。餌及び水道水は不断に与え、実験すべて日中の時間に実行した。
アナンダミド[エタノールアミン−1−3H−]を、アメリカンラジオケミカルズ社から入手した(60Ci/mmolの比放射能)。その他すべての試薬は、シグマアルドリッチ社から入手した。Optiphase Supermixをパーキンエルマー社から入手した。
組織を氷上で解凍し; 肝臓をPrecellys 24 Dual Tissue Homogenizer(バーティンテクノロジーズ(Bertin Technologies))によって、氷中、5分のインターバルで5秒の2サイクル、ホモジネートし、脳を、Heidolph Silent Crusher M(probe 8F/M)を用いて、約45秒間、最高速度でホモジネートした。ホモジネート中の全タンパク質を、BioRadタンパク質アッセイ(BioRad)を用い、BSA(50〜250μg/ml)の標準曲線を使用して定量した。
反応混合物(200μlの全体積)は:1mMのEDTA、10mMのTris pH7.6中、2μMのAEA(2μMのAEA+5nMの3H−AEA)、脂肪酸を含まない0.1%のBSA、15μg(脳)又は1.5μg(肝臓)のタンパク質を含有していた。37℃での15分のプレインキュベーション期の後、基質溶液(冷AEA+放射標識されたAEA+BSA)の添加により反応が開始した。反応は、肝臓試料については7分間、脳試料については10分間実行し、400μLのクロロホルム:メタノール(1:1、v/v)溶液の添加により停止させた。反応試料を二回ボルテックスし、5分間氷上に放置し、その後、微量遠心管中で遠心分離した(7分、7000rpm)。200μlの上清を、24ウェルプレートに事前に分配されたOptiphase Supermixシンチレーション反応混液800μlに加えた。カウント毎分(cpm)を、MicrobetaTriLuxシンチレーションカウンター中で定量した。各アッセイにおいて、ブランク試料(タンパク質無し)を準備した。残った酵素活性の百分率を、対照に関して、そしてブランクを差し引いた後に計算した。
試験化合物の安定性を、NADPHの存在下、及び非存在下で、MLM(マウスの肝臓のミクロソーム)、又はHLM(ヒトの肝臓のミクロソーム)中で実行した。
化合物1=(N−メチル−4−(3−(スルファモイルアミノ)フェニル)−N−(テトラヒドロ−2H−ピラン−4−イル)−1H−イミダゾール−1−カルボキサミド)。
化合物2=((4−(4−ヒドロキシ−3−メチルフェニル)−N−メチル−N−(1−プロピオニルピペリジン−4−イル)−1H−イミダゾール−1−カルボキサミド)。
化合物3=((N−(1−(シクロプロパンカルボニル)ピペリジン−4−イル)−4−(4−ヒドロキシ−3−メチルフェニル)−N−メチル−1H−イミダゾール−1−カルボキサミド)。
以下の表に、化合物の代謝安定性を示す。安定性データは、MLM又はHLMに1時間、曝露した後の残留化合物の%として与えられている。100%は、代謝反応が全くないことを意味しており、0%は完全な酵素分解に対応している。「CYP−」は、CYP代謝反応に基本的に重要である補助因子(NADPH)の非存在を指す。従って「CYP−」は、対照値と見なすことができる。「CYP+」は、補助因子の存在を指し、試験化合物の安定性に応じて酵素分解が生じることがある。見てわかる通り、すべての化合物は、代謝的に安定である。
Claims (14)
- 前記薬学的に許容される塩が、塩酸塩、酢酸塩、トリフルオロ酢酸塩、メタンスルホン酸塩、2−ヒドロキシプロパン−1,2,3−トリカルボン酸塩、(2R,3R)−2,3−ジヒドロキシコハク酸塩、リン酸塩、硫酸塩、安息香酸塩、2−ヒドロキシ−安息香酸塩、S−(+)−マンデル酸塩、S−(−)−マレイン酸塩、S−(−)ピログルタミン酸塩、ピルビン酸塩、p−トルエンスルホン酸塩、1−R−(−)−カンファースルホン酸塩、フマル酸塩、マレイン酸塩又はシュウ酸塩である、請求項1に記載の化合物。
- 請求項1又は2に記載の化合物を、1又は2以上の薬学的に許容される賦形剤とともに含む医薬組成物。
- 経口投与向けである、請求項3に記載の医薬組成物。
- 殺菌済み注射可能な調製物の形態である、請求項3に記載の医薬組成物。
- 症状の発症又は兆候がFAAH酵素の基質と関連する症状の処置又は予防における使用のための、請求項3から5のいずれか一項に記載の医薬組成物。
- 前記症状が、エンドカンナビノイド系と関連する疾患である、請求項6に記載の医薬組成物。
- 前記疾患が、食欲抑制、肥満、代謝疾患、悪液質、無食欲症、疼痛、炎症、神経毒性、神経外傷、脳卒中、多発性硬化症、脊髄損傷、パーキンソン病、レボドパ誘発性ジスキネジア、ハンチントン病、ジル‐ド‐ラ‐ツレット症候群、遅発性ジスキネジア、ジストニア、筋萎縮性側索硬化症、アルツハイマー病、てんかん、統合失調症、不安症、うつ病、不眠症、悪心、嘔吐、アルコール疾患、薬物依存症、高血圧、循環性ショック、心筋再潅流傷害、アテローム性動脈硬化、ぜんそく、高眼圧症(ocular hypertension)、緑内障、網膜症、癌、炎症性腸疾患、急性及び慢性肝疾患、関節炎並びに骨粗しょう症から選択される、請求項7に記載の医薬組成物。
- 前記薬物依存症が、オピエート、ニコチン、コカイン、アルコール及び精神刺激薬の依存症から選択される、請求項8に記載の医薬組成物。
- 前記急性及び慢性肝疾患が、肝炎及び肝硬変から選択される、請求項8に記載の医薬組成物。
- 1又は2以上の追加の医薬的活性成分をさらに含む、請求項3から10のいずれか一項に記載の医薬組成物。
- 前記1又は2以上の追加の医薬的活性成分が、アナンダミド、オレイルエタノールアミド及びパルミトイルエタノールアミドから選択される、請求項11に記載の医薬組成物。
- 1又は2以上の追加の医薬活性成分と同時に、又はずらして投与するための、請求項3から10のいずれか一項に記載の医薬組成物。
- 前記1又は2以上の追加の医薬的活性成分が、アナンダミド、オレイルエタノールアミド及びパルミトイルエタノールアミドから選択される、請求項13に記載の医薬組成物。
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RS56297B1 (sr) | 2017-12-29 |
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