JP2019055953A - グルタルイミド誘導体を含む医薬組成物、及び好酸球性疾患を処置するためのその適用 - Google Patents
グルタルイミド誘導体を含む医薬組成物、及び好酸球性疾患を処置するためのその適用 Download PDFInfo
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- JP2019055953A JP2019055953A JP2018203599A JP2018203599A JP2019055953A JP 2019055953 A JP2019055953 A JP 2019055953A JP 2018203599 A JP2018203599 A JP 2018203599A JP 2018203599 A JP2018203599 A JP 2018203599A JP 2019055953 A JP2019055953 A JP 2019055953A
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Abstract
Description
好酸球は、自然免疫の細胞である。好酸球は、骨髄で産生され、好ましくは血液中を循環する。好酸球の主なエフェクター機能は、各種刺激による活性化に応答しての細胞質顆粒の即時放出である。細胞質顆粒は、炎症誘発性メディエーター:サイトカイン、ケモカイン、脂質−及び神経伝達物質(neuromediators)、成長因子、並びにカチオン性タンパク質を含む。好酸球のカチオン性タンパク質は、4つのクラス:主要塩基性タンパク質(MBP)、好酸球ペルオキシダーゼ(EPO)、好酸球カチオン性タンパク質(ECP)、及び好酸球誘導神経毒(EDN)を含む。これらのタンパク質は、共同して、感染性微生物及び宿主の組織の両方に対して細胞毒性作用を有し、好酸球性炎症を惹起する[Hogan SP, Rosenberg HF, Moqbel R, et al. Eosinophils: biological properties and role in health and disease//Clin Exp Allergy. 2008; 38(5):709-50]。
本発明は、12.04.2013の出願RU 2013116826に開示される一般式(I):
R1及びR’1は、独立して水素、又はC1−C6アルキル、例えば、メチルであり;
R2は、場合によりC1−C6アルキルで置換された
本発明で用いられる好ましい化合物は、一般式(I):
R2は、
上述の一般式(I)のグルタルイミド誘導体の合成は、12.04.2013の出願RU 2013116826に開示されている。
材料及び方法
得られた化合物の同一性を、溶媒系:クロロホルム−メタノール(9:1)(1)、クロロホルム−メタノール(1:1)(2)中、プレート「Kieselgel 60 F254」(「Merck」、ドイツ)による薄層クロマトグラフィー(TLC)により評価した。
1−(2−(1H−イミダゾール−4−イル)エチル)ピペリジン−2,6−ジオン(化合物1)
N,N’−ジメチルホルムアミド(60mL)、及び1,5−ペンタン二酸の2−(イミダゾール−4−イル)−エタンアミド(20g)を、250mLの平底フラスコに充填した。激しく撹拌しながらカルボニルジイミダゾール(17.3g;1.2当量)を加えた。反応混合物を撹拌しながら90℃まで2時間加熱した。反応は、1H−NMR分光法により制御した(試料(0.5mL)を硫酸エーテルで希釈し、沈澱物をDMSO−d6に溶解した)。出発物質である1,5−ペンタン二酸の2−(イミダゾール−4−イル)−エタンアミドが反応塊中に存在しなくなったら、塊を冷却し、3倍量のメチルtert−ブチルエーテル(180mL)へ注いだ。反応混合物を1時間放置し、沈殿物をろ過し、メチルtert−ブチルエーテル60mLで洗浄し、乾燥した。粗生成の1−(2−(1H−イミダゾール−4−イル)エチル)ピペリジン−2,6−ジオンの収量は、12.4g(67%)であった。
1−(2−(1,3−ベンゾチアゾール−2−イル)エチル)ピペリジン−2,6−ジオン(化合物4)
1,5−ペンタン二酸の2−(1,3−ベンゾチアゾール−2−イル)エタンアミド(22g;0.075mol)及び無水酢酸(23g;0.225mol)の混合物を、ジオキサン150mL中で3時間沸騰させた。真空下でジオキサンを除去し、水200mLを加え、混合物を、30%水酸化ナトリウムで中性pHまで中和した。沈澱した油状物を結晶が形成されるまで摩砕した。沈澱を、クロマトグラフィーで精製した(SiCO2 60〜100μm、溶離剤:酢酸エチル−ヘキサン(1:1))。LC/MS、保持時間2.26分での個々のピーク、[M+H]+=275。条件AでのHPLC、保持時間9.3分での個々のピーク。1H-NMR (400.13 MHz, DMSO-d6, δ, m.d., J/Hz): 1.85 (quint, 2H, CH2CH2CH2, J= 6.8 Hz); 2.59 (t, 4H, CH2CH2CH2, J=6.8 Hz); 3.24 (t, 2H, CH2C, J= 7.3 Hz); 4.08 (t, 2H,CH2N, J=7.3 Hz); 7.43, 7.49 (t, 1H, Ar, J= 7,6 Hz); 7.96, 8.04 (d, 1H, Ar, J= 7,6 Hz)。
コーティング錠、2mg、10mg、及び100mg
材料及び方法
組織標本の形態学的研究を、光学顕微鏡(Leica DM LS, Leica Microsystems、ドイツ)を用いて行った。顕微鏡Leica DM LSにマウントした接眼ミクロメータースケールを用いて、微細形態計測分析(micromorphometric analysis)を行った。デジタルカメラ(Leica DC 320)により、顕微鏡写真を作成した。
ソフトウエアであるStatistica 6.0による偏差統計学的方法(variation statistics method)を用いて、得られた結果の数学的分析を行った。データは、記述統計学により解析した:データの正規分布は、シャピロ−ウィルク検定により確認した。全てのデータが正規分布に適合したので、群間偏差の解析を、スチューデントのt検定などのパラメトリック法により行った。p<0.05であれば、差は有意であると考えられた。
以下に示す多数の実施例により、請求する一般式(I)の化合物の生物学的活性が説明されている。
モルモットの喘息モデルにおける一般式(I)の化合物の有効性の評価
モルモットにおける気管支喘息は、標準的な方法[Ricciardolo FL, Nijkamp F, De Rose V, Folkerts G. The guinea pig as an animal model for asthma// Current Drug Targets. 2008 Jun; 9(6):452-65]によって誘発した。卵白アルブミン(Sigma)100μg/mL及び水酸化アルミニウム100mg/mLを含有する溶液0.5mLを非経口的に1回投与することにより、動物を免疫化した。無傷(intact)の動物は、生理学的食塩水0.5mLを投与された。
ラットのセファデックス誘発好酸球増加性肺炎症のモデルにおける一般式(I)の化合物の有効性の評価
ラットのセファデックス誘発好酸球性肺炎症のモデルを、標準的な方法により実現した[Evaldsson C, Ryden I, Uppugunduri S. Isomaltitol exacerbates neutrophilia but reduces eosinophilia: new insights into the sephadex model of lung inflammation//Int Arch Allergy Immunol. 2011; 154(4):286-94]。Sephadex G-200(Pharmacia、スエーデン)を、雄性Wistar系ラットに5mg/kgの投与量で、吸入により1回投与した。検討化合物を動物に、胃内経路により4回:セファデックス投与の24時間及び1時間前、並びに24時間及び45時間後、投与した。参考製剤であるブデソニドを、同じスキームにより、0.5mg/kgの投与量で吸入により投与した。気管支肺胞洗浄液を、セファデックス吸入の48時間後に採取し、洗浄液中の総リンパ球数及び白血球率(leukocyte formula)を求めた。1群中のラットの数は、7〜10であった。
モルモットのロイコトリエン誘発好酸球性肺炎症モデルにおける一般式(I)の化合物の有効性の評価
モルモットのロイコトリエン誘発好酸球性肺炎症のモデルを、標準的な方法により実現した[Underwood DC1, Osborn RR, Newsholme SJ, Torphy TJ, Hay DW. Persistent airway eosinophilia after leukotriene (LT) D4 administration in the guinea pig: modulation by the LTD4 receptor antagonist, pranlukast, or an interleukin-5 monoclonal antibody// Am J Respir Crit Care Med. 1996 Oct; 154(4 Pt 1):850-7]。インターロイキンD4(LTD4, Cayman Chemical, 米国)の濃度10mg/kgの溶液(流速250mL/hr)を、二重チャンバープレチスモグラフ(Emka Technologies, フランス)の条件下、雄性モルモット(250〜300g)に1分間吸入させた。検討化合物を動物に、胃内経路により4回:LTD4吸入の24時間及び1時間前、並びに24時間及び45時間後、投与した。参考製剤であるモンテルカスト(0.8mg/kg)を、胃内経路により、LTD4の吸入の1時間前に1回投与した。気管支肺胞洗浄液を、LTD4の吸入の48時間後に採取し、洗浄液中の総リンパ球数及び白血球率(leukocyte formula)を求めた。1群中のモルモットの数は、8であった。
モルモットのアレルギー性鼻炎モデルにおける一般式(I)の化合物の有効性の評価
モルモットのアレルギー性鼻炎モデルを、標準的な方法により実現した[Vishnu N. Thakare, M.M. Osama, Suresh R. Naik. Therapeutic potential of curcumin in experimentally induced allergic rhinitis in guinea pigs // Int Immunopharmacol. 2013 Sep; 17(1):18-25]。
マウスの逆症療法皮膚炎(allopathic dermatitis)のモデルにおける一般式(I)の化合物の有効性の評価
逆症療法皮膚炎のモデルを、標準的な方法により実現した[Mechanism of dinitrochlorobenzene-induced dermatitis in mice: role of specific antibodies in pathogenesis//PLoS One. 2009; 4(11)]。
検討の0及び12日目に、95%エタノール中の1−クロロ−2,4−ジニトロベンゼン(DNCB, Sigma-Aldrich, 米国)の2%溶液100μLを、雄性Balb/c系マウスの背部の剃毛した部位に適用した。検討の17日目、動物の右の「検討」耳に、2%DNCBのアルコール溶液20μLを1時間の間隔をおいて2回適用した。検討化合物及び参照製剤であるデキサメサゾンを、検討の8〜17日目の間1日1回胃内経路により投与した。
Claims (16)
- 好酸球性疾患が、気管支喘息、アレルギー性鼻炎、ポリープ状鼻副鼻腔症、好酸球性結腸炎、好酸球性症候群、アレルギー性結膜炎、アトピー性皮膚炎、チャーグ−ストラウス症候群、アナフィラキシーショック、クインケ浮腫、好酸球性脈管炎、好酸球性食道炎、好酸球性胃腸炎、又は線維症である、請求項1に記載の治療薬。
- 好酸球性疾患が、気管支喘息、アレルギー性鼻炎、ポリープ状鼻副鼻腔症、好酸球性結腸炎、好酸球性症候群、アレルギー性結膜炎、アトピー性皮膚炎、チャーグ−ストラウス症候群、アナフィラキシーショック、クインケ浮腫、好酸球性脈管炎、好酸球性食道炎、好酸球性胃腸炎、又は線維症である、請求項5に記載の医薬組成物。
- 好酸球性疾患が、気管支喘息、アレルギー性鼻炎、ポリープ状鼻副鼻腔症、好酸球性結腸炎、好酸球性症候群、アレルギー性結膜炎、アトピー性皮膚炎、チャーグ−ストラウス症候群、アナフィラキシーショック、クインケ浮腫、好酸球性脈管炎、好酸球性食道炎、好酸球性胃腸炎、又は線維症である、請求項9に記載の方法。
- 好酸球性疾患が、気管支喘息、アレルギー性鼻炎、ポリープ状鼻副鼻腔症、好酸球性結腸炎、好酸球性症候群、アレルギー性結膜炎、アトピー性皮膚炎、チャーグ−ストラウス症候群、アナフィラキシーショック、クインケ浮腫、好酸球性脈管炎、好酸球性食道炎、好酸球性胃腸炎、又は線維症である、請求項13に記載の使用。
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