JP6430015B2 - 新規クロモンオキシム誘導体、および代謝型グルタミン酸受容体のアロステリックモジュレーターとしてのそれの使用 - Google Patents
新規クロモンオキシム誘導体、および代謝型グルタミン酸受容体のアロステリックモジュレーターとしてのそれの使用 Download PDFInfo
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- JP6430015B2 JP6430015B2 JP2017530425A JP2017530425A JP6430015B2 JP 6430015 B2 JP6430015 B2 JP 6430015B2 JP 2017530425 A JP2017530425 A JP 2017530425A JP 2017530425 A JP2017530425 A JP 2017530425A JP 6430015 B2 JP6430015 B2 JP 6430015B2
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Classifications
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Description
EP-A-0 787 723は、mGluRアンタゴニスト活性をもつとされる特定のシクロプロパクロメンカルボン酸誘導体に関する。
したがって、本発明は、化合物6−(3−モルホリン−4−イル−プロピル)−2−(チエノ[3,2−c]ピリジン−6−イル)−4H−クロメン−4−オン オキシムまたはその医薬的に許容できる塩、溶媒和物もしくはプロドラッグに関する。
図1:ラットに経口投与(10mg/kg)した後のPXT002331およびPXT001858の脳曝露。
図3:ラットに経口投与(10mg/kg)した後のPXT002331およびPXT001858の脳レベル。
図5:1−メチル−4−フェニル−1,2,3,6−テトラヒドロピリジン(MPTP)パーキンソン病のマカク属(macaque)モデルにおけるPXT002331の抗パーキンソン効力の評価(参照:実施例3)。(A)単独処置としてのPXT002331;1日2回、4日間の経口投与、4日目にパーキンソンスコアの査定;データは2時間にわたる観察の平均+標準誤差である(グループ当たりn=7;最初に用いた8匹のサルのうち1匹を除外した);“Veh”=ビヒクル;“LD opt”=L−ドーパ最適用量”;*=P<0.05 対ビヒクル;***=P<0.001 対ビヒクル;統計解析:フリードマン検定(Friedman)に続いてダン検定(Dunn’s)。(B)PXT002331(25mg/kg)+低用量のL−ドーパ(4〜9mg/kg)を用いた併用処置 − パーキンソン病タイムコース;1日2回、4日間の経口投与、4日目に査定;L−ドーパ最適用量(“LD opt”):>20mg/kg;L−ドーパ最適下用量(“LD so”):4〜9mg/kg;L−ドーパ(最適下用量)とPXT002331の併用投与:1日2回/4日間。(C)PXT002331+低用量のL−ドーパを用いた併用処置 − 低用量のL−ドーパおよびPXT002331で処置したサルについてのパーキンソンスコアを、低用量のL−ドーパ単独と比較した相異、および最適用量のL−ドーパと比較した相異;4日目に、L−ドーパ投与後1−2時間目(すなわち、PXT002331投与後2−3時間目)に査定;PXT002331+L−ドーパで処置したすべてのサルがパーキンソンスコアの有意の改善を示した。(D)PXT002331+低用量のL−ドーパを用いた併用処置 − 種々の用量のPXT002331についての用量−応答評価;4日目にパーキンソンスコアの査定;“Veh”=ビヒクル;“low LD”=低用量のL−ドーパ;“LD opt”=最適用量のL−ドーパ;*=P<0.05 対 低LD;統計解析:ノンパラメトリック一元配置分散分析(対応あり)(non-parametric one-way repeated, measures ANOVA)(フリードマン検定)、続いてダンの多重比較(Dunn’s multiple comparison);N=7。(E)経口投与した際のL−ドーパ(低用量または最適用量)と併用したPXT002331についての初期PDサルモデルにおけるコンピューター処理歩行活動;*=P<0.05 対ビヒクル;**=P<0.01 対ビヒクル;***=P<0.001 対ビヒクル;統計解析:フリードマン検定に続いてダネット検定(Dunnett’s);N=5(6匹のサル/1匹は除外)。(F)PXT002331+最適用量のL−ドーパを用いた併用処置 − 能力障害スコアおよびジスキネジー(運動障害)スコア。
1.下記の式(I)の化合物:
2.式(I)に含まれるオキシム基において化合物が(E)−立体配置を有する、項目1の化合物。
4.医薬として使用するための、項目1〜3のいずれか1項の化合物。
5.項目1〜3のいずれか1項の化合物および医薬的に許容できる賦形剤を含む、医薬組成物。
14.パーキンソン病の治療または防止に使用するための、項目1〜3のいずれか1項の化合物または項目5の医薬組成物。
16.パーキンソン病を処置する方法であって、項目1〜3のいずれか1項の化合物または項目5の医薬組成物をその必要がある対象に投与することを含む方法。
下記の例を参照して以下に本発明を記載する;それらは説明のためのものにすぎず、本発明の範囲を限定するものと解釈すべきではない。
1)一般的な合成経路
本発明による式(I)の化合物(すなわち、PXT002331)は、容易に入手できる出発物質から、溶液相もしくは固相化学プロトコルまたは溶液相および固相混合プロトコルを用いる幾つかの合成法により製造できる。たとえば、式(I)の化合物は下記に示す合成スキームを用いて製造できる。
オキシムの導入は、誘導体IVとヒドロキシルアミン塩酸塩(HONH2,HCl)をピリジンまたはエタノール中においてマイクロ波条件下で反応させてクロモンオキシム高次中間体(advanced intermediate)を直接得ることにより達成でき、それは数工程の反応でPXT002331になる。PXT002331になるこの高次中間体は、上記に示した2工程法により、エタノール中でtert−ブチルヒドロキシルアミン塩酸塩(tBuONH2,HCl)を用い、続いて塩酸(HCl)などの酸性条件下で、極性溶媒、たとえばTHFおよび酢酸の混合物中におけるtert−ブチル基の脱保護による後続工程により得ることもできる。
アルキレン側鎖の導入は、パラジウム触媒によるクロスカップリング反応、たとえば市販の亜鉛試薬および適宜な配位子/パラジウム触媒系を用いる根岸クロスカップリングにより達成される。後続の官能化、続いて弱い還元剤、たとえばトリアセトキシボロヒドリドを用いる標準的な還元アミノ化により、高次中間体VIIが良好な収率で得られる。酸性条件下でのオキシム保護基の最終的な脱保護により、式(I)の化合物、すなわちPXT002331が得られる。
下記の実験のセクションに用いた市販の出発物質は、別にレポートしない限りAldrich、Sigma、ACROSまたはABCRから購入された。
HPLC分析は、Waters X−bridgeTM C8 50mm×4.6mmカラムを用いて下記に従って得られた:流速2mL/分;8分の勾配 H2O:CH3CN:TFA 100:0:0.1%から0:100:0.05%まで,UV検出付き(254nm)。
工程1および2: 6−ブロモ−2−(チエノ[3,2−c]ピリジン−6−イル)−4H−クロメン−4−オン(3)
収率:83%.
LC/MS:質量 実測値(m/z, M+1, 358.0),面積94.78%.
1H NMR (DMSO-d6, 400MHz) δ 9.32 (s, 1H), 9.06 (s, 1H), 8.15 (m, 2H), 8.06 (m, 1H), 7.84 (d, J 5.4 Hz, 1H), 7.77 (d, J 5.4 Hz, 1H), 7.32 (s, 1H)。
収率:83%.
LC/MS:質量 実測値(m/z, M+1, 429.0),面積97.83%.
1H NMR (DMSO-d6, 400MHz) δ 9.25 (s, 1H), 8.78 (s, 1H), 8.05 (m, 2H), 7.71 (m, 2H), 7.59 (s, 1H), 7.48 (s, 1H), 1.40 (s, 9H)。
収率:82%
HPLC: 93.00% (254nm), RT: 2.50分.
LC/MS:質量 実測値(m/z, M+1, 451.0),面積93.96%.
1H NMR (DMSO-d6, 400MHz) δ 9.27 (s, 1H), 8.77 (s, 1H), 8.05 (d, J 5.4 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J 5.4 Hz, 1H), 7.62 (s, 1H), 7.43 (m, 2H), 4.85 (m, 1H), 3.93 (m, 2H), 3.80 (m, 2H), 2.75 (m, 2H), 1.90 (s, 2H), 1.39 (s, 9H)。
収率:92%
LC/MS:質量 実測値(m/z, M+1, 407.3),面積91%.
1H NMR (CDCl3, 400MHz) δ 9.79 (s, 1H), 9.09 (s, 1H), 8.39 (s, 1H), 7.82 (s, 1H), 7.67 (s, 1H), 7.52 (d, J 5.4 Hz, 1H), 7.43 (d, J 5.4 Hz, 1H), 7.17 (m, 2H), 2.93 (m, 2H), 2.77 (s, 2H), 1.37 (s, 9H)。
収率:63%.
HPLC: 95.97% (254nm).
LC/MS:質量 実測値(m/z, M+1, 478.3),面積96.62%.
1H NMR (DMSO-d6, 400MHz) δ 9.24 (s, 1H), 8.74 (s, 1H), 8.03 (d, J 5.4 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J 5.4 Hz, 1H), 7.59 (m, 1H), 7.39 (m, 2H), 3.56 (m, 4H), 2.65 (m, 2H), 2.28 (m, 6H), 1.73 (m, 2H), 1.36 (s, 9H)。
収率:90%
HPLC純度: 98.44% (254nm). E/Z比=97.54% / 1.75%.
LC/MS:質量 実測値(m/z, M+, 422.3),面積97.3%.
1H NMR (DMSO, 400MHz) δ 11.06 (brs, 1H), 10.72 (brs, 1H), 9.28 (s, 1H), 8.80 (s, 1H), 8.07 (d, J 5.4 Hz, 1H), 7.76-7.70 (m, 3H), 7.47-7.41 (m, 2H), 3.95 (m, 2H), 3.80 (m, 2H), 3.42, (m, 2H), 3.08 (m, 4H), 2.71 (m, 2H), 2.10 (m, 2H)。
本発明による式(I)の化合物(すなわち、PXT002331)を、WO 2011/051478の例171に記載されたカルシウムアッセイを用いて、ヒトmGluR4に対するそれのアゴニストおよび/またはポジティブアロステリックモジュレーター活性について試験した。PXT002331はpEC50=7.12の力価をもつことが認められ(約0.076μMのEC50に相当する)、それは7.44のpEC50をもつ(約0.036μMのEC50に相当する)WO 2011/051478の例127の化合物(すなわち、“PXT001858”)のものに匹敵する。
PXT002331およびPXT001858を10mg/kgで雄Sprague−Dawleyラットに経口投与(p.o.)した。投与体積は10ml/kgであった。並行してPXT002331を1mg/kgで2ml/kgの投与体積により静脈内(i.v.)にも投与した。血液試料(200μl)を、経口投与については15分から24時間まで、静脈内投与については5分から24時間までの範囲の時点で、0.2% K2EDTAを入れた氷冷チューブに採集した。チューブを10,000rpmで5分間、4℃で遠心した。血漿(上清)を別のチューブに分離し、分析するまで−80℃で保存した。動物3匹の2グループをそれぞれの投与経路に用いた:1グループにおいては24時間の期間にわたって血液試料を採集して血漿曝露を決定し、第2グループにおいては血液と脳を最後の1時点で採集して(0.5、1.0、1.5、2.0、4.0時間)、脳曝露の動態および脳/血漿比を決定した。
血漿試料および脳ホモジェネート中の親化合物(遊離塩基)をそれぞれLC−MS/MS法により分析した。濃度をng/ml血漿またはng/g脳組織で表示する。
10mg/kgで、同じビヒクル(Tween−80/エタノール/30% HPBCD(2/10/88))を用いて、PXT002331はそれのAUC(1.1倍)およびCmax(0.7倍)に反映されるようにPXT001858に匹敵する血漿曝露を示した。この実験におけるPXT002331の経口による生物学的利用能は39%であった。それらの経口吸収が類似するにもかかわらず、PXT002331は、PXT001858と比較した場合、より高い脳/血漿比(6.5対2.0,T=1.5時間;図4を参照)をもち、脳AUCの3倍改善をもたらす。帰納的に、可能性のある1つの仮説は経口吸収に際しての腸および肝臓における第II相コンジュゲーションの相異を拠りどころとすることができた。両方の化合物をインビトロでUGT(UDP−グルクロノシルトランスフェラーゼ)の存在下でアッセイすると、PXT002331はPXT001858と比較してはるかに低いレベルのグルクロニデーションを示した(参照:下記の表)。それにもかかわらず、インビトロでみられたこの相異自体ではPXT002331で得られた予想外に有利なPK結果を説明することはできない。これらの実験で得られた結果を下記の表1〜3および図1〜4にまとめる。
本発明による式(I)の化合物(すなわち、PXT002331)の抗パーキンソン効力を、1−メチル−4−フェニル−1,2,3,6−テトラヒドロピリジン(MPTP)パーキンソン病のマカク属モデル(マカク属カニクイザル(Macaca fascicularis)の種)を用いて評価した;これはパーキンソン病の臨床的および病理学的特徴の大部分を再現し、“ゴールドスタンダード”とみなされる(MPTPモデルについて、Porras G et al., Cold Spring Harb Perspect Med., 2(3):a009308, 2012 およびそれに引用された参考文献を参照)。
Claims (22)
- 下記の式(I)の化合物:
またはその医薬的に許容できる塩、もしくは溶媒和物。 - 式(I)に含まれるオキシム基において化合物が(E)−立体配置を有する、請求項1に記載の化合物。
- 前記医薬的に許容できる塩が塩酸塩である、請求項1または2に記載の化合物。
- 医薬を調製するための、請求項1〜3のいずれか1項に記載の化合物の使用。
- 請求項1〜3のいずれか1項に記載の化合物および医薬的に許容できる賦形剤を含む、医薬組成物。
- 変化したグルタミン酸シグナル伝達および/または機能に関連する状態、あるいはグルタミン酸レベルまたはシグナル伝達の変化により影響を受ける可能性のある状態の治療または防止に使用するための、請求項5に記載の医薬組成物。
- 前記変化したグルタミン酸シグナル伝達および/または機能に関連する状態、あるいはグルタミン酸レベルまたはシグナル伝達の変化により影響を受ける可能性のある状態が、認知症、パーキンソン症候群および運動障害、急性もしくは慢性疼痛、不安障害、統合失調症、気分障害、内分泌性および代謝性疾患、糖尿病、内分泌腺の障害、低血糖症、または癌から選択される、請求項6に記載の医薬組成物。
- 前記状態が前記認知症であり、
さらに、前記認知症が、アルツハイマー型認知症(DAT);アルツハイマー病;ピック病;血管性認知症;レビー小体病;アルコール中毒、甲状腺機能低下症およびビタミンB12欠乏症を含む代謝性、毒性および欠乏性疾患に起因する認知症;エイズ−認知症複合疾患;クロイツフェルト−ヤコブ病;または非定型亜急性海綿状脳症から選択される、請求項7に記載の医薬組成物。 - 前記状態が前記パーキンソン症候群および運動障害から選択され、
さらに、前記パーキンソン症候群および運動障害が、パーキンソン病;多系統萎縮;進行性核上麻痺;大脳皮質基底核変性症;肝レンズ核変性症;ハンチントン病および片側バリスムを含む舞踏病;アテトーシス;痙性斜頚、職業性運動障害およびジル−ド−ラ−ツレット症候群を含むジストニア;レボドパ誘発性ジスキネジーを含む遅発性または薬物誘発性ジスキネジー;振戦;あるいはミオクロヌスから選択される、請求項7に記載の医薬組成物。 - 前記状態が前記不安障害であり、
さらに、前記不安障害が、パニック障害;恐怖症;強迫性障害;外傷後ストレス障害を含むストレス障害;または全般性不安障害から選択される、請求項7に記載の医薬組成物。 - 前記状態が前記気分障害であり、
さらに、前記気分障害が、抑うつ障害または双極性障害から選択される、請求項7に記載の医薬組成物。 - パーキンソン病の治療または防止に使用するための、請求項5に記載の医薬組成物。
- 前記医薬組成物が経口投与のためのものである、請求項6〜12のいずれか1項に記載の医薬組成物。
- 変化したグルタミン酸シグナル伝達および/または機能に関連する状態、あるいはグルタミン酸レベルまたはシグナル伝達の変化により影響を受ける可能性のある状態の治療または防止に用いる医薬を調製するための、請求項1〜3のいずれか1項に記載の化合物の使用。
- 前記変化したグルタミン酸シグナル伝達および/または機能に関連する状態、あるいはグルタミン酸レベルまたはシグナル伝達の変化により影響を受ける可能性のある状態が、認知症、パーキンソン症候群および運動障害、急性もしくは慢性疼痛、不安障害、統合失調症、気分障害、内分泌性および代謝性疾患、糖尿病、内分泌腺の障害、低血糖症、または癌から選択される、請求項14に記載の使用。
- 前記状態が前記認知症であり、
さらに、前記認知症が、アルツハイマー型認知症(DAT);アルツハイマー病;ピック病;血管性認知症;レビー小体病;アルコール中毒、甲状腺機能低下症およびビタミンB12欠乏症を含む代謝性、毒性および欠乏性疾患に起因する認知症;エイズ−認知症複合疾患;クロイツフェルト−ヤコブ病;または非定型亜急性海綿状脳症から選択される、請求項15に記載の使用。 - 前記状態が前記パーキンソン症候群および運動障害から選択され、
さらに、前記パーキンソン症候群および運動障害が、パーキンソン病;多系統萎縮;進行性核上麻痺;大脳皮質基底核変性症;肝レンズ核変性症;ハンチントン病および片側バリスムを含む舞踏病;アテトーシス;痙性斜頚、職業性運動障害およびジル−ド−ラ−ツレット症候群を含むジストニア;レボドパ誘発性ジスキネジーを含む遅発性または薬物誘発性ジスキネジー;振戦;あるいはミオクロヌスから選択される、請求項15に記載の使用。 - 前記状態が前記不安障害であり、
さらに、前記不安障害が、パニック障害;恐怖症;強迫性障害;外傷後ストレス障害を含むストレス障害;または全般性不安障害から選択される、請求項15に記載の使用。 - 前記状態が前記気分障害であり、
さらに、前記気分障害が、抑うつ障害または双極性障害から選択される、請求項15に記載の使用。 - パーキンソン病の治療または防止に用いる医薬を調製するための、請求項1〜3のいずれか1項に記載の化合物の使用。
- 前記医薬が経口投与のためのものである、請求項14〜20のいずれか1項に記載の使用。
- パーキンソン病を処置する方法であって、請求項1〜3のいずれか1項に記載の化合物をその必要がある対象に投与することを含み、前記対象が非ヒト動物である、前記方法。
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JP2018528205A (ja) * | 2015-08-27 | 2018-09-27 | プレクストン・セラピューティクス・ソシエテ・アノニム | レボドパ誘発性ジスキネジア療法のための脳透過性クロモンオキシム誘導体 |
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NZ728853A (en) * | 2014-08-27 | 2018-04-27 | Prexton Therapeutics Sa | Novel chromone oxime derivative and its use as allosteric modulator of metabotropic glutamate receptors |
AU2019309448B2 (en) | 2018-07-26 | 2024-08-29 | Domain Therapeutics | Substituted quinazolinone derivatives and their use as positive allosteric modulators of mGluR4 |
Family Cites Families (14)
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US4065467A (en) | 1973-12-27 | 1977-12-27 | Carlo Erba, S. P. A. | 5:6-Benzo δ-pyrone derivatives and process for their preparation |
US4777252A (en) | 1987-08-13 | 1988-10-11 | E. R. Squibb & Sons, Inc. | 2-oxo-1-[[(substituted sulfonyl)amino]-carbonyl]azetidines |
JP3993651B2 (ja) | 1994-10-21 | 2007-10-17 | アスビオファーマ株式会社 | シクロプロパクロメンカルボン酸誘導体 |
EP1298129A3 (en) | 2001-09-28 | 2003-06-04 | Central Glass Company, Limited | Process for producing 4-sustituted benzopyran derivatives |
PE20040801A1 (es) | 2002-12-12 | 2004-11-25 | Hoffmann La Roche | Derivados de pirazina y piridina 5-sustituidos como activadores de glucoquinasa |
EP1615906A1 (en) | 2003-04-03 | 2006-01-18 | Vertex Pharmaceuticals Incorporated | Compositions useful as inhibitors of protein kinases |
WO2007011701A1 (en) | 2005-07-15 | 2007-01-25 | Transform Pharmaceuticals, Inc. | Novel hydrochloride salts of levodopa |
EP2181110A2 (en) | 2007-07-13 | 2010-05-05 | ADDEX Pharma S.A. | Novel heteroaromatic derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors |
GB0713686D0 (en) | 2007-07-13 | 2007-08-22 | Addex Pharmaceuticals Sa | New compounds 2 |
AU2010311321B2 (en) * | 2009-10-30 | 2014-11-27 | Prexton Therapeutics S.A. | Novel oxime derivatives and their use as allosteric modulators of metabotropic glutamate receptors |
BR122021013836B1 (pt) | 2009-12-04 | 2022-05-24 | Sunovion Pharmaceuticals, Inc. | Composto e seu uso, composição farmacêutica |
EP2804870B1 (en) * | 2012-01-18 | 2016-11-30 | ADDEX Pharma S.A. | 2-AMINO-4,5,6,8-TETRAHYDROPYRAZOLO[3,4-b]THIAZOLO [4,5-d]AZEPINE DERIVATIVES AND THEIR USE AS ALLOSTERIC MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS |
NZ728853A (en) * | 2014-08-27 | 2018-04-27 | Prexton Therapeutics Sa | Novel chromone oxime derivative and its use as allosteric modulator of metabotropic glutamate receptors |
EP3341380B1 (en) | 2015-08-27 | 2019-11-13 | Prexton Therapeutics SA | Brain-penetrant chromone oxime derivative for the therapy of levodopa-induced dyskinesia |
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JP2018528205A (ja) * | 2015-08-27 | 2018-09-27 | プレクストン・セラピューティクス・ソシエテ・アノニム | レボドパ誘発性ジスキネジア療法のための脳透過性クロモンオキシム誘導体 |
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