JP6704252B2 - 位置特異的非対称重水素富化カテコールアミン誘導体および前記化合物を含有する医薬 - Google Patents
位置特異的非対称重水素富化カテコールアミン誘導体および前記化合物を含有する医薬 Download PDFInfo
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- JP6704252B2 JP6704252B2 JP2015555754A JP2015555754A JP6704252B2 JP 6704252 B2 JP6704252 B2 JP 6704252B2 JP 2015555754 A JP2015555754 A JP 2015555754A JP 2015555754 A JP2015555754 A JP 2015555754A JP 6704252 B2 JP6704252 B2 JP 6704252B2
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Description
R1は重水素であり、
R2およびR3は独立して水素および重水素から選択され、前記R2およびR3の少なくとも一つは、0.02モル%〜100モル%の重水素の範囲で重水素富化しており、および
R2およびR3の重水素富化は互いに異なり、R2およびR3の間の重水素富化の差は少なくとも5%ポイントであり、
R4は水素、重水素、C1〜C6アルキルまたはC5〜C6シクロアルキル、重水素化されたC1〜C6アルキルもしくはC5〜C6シクロアルキル、または生理的条件下で容易に加水分解または酵素的に切断可能な基である〕
の重水素化カテコールアミン誘導体、ならびにそれらの生理学的に許容される塩および光学的に純粋な形態でのそれらの立体異性体、エナンチオマーまたはジアステレオマーを提供することによって、本発明に従って解決される。
R4は水素、重水素、C1〜C6アルキルまたはC5〜C6シクロアルキル、重水素化されたC1〜C6アルキルもしくはC5〜C6シクロアルキル、または生理的条件下で容易に加水分解または酵素的に切断可能な基である〕の化合物ならびにそれらの生理学的に許容される塩および光学的に純粋な形態でのそれらの立体異性体、エナンチオマーまたはジアステレオマーを、
一般式IのR2およびR3位の重水素富化が0.02モル%〜100モル%の重水素の範囲になるように調節する比率で、
混合して得られる重水素化カテコールアミン誘導体を提供することによっても解決される。
L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸、
L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)メチルプロピオネート、
L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)エチルプロピオネート、
L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)プロピルプロピオネート、
L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)シクロヘキシルプロピオネート、
L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)過重水素化メチルプロピオネート、
L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)過重水素化エチルプロピオネート、
L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)過重水素化プロピルエチルプロピオネート、
L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)過重水素化シクロヘキシルプロピオネート、
ならびにそれらの生理学的に許容される塩および光学的に純粋な形態でのそれらの立体異性体、エナンチオマーまたはジアステレオマー
を含むリストから選択され、
L-2-アミノ-2,3-ジジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸、
L-2-アミノ-2,3-ジジューテロ-3-(3,4-ジヒドロキシフェニル)メチルプロピオネート、
L-2-アミノ-2,3-ジジューテロ-3-(3,4-ジヒドロキシフェニル)エチルプロピオネート、
L-2-アミノ-2,3-ジジューテロ-3-(3,4-ジヒドロキシフェニル)プロピルプロピオネート、
L-2-アミノ-2,3-ジジューテロ-3-(3,4-ジヒドロキシフェニル)シクロヘキシルプロピオネート、
L-2-アミノ-2,3-ジジューテロ-3-(3,4-ジヒドロキシフェニル)過重水素化メチルプロピオネート、
L-2-アミノ-2,3-ジジューテロ-3-(3,4-ジヒドロキシフェニル)過重水素化エチルプロピオネート、
L-2-アミノ-2,3-ジジューテロ-3-(3,4-ジヒドロキシフェニル)過重水素化プロピルエチルプロピオネート、
L-2-アミノ-2,3-ジジューテロ-3-(3,4-ジヒドロキシフェニル)過重水素化シクロヘキシルプロピオネート、
ならびにそれらの生理学的に許容される塩および光学的に純粋な形態でのそれらの立体異性体、エナンチオマーまたはジアステレオマー
を含むリストから選択される、重水素化カテコールアミン誘導体である。
(ii)少なくとも一つの一般式I:
(iii)少なくとも5〜20%ポイントの範囲である、あらかじめ定義されたR2およびR3の間の重水素富化の差が得られる割合で、
混合することによる、本願発明の重水素化カテコールアミン誘導体の調製方法である。
パーキンソン病の6-ヒドロキシドーパミン(6-OHDA)げっ歯類モデルにおける、側鎖の特定の位置での異なる重水素富化を有する重水素化されたL-DOPA誘導体の投与後の、運動能力と運動障害(ジスキネジア)の発達に及ぼす影響を、相互に、およびL-DOPAと比較している。試験した化合物およびこれらの化合物の特定の重水素富化は、表1に表示されている。
表1の試験化合物Dの調製
L-2-アミノ-2,3,3*-トリジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸(α,β,β*-D3-L-DOPA)
試験項目DはβR位において90%の重水素富化を有する。
Dは10モル%のL-2-アミノ-2,3(S)-ジジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸と、90モル%のL-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸(3つ全ての位置で100%の重水素富化)を混合することによって得る。
C9H8.1 2H2.9NO4の実験データ
計算: H 6.95 C 54.05 N 7.00 O 32.00
分析物: H 7.00 C 54.02 N 7.00 O 31.98
α,β,β*-D3-L-DOPAを含む、フィルムコーティングを施した錠剤
コアの組成:
α,β,β*-D3-L-DOPA(試験項目D) 40.00 mg
ポビドン 20.00 mg
ソルビトール 7.00 mg
二酸化ケイ素、高分散 2 mg
アルファ化(pregelatinated)デンプン 40.00 mg
クロスカルメロースナトリウム 13.30 mg
カルメロースナトリウム 20.05 mg
微結晶性セルロース 41.00 mg
ステアリン酸マグネシウム 2.00 mg
フィルムコーティング:
ヒドロキシプロピルメチルセルロース 16.00 mg
マクロゴール400(登録商標) 2.50 mg
酸化チタン 3.00 mg
タルク 3.00 mg
α,β,β*-D3-L-DOPA(試験項目D)と高分散二酸化ケイ素を、ポビドンおよびソルビトールの溶液と共に強制ミキサーで造粒する。顆粒を乾燥し、ふるいにかけ、アルファ化デンプン、クロスカルメロースナトリウム、カルメロースナトリウムおよび微結晶性セルロースと一緒に混合し、ステアリン酸マグネシウムと合わせて錠剤に圧縮する。錠剤は、ヒドロキシプロピルメチルセルロース、マクロゴール、二酸化チタンおよびタルクでフィルムコーティングする。
α,β,β*-D3-L-DOPAおよびカルビドーパを含む、フィルムコーティングを施した錠剤
コアの組成:
α,β,β*-D3-L-DOPA(試験項目D) 35.00 mg
カルビドーパ 25.00 mg
ポビドン 20.00 mg
ソルビトール 7.00 mg
二酸化ケイ素、高分散 2 mg
アルファ化(pregelatinated)デンプン 40.00 mg
クロスカルメロースナトリウム 13.30 mg
カルメロースナトリウム 20.05 mg
微結晶性セルロース 41.00 mg
ステアリン酸マグネシウム 2.00 mg
フィルムコーティング:
ヒドロキシプロピルメチルセルロース 16.00 mg
マクロゴール400(登録商標) 2.50 mg
酸化チタン 3.00 mg
タルク 3.00 mg
α,β,β*-D3-L-DOPA(試験項目D)、カルビドーパと高分散二酸化ケイ素を、ポビドンおよびソルビトールの溶液と共に強制ミキサーで造粒する。顆粒を乾燥し、ふるいにかけ、アルファ化デンプン、クロスカルメロースナトリウム、カルメロースナトリウムおよび微結晶性セルロースと一緒に混合し、ステアリン酸マグネシウムと合わせて錠剤に圧縮する。錠剤は、ヒドロキシプロピルメチルセルロース、マクロゴール、二酸化チタンおよびタルクでフィルムコーティングする。
マイクロカプセル化されたα,β,β*-D3-L-DOPAおよびカルビドーパを含む、フィルムコーティングを施した錠剤
コアの組成:
α,β,β*-D3-L-DOPA(試験項目D) 40.00 mg
カルビドーパ 25.00 mg
酒石酸 5.00 mg
ポビドン 20.00 mg
ソルビトール 7.00 mg
オイドラギットRL(登録商標)固体 20.00 mg
二酸化ケイ素、高分散 2 mg
アルファ化(pregelatinated)デンプン 40.00 mg
クロスカルメロースナトリウム 13.30 mg
カルメロースナトリウム 20.05 mg
微結晶性セルロース 41.00 mg
ステアリン酸マグネシウム 2.00 mg
フィルムコーティング:
ヒドロキシプロピルメチルセルロース 16.00 mg
マクロゴール400(登録商標) 2.50 mg
酸化チタン 3.00 mg
タルク 3.00 mg
α,β,β*-D3-L-DOPA(試験項目D)、カルビドーパ、ソルビトールおよびオイドラギットを酒石酸、高分散二酸化ケイ素、ポビドン、アルファ化デンプン、クロスカルメロースナトリウム、カルメロースナトリウムおよび微結晶性セルロースと一緒にバレルミキサー中でマイクロカプセル化し、均質化し、ステアリン酸マグネシウムと合わせて錠剤に圧縮する。錠剤は、ヒドロキシプロピルメチルセルロース、マクロゴール、二酸化チタンおよびタルクでフィルムコーティングする。
マイクロカプセル化されたα,β,β*-D3-L-DOPAおよびベンゼラジドを含む、フィルムコーティングを施した錠剤
コアの組成:
α,β,β*-D3-L-DOPA(試験項目D) 40.00 mg
ベンゼラジド 25.00 mg
酒石酸 5.00 mg
ポビドン 20.00 mg
ソルビトール 7.00 mg
オイドラギットRL(登録商標)固体 20.00 mg
二酸化ケイ素、高分散 2 mg
アルファ化(pregelatinated)デンプン 40.00 mg
クロスカルメロースナトリウム 13.30 mg
カルメロースナトリウム 20.05 mg
微結晶性セルロース 41.00 mg
ステアリン酸マグネシウム 2.00 mg
フィルムコーティング:
ヒドロキシプロピルメチルセルロース 16.00 mg
マクロゴール400(登録商標) 2.50 mg
酸化チタン 3.00 mg
タルク 3.00 mg
α,β,β*-D3-L-DOPAおよびベンゼラジドを含む、フィルムコーティングを施した錠剤
コアの組成:
α,β,β*-D3-L-DOPA(試験項目D) 35.00 mg
ベンゼラジド 25.00 mg
ポビドン 20.00 mg
ソルビトール 7.00 mg
二酸化ケイ素、高分散 2 mg
アルファ化(pregelatinated)デンプン 40.00 mg
クロスカルメロースナトリウム 13.30 mg
カルメロースナトリウム 20.05 mg
微結晶性セルロース 41.00 mg
ステアリン酸マグネシウム 2.00 mg
フィルムコーティング:
ヒドロキシプロピルメチルセルロース 16.00 mg
マクロゴール400(登録商標) 2.50 mg
酸化チタン 3.00 mg
タルク 3.00 mg
α,β,β*-D3-L-DOPA(試験項目D)、ベンゼラジドと高分散二酸化ケイ素を、ポビドンおよびソルビトールの溶液と共に強制ミキサーで造粒する。顆粒を乾燥し、ふるいにかけ、アルファ化デンプン、クロスカルメロースナトリウム、カルメロースナトリウムおよび微結晶性セルロースと一緒に混合し、ステアリン酸マグネシウムと合わせて錠剤に圧縮する。錠剤は、ヒドロキシプロピルメチルセルロース、マクロゴール、二酸化チタンおよびタルクでフィルムコーティングする。
α,β,β*-D3-L-DOPA、カルビドーパおよびエンタカポンを含む、フィルムコーティングを施した錠剤
コアの組成:
α,β,β*-D3-L-DOPA(試験項目D) 40.00 mg
カルビドーパ 25.00 mg
エンタカポン 200.00 mg
ポビドンK30 20.00 mg
クロスポビドンタイプB 15.00 mg
マンニトール 9.00 mg
二酸化ケイ素、高分散 2 mg
アルファ化(pregelatinated)デンプン 40.00 mg
クロスカルメロースナトリウム 13.30 mg
カルメロースナトリウム 20.05 mg
微結晶性セルロース 41.00 mg
ステアリン酸マグネシウム 2.00 mg
フィルムコーティング:
ヒドロキシプロピルメチルセルロース 16.00 mg
マクロゴール400(登録商標) 2.50 mg
酸化チタン 3.00 mg
タルク 3.00 mg
Claims (15)
- 重水素化カテコールアミン組成物であって、
(i)L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸、またはその生理学的に許容される塩、および
(ii)L-2-アミノ-2,3-ジジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸、またはその生理学的に許容される塩
を含み、
前記化合物(i)の割合が、0.1モル%〜99.9モル%の範囲内である、重水素化カテコールアミン組成物。 - 化合物(i)の割合が、78モル%〜95モル%の範囲内である、請求項1に記載の組成物。
- 化合物(i)の割合が、88モル%〜92モル%の範囲内である、請求項1に記載の組成物。
- 薬理学的に活性な量の、10モル%のL-2-アミノ-2,3-ジジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸またはその生理学的に許容される塩、および90モル%のL-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸またはその生理学的に許容される塩の混合物を含む、請求項1〜5のいずれか一項に記載の組成物。
- 80モル%の前記L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸、および20モル%の前記L-2-アミノ-2,3-ジジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸を含む、請求項1〜5のいずれか一項に記載の組成物。
- 85モル%の前記L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸、および
15モル%の前記L-2-アミノ-2,3-ジジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸
を含む、請求項1〜5のいずれか一項に記載の組成物。 - 70モル%の前記L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸、および
30モル%の前記L-2-アミノ-2,3-ジジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸
を含む、請求項1〜5のいずれか一項に記載の組成物。 - 前記L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸における1つのβ位における重水素富化が、約90モル%である、請求項1〜9のいずれか一項に記載の組成物。
- 前記L-2-アミノ-2,3,3-トリジューテロ-3-(3,4-ジヒドロキシフェニル)プロピオン酸における1つのβ位における重水素富化が、少なくとも98モル%である、請求項1〜9のいずれか一項に記載の組成物。
- 薬理学的に活性な量の、カルビドーパ、ベンセラジドもしくはエンタカポン、またはそれらの混合物をさらに含む、請求項1〜11のいずれか一項に記載の組成物。
- 薬学的に許容されるアジュバントまたは添加剤をさらに含む、請求項1〜12のいずれか一項に記載の組成物。
- パーキンソン病、むずむず脚症候群、筋萎縮性側索硬化症または多系統萎縮症の治療における使用のための、請求項1〜13のいずれか一項に記載の組成物。
- パーキンソン病の治療における使用のための、請求項1〜14のいずれか一項に記載の組成物。
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EP2918266A1 (en) | 2014-03-11 | 2015-09-16 | CDRD Berolina AB | Composition comprising a dopamine agonist and an L-DOPA derivative for treating Parkinson's disease |
EP3359148A1 (en) * | 2015-10-09 | 2018-08-15 | Teva Pharmaceuticals International GmbH | Combination of deuterated levodopa with carbidopa and opicapone for the treatment of parkinson`s disease |
CA3116198A1 (en) * | 2018-10-18 | 2020-04-23 | Oncopeptides Ab | Compounds containing deuterium |
EP3886986A1 (en) * | 2018-12-06 | 2021-10-06 | IntraBio Ltd | Deuterated analogs of acetyl-leucine |
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DE2049115C3 (de) | 1970-10-06 | 1981-07-30 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai, Tokyo | Verwendung von Calcium-5-butylpicolinat und/oder Calcium-5-pentylpicolinat bei der Bekämpfung des Parkinsonismus mit 3-(3,4-Dihydroxyphenyl)-L-alanin (L-Dopa) |
DE10261807A1 (de) | 2002-12-19 | 2004-07-01 | Turicum Drug Development Ag | Deuterierte Catecholaminderivate sowie diese Verbindungen enthaltende Arzneimittel |
UA97795C2 (uk) * | 2006-02-17 | 2012-03-26 | Бьордз Фарма Гмбх Бероліна Інновейтів Ресерч Унд Девелопмент Сервісіз | Дейтеровані похідні катехоламіну і медикаменти, що містять згадані сполуки |
GB0904300D0 (en) * | 2009-03-12 | 2009-04-22 | Amarin Neuroscience Ltd | Essential fatty acid compounds |
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CN104968643A (zh) | 2015-10-07 |
IL260018A (en) | 2018-07-31 |
EA201500739A1 (ru) | 2015-11-30 |
IL239733A0 (en) | 2015-08-31 |
HK1214241A1 (zh) | 2016-07-22 |
US20200163918A1 (en) | 2020-05-28 |
EP2953926B1 (en) | 2021-10-20 |
AU2018247203A1 (en) | 2018-11-01 |
MX370884B (es) | 2020-01-09 |
BR112015016889A8 (pt) | 2018-01-23 |
WO2014122184A1 (en) | 2014-08-14 |
ES2901752T3 (es) | 2022-03-23 |
JP2016513084A (ja) | 2016-05-12 |
BR112015016889A2 (pt) | 2017-07-11 |
CN104968643B (zh) | 2020-03-03 |
CA2897132A1 (en) | 2014-08-14 |
MX2015010087A (es) | 2016-04-21 |
HK1214810A1 (zh) | 2016-08-05 |
KR20150115807A (ko) | 2015-10-14 |
US20150376117A1 (en) | 2015-12-31 |
IL260018B (en) | 2020-01-30 |
AU2014214055A1 (en) | 2015-07-16 |
EA028931B1 (ru) | 2018-01-31 |
US9567289B2 (en) | 2017-02-14 |
CA2897132C (en) | 2021-05-25 |
EP2953926A1 (en) | 2015-12-16 |
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