JP5548916B2 - カワラクトン誘導体を含有する医薬製剤 - Google Patents
カワラクトン誘導体を含有する医薬製剤 Download PDFInfo
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- JP5548916B2 JP5548916B2 JP2009050659A JP2009050659A JP5548916B2 JP 5548916 B2 JP5548916 B2 JP 5548916B2 JP 2009050659 A JP2009050659 A JP 2009050659A JP 2009050659 A JP2009050659 A JP 2009050659A JP 5548916 B2 JP5548916 B2 JP 5548916B2
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Description
式1
本発明の特徴は、上記の式I中のR1がCl、R2がCl、R3がCH2OCH3、R4がOCH3である請求項1に記載のカワラクトン誘導体である。
本発明の別の特徴は、上記の式I中のハロゲンが塩素原子であるカワラクトン誘導体を含有することを特徴とする医薬製剤である。
カワラクトン誘導体の薬学的に許容し得る塩としては、例えば非毒性の有機または無機酸からの、化合物の従来の非毒性塩または第四アンモニウム塩がある。例えば、このような従来の非毒性塩としては、塩酸、臭化水素酸、硫酸、スルファミン酸、リン酸、硝酸等のような無機酸から誘導されたもの;ならびに酢酸、プロピオン酸、コハク酸、グリコール酸、ステアリン酸、乳酸、リンゴ酸、酒石酸、クエン酸、アスコルビン酸、パルミチン酸、マレイン酸、ヒドロキシマレイン酸、フェニル酢酸、グルタミン酸、安息香酸、サリチル酸、スルファニル酸、2−アセトキシ安息香酸、フマル酸、トルエンスルホン酸、メタンスルホン酸、エタンジスルホン酸、シュウ酸、イソチオン酸等のような有機酸から調製された塩がある。
ラウリル硫酸ナトリウムおよびステアリン酸マグネシウムのような湿潤剤、乳化剤および潤滑剤、ならびに着色剤、放出剤、被覆剤、甘味料、香味剤および香料、保存料および酸化防止剤もまた組成物中に存在してもよい。
(A)カワラクトン誘導体−81
2’,6’-Dichlorokawapyrone=(E)-6-(2,6-dichlorostyryl)-4-methoxy-2H -pyran-2-one:
mp. 190℃ (EtOAc-hexane) pale yellow powders, C14H10O3Cl2MW 296. EIMS m/z (rel. int.): 296 (M+, 100), 261 (98), 225 (9), 205 (14), 162 (18), 135 (16), 125 (20), 99 (14), 69 (20). 1H-NMR (400 MHz, CDCl3) d: 3.84 (3H, s, OCH3), 5.54 (1H, d, J= 2.2 Hz, H-3), 6.00 (1H, d, J= 2.2 Hz, H-5 ), 6.73 (1H, d, J= 16.2 Hz, H-7), 7.16 (1H, t, J= 8.2 Hz, H-4’), 7.35 (2H, d, J= 8.2 Hz, H-3’,5’), 7.53 (1H, d, J= 16.2 Hz, H-8). 13C-NMR (100 MHz, CDCl3) d: 56.0 (OCH3), 89.6 (C-3), 102.8 (C-5), 127.2 (C-7), 128.8 (C-3’,5’), 129.2 and 129.3 (C-8 or C-4’ interchangeable), 132.7 (C-1’), 134.8 (C-2’,6’), 157.5 (C-6), 163.6 (C-2), 170.7 (C-3).
(B)カワラクトン誘導体−32
2’,6’-Dichloro-5-methoxymethylkawapyrone=(E)-6-(2,6-dichlorostyryl)-4-methoxy-5-
(ethoxymethyl)-2H-pyran-2-one:
mp. 175-176℃(MeOH) colorless needles, C16H14O4Cl2 MW 340. EIMS m/z (rel. int.): 340 (M+, 100), 309 (58), 281 (14), 273 (11), 245 (14), 199 (34), 171 (27), 141 (28), 135 (24), 109 (8), 99 (16), 69 (15). 1H-NMR (400 MHz, CDCl3) d: 3.37 (3H, s, 9-OCH3), 3.89 (3H, s, 4-OCH3), 4.32 (2H, s H-9), 5.59 (1H, s, H-3), 7.17 (1H, d, J= 8.2 Hz, H-4’ ), 7.21 (1H, d, J= 16.2 Hz, H-7), 7.35 (2H, d, J= 8.2 Hz, H-3’,5’), 7.36 (2H, d, J= 8.2 Hz, H-3’,5’), 7.63 (1H, d, J= 16.2 Hz, H-8). 13C-NMR (100 MHz, CDCl3) d: 56.5 (4-OCH3), 58.2 (9-OCH3), 62.1 (C-9), 89.6 (C-3), 110.1 (C-5), 124.4 (C-7), 128.9 (C-3’,5’), 129.3 (C-4’), 130.6 (C-8), 133.0 (C-1’), 134.9 (C-2’,6’), 157.1 (C-6), 162,7 (C-7), 169.7 (C-3).
カワラクトン誘導体−81 カワラクトン誘導体−32
以下の誘導体はカワラクトン誘導体−81の合成法に準じて、合成した。
(C)カワラクトン誘導体−03
2’-fluorokawapyrone= (E)-6-(2-fluorostyryl)-4-methoxy-2H-pyran-2-one:
mp. 128-130℃(MeOH) pale yellow needles, C14H11O3F MW 246. EIMS m/z (rel. int.): 246 (M+, 100), 218 (68), 198 (14), 175 (50), 147 (21), 101 (22). 1H-NMR (400 MHz, CDCl3) d: 3.84 (3H, s, OCH3), 5.51 (1H, d, J= 2.2 Hz, H-3), 5.98 (1H, d, J= 2.2 Hz, H-5), 6.73 (1H, d, J= 16.1 Hz, H-7), 7.09 (1H, m, H-3’), 7.15 (1H, t, J= 7.6 Hz, H-5’), 7.30 (1H, m, H-6’), 7.49 (1H, t, J= 7.6 Hz, H-4’), 7.56 (1H, d, J= 16.1 Hz, H-8).
(D)カワラクトン誘導体−04
4’-fluorokawapyrone= (E)-6-(4-fluorostyryl)-4-methoxy-2H-pyran-2-one:
mp. 143-145℃(EtOAc) colorless needles, C14H11O3F MW 246. EIMS m/z (rel. int.): 246 (M+, 100), 218 (44), 175 (32), 147 (13). 1H-NMR (400 MHz, CDCl3) d: 3.83 (3H, s, OCH3), 5.49 (1H, d, J= 2.2 Hz, H-3), 5.94 (1H, d, J= 2.2 Hz, H-5), 6.50 (1H, d, J= 16.7 Hz, H-7), 7.07 (1H, d, J= 16.7 Hz, H-8), 7.08 (2H, d, J= 8.5 Hz, H-3’,5’), 7.49 (2H, J= 8.5 Hz, H-2’,6’).
(E)カワラクトン誘導体−05
3’-fluorokawapyrone= (E)-6-(3-fluorostyryl)-4-methoxy-2H-pyran-2-one:
mp. 170-173℃(EtOAc-hexane) pale yellow crystals, C14H11O3F MW 246. EIMS m/z (rel. int.): 246 (M+, 100), 218 (36), 203 (12), 175 (35), 149 (14), 121 (6), 101 (10). 1H-NMR (400 MHz, CDCl3) d: 3.85 (3H, s, OCH3), 5.51 (1H, d, J= 1.9 Hz, H-3), 5.96 (1H, d, J= 1.9 Hz, H-5), 6.57 (1H, d, J= 15.9 Hz, H-7), 7.03 (1H, m, H-4’), 7.19 (1H, d, J= 2.4 Hz, H-2’), 7.23 (1H, m, H-6’), 7.45 (1H, d, J= 15.9 Hz, H-8).
(F)カワラクトン誘導体−26
2’,4’-difluorokawapyrone=(E)-6-(2,4-difluorostyryl)-4-methoxy-2H-pyran-2-one:
mp. 169-170℃(EtOAc-hexane) pale yellow crystals, C14H10O3F2MW 264. EIMS m/z (rel. int.): 264 (M+, 100), 236 (73), 193 (32), 165 (10), 139 (6), 125 (10), 119 (15). 1H-NMR (400 MHz, CDCl3) d: 3.83 (3H, s, OCH3), 5.51 (1H, d, J= 2.4 Hz, H-3), 5.96 (1H, d, J= 2.4 Hz, H-5), 6.66 (1H, d, J= 16.7 Hz, H-7), 6.88 (2H, m, H-3’,5’), 7.47 (1H, m, H-6’), 7.50 (1H, d, J= 16.2 Hz, H-8).
(G)カワラクトン誘導体-28
(E)-6-(4-fluorostyryl)-4-ethoxy-2H-pyran-2-one:
mp. 131-133℃(EtOAc-hexane) pale yellow crystals, C15H13O3F MW 264. EIMS m/z (rel. int.): 264 (M+, 19), 246 (100), 218 (42), 203 (7), 175 (30), 149 (25), 121 (11), 101 (12), 69 (9).
(H)カワラクトン誘導体−25
2’,5’-dichlorokawapyrone= (E)-6-(2,5-dichlorostyryl)-4-methoxy-2H-pyran-2-one:
mp. 157-159℃(EtOAc-hexane) pale yellow rectangles, C14H10O3Cl2MW 296. EIMS m/z (rel. int.): 296 (M+, 88), 261 (100), 225 (16), 162 (16), 135 (13), 125 (17), 99 (18). 1H-NMR (400 MHz, CDCl3) d: 3.86 (3H, s, OCH3), 5.60 (1H, s, H-3), 5.83 (1H, s, H-5), 7.16 (1H, d, J= 16.2 Hz, H-7), 7.21 (1H, dd, J= 8.8, 2.4 Hz, H-4’), 732 (1H, d, J= 8.8 Hz, H-3’), 7.68 (1H, d, J= 2.4 Hz, H-6’), 7.79 (1H, d, J= 16.2 Hz, H-8).
(I)カワラクトン誘導体−27
2’,4’-dichlorokawapyrone= (E)-6-(2,4-dichlorostyryl)-4-methoxy-2H-pyran-2-one:
mp. 136-137℃(EtOAc-hexane) pale yellow needles, C14H10O3Cl2MW 296. EIMS m/z (rel. int.): 296 (M+, 100), 261 (63), 225 (21), 199 (10), 162 (17), 135 (17), 125 (16), 99 (13). 1H-NMR (400 MHz, CDCl3) d: 3.84 (3H, s, OCH3), 5.53 (1H, d, J= 2.4 Hz, H-3), 6.00 (1H, d, J= 2.4 Hz, H-5), 6.56 (1H, d, J= 16.2 Hz, H-7), 7.26 (1H, d, J= 2.2 Hz, H-3’), 7.42 (1H, dd, J= 8.8, 2.2 Hz, H-5’), 7.53 (1H, d, J= 8.8 Hz, H-6’), 7.76 (1H, d, J=16.2 Hz, H-8).
(J)カワラクトン誘導体−80
2’,6’-difluorokawapyrone= (E)-6-(2,6-difluorostyryl)-4-methoxy-2H-pyran-2-one:
pale yellow crystals, C14H10O3F2MW 264. EIMS m/z (rel. int.): 264 (M+, 100), 236 (95), 193 (26), 165 (21), 139 (14), 119 (14), 99 (7). 1H-NMR (400 MHz, acetone-d6) d: 3.92 (3H, s, OCH3), 5.59 (1H, d, J= 2.4 Hz, H-3), 6.34 (1H, d, J= 2.4 Hz, H-5), 7.10 (1H, d, J= 16.6 Hz, H-7), 7.12 (2H, t, J= 8.6 Hz, H-3’,5’), 7.41 (1H, d, J= 16.6 Hz, H-8), 7.46 (1H, br t, J= 8.6 Hz, H-4’).
ホタルルシフェラーゼ遺伝子の発現を制御するチミジンキナーゼ遺伝子のプロモーターの上流にARE(antioxidant response element)を配置したAREレポーター遺伝子と、チミジンキナーゼ遺伝子のプロモーターによりウミシイタケルシフェラーゼ遺伝子の発現が制御されるコントロール遺伝子を、TransIT-LT1(Mirus Bio社製)を用いて、ラット褐色細胞腫PC12細胞(=神経細胞のモデル細胞)に導入した。
PC12細胞を10, 20, 50, 100mMのカワラクトン誘導体―32で24時間処理した。対照は溶媒のDMSOだけで処理した。これらの培養に対して常法に従ってトリパンブルー色素排除試験を行い、染色されない生細胞の数を計数した。対照の培養での生細胞数を100% とした相対的な生細胞数を図2に示す。
実施例1に記した方法に従って、褐色細胞腫PC12細胞において、図3Aに示す天然由来カワラクトン(Yangonin・Kawain・Methysticin)とカワラクトン誘導体―32を10 mM濃度でAREエンハンサー活性に対する効果を比較検討した。
PC12細胞を10 mMの天然由来カワラクトン(Yangonin・Kawain)とカワラクトン誘導体―32で24 時間処理した。対照は溶媒のDMSOだけで処理した。この細胞をプロテアーゼインヒビターカクテル(Sigma社製)を添加したRIPAバッファー(10 mM Tris-HCl, pH 7.5, 1% NonidetP-40, 0.1% Sodium deoxycholate, 0.1% SDS, 150 mM NaCl, 1 mMEDTA)で溶解し、15,000×g, 4℃, 15 minで 遠心分離後、その上清を細胞溶解タンパク試料とした。このタンパク試料各10 mgを常法に従って10% SDSポリアクリルアミドゲル電気泳動により展開後、ゲルからセミドライ型転写装置を用いてPVDF膜に転写し、ウェスタンブロッティングを行った。洗浄液は 0.1% Tween 20含有トリス緩衝液 (TBS-T)を、ブロッキング液は 5% スキムミルクTBS-T溶液を、一次抗体はウサギ由来抗HO-1ポリクローナル抗体(Stressgen社製)を5,000倍希釈にて、二次抗体はヒツジ由来抗マウス IgG抗体(HRP標識, GE Healthcare社製)を3,000倍希釈にて、それぞれ用いた。検出はECL Plus Western Blotting Detection System(GE Healthcare社製)を用いた化学発光法で行った。HO-1のシグナルを検出後、Restore Western Blot Stripping Buffer(Pierce社製)を用いてストリッピングを行い、b-アクチンに対する抗体反応・検出を行った。一次抗体に抗 b-アクチンモノクローナル抗体(クローンAC-15, Sigma社製)を10,000倍希釈にて、二次抗体にロバ由来抗ウサギ IgG抗体(HRP標識, GE Healthcare社製)を6,000倍希釈にて用いた他は、上記HO-1に対するのと同様に行った。結果を図4に示す。
HepG2(肝臓)、C6(グリア)、HDF(皮膚)細胞を10 mMの天然由来カワラクトン(Yangonin)とカワラクトン誘導体―32で24時間処理後、実施例4に記した方法に従って、HO-1 タンパクの発現誘導を調べた結果を図5に示す。
活性成分(カワラクトン誘導体―32)100mgをそれぞれ含有する錠剤を以下の方法で配合したものは、神経変性疾患、虚血性脳血管障害、心筋細胞障害等の予防治療剤とすることが出来る。
成分 (100錠当たり)
活性成分 ……… 10.0g
乳糖 ……… 50.7g
小麦デンプン ……… 7.5g
ポリエチレングリコール
6000 ……… 5.0g
タルク ……… 5.0g
マグネシウム ステアレート……… 1.8g
脱イオン水 ……… 適量
まず、固状の有効成分の粒径を0.6mmメッシュ篩を用いて整粒した。整粒後の有効成分、乳糖、タルク、マグネシウムステアレート、及び処方半量の小麦デンプンを混和した。残余半量の小麦デンプンを上記水40mLに懸濁し、ついで、前記水100mL中にポリエチレングリコールの処方量が含まれ、煮沸された溶液に加えた。得られたパスタに賦形剤(pulverulent)を加え、水を追加して、この混合物を顆粒化する。得られた顆粒を35℃で一夜乾燥、1.2mmメッシュの篩を通して整粒した後、両面がレンズ状で径が約6mmの錠剤を打錠して製造した。
活性成分100mgをそれぞれ含有する、チューイング錠(tablet for chewing) を以下の方法で製造した。
成分 (100錠当たり)
活性成分 ……… 10.0g
マンニトール ……… 230.0g
乳糖 ……… 150.0g
タルク ……… 21.0g
グリシン ……… 12.5g
ステアリン酸 ……… 10.0g
サッカリン ……… 1.5g
5%ゼラチン溶液 ……… 適量
まず、固状の有効成分の粒径を0.25mmメッシュ篩を用いて整粒した。
マンニトールと乳糖を混和し、ゼラチン溶液を添加して顆粒化、2mmメッシュ篩と用いて整粒化、50℃で乾燥した後、1.7mmメッシュの篩を用いて整粒した。グリシンとサッカリンとを注意深く混合した整粒済み活性成分、マンニトール、乳糖顆粒、ステアリン酸、及びタルクを混和した。ついで、この完全に混和した組成物を、両面がレンズ状で上面に割り溝を形成した径が約10mmの錠剤を打錠して製造した。
活性成分300mgをそれぞれ含有する錠剤を以下の方法で製造した。
成分 (100錠当たり)
活性成分 ……… 30.0g
乳糖 ……… 328.5g
コーンスターチ ……… 17.5g
ポリエチレングリコール
6000 ……… 5.0g
タルク ……… 25.0g
マグネシウム ステアレート……… 4.8g
脱イオン水 ……… 適量
まず、固状の有効成分の粒径を0.6mmメッシュ篩を用いて整粒した。
整粒後の有効成分、乳糖、タルク、マグネシウム ステアレート、及び処方半量のデンプンを混和した。残余半量のデンプンを水65mLに懸濁し、ついで、前記水260mL中にポリエチレングリコール処方量が含まれる煮沸溶液にこれを加えた。得られたパスタに賦形剤(pulverulent)を加え、水を追加して、この混合物を顆粒化する。得られた顆粒を35℃で一夜乾燥、1.2mmメッシュの篩を通して整粒した後、両面がレンズ状で上面に割り溝を形成した径が約10mmの錠剤を打錠して製造した。
例えば、2.0%注射剤は以下の方法で製造することができる。
活性成分 ……… 50.0g
塩化ナトリウム ……… 22.5g
リン酸緩衝液、pH7.4 ……… 300.0g
脱イオン水に溶解して全量2500.0mLとする。
Claims (8)
- 式Iに示すカワラクトンの誘導体を含有し、抗酸化酵素の発現を増強する、医薬製剤。
式I
(式中、R1 及びR2の一方が水素原子であり、他方がハロゲン原子であるか、又は両方がハロゲン原子である。R3はH、Me、又は−CH2OMeであり、R4はOMe、OEt、又はOPrである。) - 式Iに示すカワラクトンの誘導体を含有し、酸化ストレスの関連する疾患を予防治療する、医薬製剤。
式I
(式中、R 1 及びR 2 の一方が水素原子であり、他方がハロゲン原子であるか、又は両方がハロゲン原子である。R 3 はH、Me、又は−CH 2 OMeであり、R 4 はOMe、OEt、又はOPrである。) - 上記酸化ストレスの関連する疾患は、酸化ストレスの関連する癌、神経変性疾患、虚血性脳血管障害、虚血性心疾患、炎症性腸疾患、眼疾患、又はリウマチである、請求項2記載の医薬製剤。
- 式I中のハロゲンが塩素原子である、請求項1〜3のいずれか1項に記載の医薬製剤。
- 式I中のR1がCl、R2がCl、R3がCH2OCH3、R4がOCH3である、請求項1〜4のいずれかに記載の医薬製剤。
- 式Iに示すカワラクトンの誘導体を含有する、抗酸化ストレス剤。
式I
(式中、R 1 及びR 2 の一方が水素原子であり、他方がハロゲン原子であるか、又は両方がハロゲン原子である。R 3 はH、Me、又は−CH 2 OMeであり、R 4 はOMe、OEt、又はOPrである。) - 式I中のハロゲンが塩素原子である、請求項6記載の抗酸化ストレス剤。
- 式I中のR 1 がCl、R 2 がCl、R 3 がCH 2 OCH 3 、R 4 がOCH 3 である、請求項6又は7記載の抗酸化ストレス剤。
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