JP5934839B2 - ベルベノン誘導体を含有する退行性脳疾患治療または予防用薬学組成物 - Google Patents
ベルベノン誘導体を含有する退行性脳疾患治療または予防用薬学組成物 Download PDFInfo
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- JP5934839B2 JP5934839B2 JP2015515940A JP2015515940A JP5934839B2 JP 5934839 B2 JP5934839 B2 JP 5934839B2 JP 2015515940 A JP2015515940 A JP 2015515940A JP 2015515940 A JP2015515940 A JP 2015515940A JP 5934839 B2 JP5934839 B2 JP 5934839B2
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- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical group C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 102000013498 tau Proteins Human genes 0.000 description 1
- 108010026424 tau Proteins Proteins 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 235000010374 vitamin B1 Nutrition 0.000 description 1
- 239000011691 vitamin B1 Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 229940033203 vitamin b6 0.5 mg Drugs 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
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- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/86—Ketones containing a keto group bound to a six-membered aromatic ring containing —CHO groups
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- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
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- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A23L35/00—Food or foodstuffs not provided for in groups A23L5/00 – A23L33/00; Preparation or treatment thereof
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- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
- C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
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- C07C49/794—Ketones containing a keto group bound to a six-membered aromatic ring having unsaturation outside an aromatic ring
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- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
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Description
R1、R2、R3、R4、及びR5は、それぞれ独立して水素原子、F、Cl、Br及びIから選択されたハロゲン原子、ヒドロキシ基、C1〜C3アルキル基、C1〜C3アルコキシ基、アミノ基、C1〜C3アルキルアミン基、C1〜C3アルキルジアミン基、炭素数5〜8の芳香環、炭素数5〜8のシクロ環、及び炭素数5〜8のヘテロ芳香環で構成された群から選択された一つ以上の置換基であり、
X、Y及びZは、それぞれ独立して炭素原子またはN、O及びS原子で構成された群から選択された一つ以上のヘテロ原子であり、
は、二重結合または単一結合を意味する。
R1、R2、R3、R4、及びR5は、それぞれ独立して水素原子、F、Cl、Br及びIから選択されたハロゲン原子、ヒドロキシ基、C1〜C3アルキル基、C1〜C3アルコキシ基、アミノ基、C1〜C3アルキルアミン基、C1〜C3アルキルジアミン基、炭素数5〜8の芳香環、炭素数5〜8のシクロ環、及び炭素数5〜8のヘテロ芳香環で構成された群から選択された一つ以上の置換基であり、
X、Y及びZは、それぞれ独立して炭素原子またはN、O及びS原子で構成された群から選択された一つ以上のヘテロ原子であり、
は、二重結合または単一結合を意味する。
(1S,5R)−4−(4−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3a);
(1S,5R)−4−(4−ヒドロキシ−2−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3b);
(1S,5R)−4−(3,4−ジヒドロキシスチリル)−6,6−ジメチルビシクルロ[3.1.1]ヘプト−3−エン−2−オン(3c);
(1S,5R)−4−(3−ブロモ−4−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3d);
(1S,5R)−4−(4−ヒドロキシ−2,6−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3e);
(1S,5R)−4−(3,4−ジヒドロキシ−5−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3f);
(1S,5R)−4−(3−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3g);
(1S,5R)−4−(2−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3h);
(1S,5R)−4−(2−ヒドロキシ−4−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3i);
(1S,5R)−6,6−ジメチル−4−スチリルビシクルロ[3.1.1]ヘプト−3−エン−2−オン(4a);
(1S,5R)−4−(4−フルオロスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4b);
(1S,5R)−4−(4−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4c);
(1S,5R)−4−(2−(ビフェニル−4−イル)ビニール)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4d);
(1S,5R)−4−(4−(1H−ピロール−1−イル)スチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4e);
(1S,5R)−4−(3,4−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4f);
(1S,5R)−4−(3,5−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4g);
(1S,5R)−4−(2,5−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4h);
(1S,5R)−4−(5−ブロモ−2−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4i);
(1S,5R)−6,6−ジメチル−4−((E)−2−(ピリジン−2−イル)ビニール)ビシクロ[3.1.1]ヘプト−3−エン−2−オン(5a);
(1S,5R)−6,6−ジメチル−4−((E)−2−(ピリジン−3−イル)ビニール)ビシクロ[3.1.1]ヘプト−3−エン−2−オン(5b);及び
(1S,5R)−6,6−ジメチル−4−((E)−2−(ピリジン−4−イル)ビニール)ビシクロ[3.1.1]ヘプト−3−エン−2−オン(5c)。
試薬及び機器
試薬級(1S)−(−)−ベルベノン、アルデヒド(aldehydes)、メチルクロロメチルエーテル(methylchloromethylether;MOM−Cl)、ジイソプロピルエチルアミン(diisopropylethylamine;DIPEA)、水酸化カリウム(potassiumhydroxide;KOH)、及びナトリウムメトキシド(sodium methoxide;NaOCH3)を市中で購入して、購入したすべての試薬及び溶媒は高純度で、水酸化カルシウムで蒸留したジクロロメタンを除いて追加精製過程を経ることなくすぐ用いて、特に言及しない限り、反応は真空処理された乾燥ガラス容器(vacuum−flame dried glassware)で乾燥窒素大気下で実行された。薄層クロマトグラフィー法(Thin−layer chromatography;TLC)は、UVで可視化するシリカゲル(Merck silica gel 60 F254)を使ってカラムクロマトグラフィーは、シリカゲル(E. Merck silica gel, 70-230, 230-400mesh)を用いた。1H−NMR及び13C−NMRスペクトルは、機器(Varian)で500MHzで測定して、化学シフト(Chemical shift)は、内部標準薬(internal standard(CDCl3:d7.26ppm)として用いたTMS(tetramethysilane)から移動をppmで記録して、結合定数(coupling constant)をヘルツ(hertz)で記録した。多重度(Multiplicity)は、下記のような略語を使った:singlet(s)、doublet(d)、doublet of doublet (dd)、doublet of doublet of doublet(ddd)、triplet(t)、triplet of doublet(td)、doublet of triplet(dt)、quartet(q)、multiplet(m)及びbroad(br)。高解像質量スペクトル(High−resolutionmassspectra;HRMS)は、機器(WatersQ−TOF micro mass spectrometer)で記録して、分光回転率(Optical rotation)は、機器(JASCO polarimeter mode lP−2000)を利用して589nmで測定した。すべての化合物純度は、下記の条件の逆相(reverse−phase)HPLCで測定して、その純度は>95%であった:方法1(Solvent A:water,Solvent B:acetonitrile)−流速:0.2mL/min:90% of B in 20min;方法2(Solvent A:water,Solvent B:acetonitrile)流速:1.0mL/min:From 40% of B to 100% in 40min。牛胎児血清(Fetal bovine serum;FBS)は、ハイクロン社(Hyclone,Logan,UT)から購入して用いて、培養液(neurobasal medium,NBM)及び補充剤(B27 supplement)は、インビトロジェン社(Invitrogen,Carlsbad,CA)から購入して用いた。すべての化学物質及び試薬は、シグマアルドリッチ 社(Sigma−Aldrich,St.Louis,MO)から購入して用いた。
アルドール縮合反応(aldol condensation)で(1S)−(−)−ベルベノンからジエン体(diene)を得るために、(1S)−(−)−ベルベノン(1,200mg、1.33mmol)を4−(メトキシメトキシ)ベンズアルデヒド(332mg、2.00mmol)とMeOH(7mL)で撹はんしてKOH(149mg、2.66mmol)で処理した。反応混合物を6時間60℃で撹はんして室温で冷却させた。少量の水を添加して混合物を24時間室温で放置した。前記混合物を減圧濃縮して黄色産物を得て、これをシリカゲルカラムクロマトグラフィーで精製して、下記の物性値を示す黄色固体状の(1S,5R)−4−(4−(メトキシメトキシ)スチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(2a)[(1S,5R)−4−(4−(methoxymethoxy)styryl)−6,6−dimethylbicyclo[3.1.1]hept−3−en−2−one(2a)]を収得して、下記の実験例の試料として用いた。(353mg、収率89%)。
mp88−90℃;
[a]20 D−211.6°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz):d7.45(d,J=8.80Hz,2H),7.04(d,J=8.80Hz,2H),6.81−6.92(m,2H),5.90(s,1H),5.20(s,2H),3.48(s,3H),3.03−3.17(m,1H),2.91(dt,J=9.48,5.53Hz,1H),2.72(t,J=5.62Hz,1H),2.12(d,J=9.29Hz,1H),1.58(s,3H),1.01(s,3H);
13C−NMR(CDCl3,75MHz);d204.25,164.57,158.00,134.51,129.75,128.73,125.62,121.83,116.44,94.171,58.09,56.09,52.78,43.59,39.98,26.72,22.10
HRMS:計算値C17H18O2(M−H)253.1229,測定値253.1221
HPLC分析結果:(方法1)100.0%(tR=3.67分)
2a化合物の製造方法と類似する方法を利用して、下記の物性値を示す(1S,5R)−4−(3−メトキシ−4,5−ビス(メトキシメトキシ)スチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(2f)[(1S,5R)−4−(3−methoxy−4,5−bis(methoxymethoxy)styryl)−6,6−dimethylbicyclo[3.1.1]hept−3−en−2−one(2f)]を収得して、下記の実験例の試料として用いた(収率90%)。
1H−NMR(CDCl3,500MHz);d6.94(d,J=1.96Hz,1H),6.84(s,2H),6.78(d,J=1.71Hz,1H),5.92(s,1H),5.22(s,2H),5.15(s,2H),3.89(s,3H),3.60(s,3H),3.52(s,3H),3.09(t,J=5.75Hz,1H),2.90(dt,J=9.48,5.53Hz,1H),2.72(td,J=5.75,1.47Hz,1H),2.10(d,J=9.29Hz,1H),1.57(s,3H),1.00(s,3H);
13C−NMR(CDCl3,75MHz);d203.92,164.02,153.63,151.19,136.64,134.76,132.10,126.91,122.43,108.91,104.88,98.37,95.33,58.19,57.11,56.07,52.70,43.78,39.93,26.70,22.11
MeOH(3mL)中2a化合物(200mg、0.67mmol)が撹はんされる溶液に、アルドール縮合反応で(1S)−(−)−ベルベノンからジエン体を得るために、10%HClを滴下して反応混合物を反応が終結する時まで一夜の間放置した。飽和NaHCO3を添加して前記反応混合物をエチルアセテートで抽出して無水MgSO4で乾燥した。最終化合物をカラムクロマトグラフィーで精製及び分離して、下記の物性値を示す黄色固体状の(1S,5R)−4−(4−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3a)[(1S,5R)−4−(4−hydroxystyryl)−6,6−dimethylbicyclo[3.1.1]hept−3−en−2−one(3a)]を収得して、下記の実験例の試料として用いた。(162mg、収率95%)
mp88−90℃.
[a]20 D−211.6°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d7.40(d,J=8.56Hz,2H),6.78−6.92(m,4H),6.45(br.s.,1H),5.91(s,1H),3.12(t,J=5.75Hz,1H),2.88−2.95(m,1H),2.74(t,J=5.62Hz,1H),2.13(d,J=9.29Hz,1H),1.58(s,3H),1.02(s,3H);
13C−NMR(CDCl3,75MHz);d205.14,165.56,157.32,135.24,129.13,128.51,124.89,121.29,116.00,58.10,53.22,43.86,40.23,26.79,22.15;
HRMS計算値C17H18O2(M−H)253.1229,測定値253.1221;
HPLC分析結果:(方法1)100.0%(tR=3.67分)
3a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色固体状の(1S,5R)−4−(4−ヒドロキシ−2−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3b)[(1S,5R)−4−(4−hydroxy−2−methoxystyryl)−6,6−dimethylbicyclo[3.1.1]hept−3−en−2−one(3b)]を収得して、下記の実験例の試料として用いた(収率97%)
mp78−80℃;
[a]20 D−140.0°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d7.45(d,J=8.07Hz,1H),7.24(d,J=16.63Hz,1H),6.88(d,J=16.38Hz,1H),6.42−6.48(m,2H),5.88(s,1H),3.86(s,3H)5.64(br.s.,1H),3.16(t,J=5.75Hz,1H),2.91(dt,J=9.35,5.59Hz,1H),2.72(td,J=5.60Hz,1H),2.12(d,J=9.29Hz,1H),1.58(s,3H),1.02(s,3H);
13C−NMR(CDCl3,75MHz);d205.53,166.76,159.17,158.94,130.48,128.48,124.75,120.62,117.50,108.19,99.19,58.10,55.53,53.25,43.87,40.33,26.80,22.16;
HRMS計算値C18H20O3(M+H)285.1491,測定値285.1480;
HPLC分析結果:(方法1)99.4%(tR=3.80分)
3a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色固体状の(1S,5R)−4−(3,4−ジヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3c)[(1S,5R)−4−(3,4−dihydroxystyryl)−6,6−dimethylbicyclo[3.1.1]hept−3−en−2−one(3c)]を収得して、下記の実験例の試料として用いた(収率84%)
mp68−70℃;
[a]20 D−208.6°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d7.13(s,1H),6.70−6.96(m,4H),5.92(s,1H),3.12(t,J=5.50Hz,1H),2.86−2.95(m,1H),2.71−2.81(m,1H),2.14(d,J=9.54Hz,1H),1.58(s,3H),1.00(s,3H);
13C−NMR(CDCl3,75MHz);d206.39,166.93,146.23,144.51,136.47,128.75,124.62,121.91,120.72,115.38,113.17,60.55,58.04,53.84,44.01,40.55,26.78,22.12;
HRMS計算値C17H18O3(M−H)269.1178,測定値269.1169;
HPLC分析結果:(方法1)100%(tR=3.47分)
3a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色固体状の(1S,5R)−4−(3−ブロモ−4−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3d)[(1S,5R)−4−(3−bromo−4−hydroxystyryl)−6,6−dimethylbicyclo[3.1.1]hept−3−en−2−one(3d)]を収得して、下記の実験例の試料として用いた(収率95%)
mp238−240℃;
[a]20 D−181.4°(c1.0,MeOH);
1H−NMR(CD3OD,500MHz);d7.75(d,J=2.20Hz,1H),7.45(dd,J=1.96,8.56Hz,1H),7.02(d,J=16.50Hz,1H),6.97(d,J=16.50Hz,1H),6.92(d,J=8.56Hz,1H),5.90(s,1H),3.24(t,J=5.99Hz,1H),2.97(td,J=5.59,9.35Hz,1H),2.62(dt,J=1.50,6.00Hz,1H),2.05(d,J=9.54Hz,1H),1.60(s,3H),0.98(s,3H);
13C−NMR(CD3OD,75MHz):d203.02,165.13,155.42,134.47,132.29,129.42,128.79,125.75,121.59,117.11,110.36,58.16,52.33,43.30,26.83,22.43;
HRMS計算値C17H17BrO2(M+H)333.0490,測定値333.0479;
HPLC分析結果:(方法1)98.9%(tR=3.91分)
3a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色固体状の(1S,5R)−4−(4−ヒドロキシ−2,6−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3e)[(1S,5R)−4−(4−hydroxy−2,6−dimethoxystyryl)−6,6−dimethylbicyclo[3.1.1]hept−3−en−2−one(3e)]を収得して、下記の実験例の試料として用いた(収率94%)
mp216−218℃;
[a]20 D−175.4°(c1.0,MeOH);
1H−NMR(DMSO−d6,500MHz);d7.28(d,J=16.50Hz,1H),7.23(d,J=16.50Hz,1H),6.12(s,2H),5.73(s,1H),3.80(s,6H),3.10(t,J=5.38Hz,1H),2.89(td,J=5.50,9.05Hz,1H),2.53(t,J=5.50Hz,1H),1.93(d,J=9.29Hz,1H),1.53(s,3H),0.91(s,3H);
13C−NMR(DMSO−d6,75MHz);d202.56,166.66,160.48,160.27,126.68,126.11,119.22,104.67,92.17,57.50,55.71,55.67,51.67,42.59,26.42,21.96;
HRMS計算値C19H22O4(M+H)315.1596,測定値315.1583;
HPLC分析結果:(方法1)99.3%(tR=3.70分)
3a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色固体状の(1S,5R)−4−(3,4−ジヒドロキシ−5−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3f)[(1S,5R)−4−(3,4−dihydroxy−5−methoxystyryl)−6,6−dimethylbicyclo[3.1.1]hept−3−en−2−one(3f)]を収得して、下記の実験例の試料として用いた(収率92%):
mp168−170℃;
[a]20 D−158.8000°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz)d6.78−6.82(m,3H),6.64(d,J=1.47Hz,1H),5.82−6.01(m,3H),3.92(s,3H),3.10(t,J=5.62Hz,1H),2.91(dt,J=9.35,5.59Hz,1H),2.74(td,J=5.69,1.59Hz,1H),2.12(d,J=9.29Hz,1H),2.04(s,2H),1.58(s,3H),1.01(s,3H);
13C−NMR(CDCl3,75MHz);d204.92,165.07,147.23,144.24,135.54,134.13,128.07,125.50,121.62,108.63,58.08,56.25,53.12,43.75,40.18,26.78,22.16;
HRMS計算値C18H20O4(M+H)301.1440,測定値301.1453;
HPLC分析結果:(方法1)100%(tR=3.46分)
3a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色固体状の(1S,5R)−4−(3−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3g)[(1S,5R)−4−(3−hydroxystyryl)−6,6−dimethylbicyclo[3.1.1]hept−3−en−2−one(3g)]を収得して、下記の実験例の試料として用いた(収率98%)
mp106−108℃;
[a]20 D−176.6°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d7.21−7.26(m,1H),7.01−7.05(m,2H),6.92(d,J=16.50Hz,1H),6.88(d,J=16.50Hz,1H),6.83−6.86(m,1H),6.46(s,1H),5.96(s,1H),3.11(t,J=5.75Hz,1H),2.93(td,J=5.53,9.48Hz,1H),2.77(dt,J=1.59,5.69Hz,1H),2.14(d,J=9.29Hz,1H),1.59(s,3H),1.01(s,3H);
13C−NMR(CDCl3,75MHz);d205.19,165.18,156.53,137.42,135.36,130.03,127.44,122.37,120.19,116.68,113.65,58.17,53.39,43.89,40.28,26.77,22.14;
HRMS計算値C17H18O2(M−H)253.1229,測定値253.1228;
HPLC分析結果:(方法2)99.3%(tR=3.73分)
3a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色固体状の(1S,5R)−4−(2−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3h)[(1S,5R)−4−(2−hydroxystyryl)−6,6−dimethylbicyclo[3.1.1]hept−3−en−2−one(3h)]を収得して、下記の実験例の試料として用いた(収率100%)
mp140−142℃;
[a]20 D−296.6°(c1.0,MeOH);
1H−NMR(CD3OD,500MHz);d7.56(dd,J=1.59,7.70Hz,1H),7.42(d,J=16.14Hz,1H),7.15(dd,J=1.59,15.53Hz,1H),7.13(d,J=16.38Hz,1H),6.80−6.87(m,2H),5.89(s,1H),3.25(t,J=5.87Hz,1H),2.99(dt,J=5.53,9.48Hz,1H),2.65(td,J=1.71,5.75Hz,1H),2.08(d,J=9.29Hz,1H),1.61(s,3H),1.01(s,3H);
13C−NMR(CD3OD,75MHz);d207.46,169.09,157.56,133.10,131.67,128.67,127.63,124.55,122.03,121.07,117.05,59.62,54.52,45.29,41.45,27.19,22.58;
HRMS計算値C17H18O2(M−H)253.1229,分析値253.1218;
HPLC分析結果:(方法1)99.4%(tR=3.80分)
3a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色ゲル状の(1S,5R)−4−(2−ヒドロキシ−4−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3i)[(1S,5R)−4−(2−hydroxy−4−methoxystyryl)−6,6−dimethylbicyclo[3.1.1]hept−3−en−2−one(3i)]を収得して、下記の実験例の試料として用いた(収率96%)
[a]20 D−91.8°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d8.46(br.s.,1H),7.37(d,J=8.56Hz,1H),7.23(d,J=16.50Hz,1H),7.17(d,J=16.00Hz,1H),6.42−6.55(m,2H),6.04(s,1H),3.78(s,3H),3.20(t,J=5.38Hz,1H),2.88−2.98(m,1H),2.76(t,J=5.14Hz,1H),2.17(d,J=9.54Hz,1H),1.59(s,3H),1.05(s,3H);
13C−NMR(CDCl3,75MHz);d206.56,167.94,161.72,156.99,132.26,130.09,125.37,119.93,116.29,106.90,101.73,57.96,55.28,53.74,43.85,40.60,26.76,22.13;
HRMS計算値C18H20O3(M+H)285.1491,測定値285.1494;
HPLC分析結果:(方法1)99.2%(tR=3.75分)
2a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色ゲル状の(1S,5R)−6,6−ジメチル−4−スチリルビシクルロ[3.1.1]ヘプト−3−エン−2−オン(4a)[(1S,5R)−6,6−dimethyl−4−styrylbicyclo[3.1.1]hept−3−en−2−one(4a)]を収得して、下記の実験例の試料として用いた(収率92%)
[a]20 D−91.8°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d7.50(d,J=7.09Hz,2H),7.35−7.40(m,2H),7.33(d,J=7.34Hz,1H),6.97(d,J=16.00Hz,1H),6.92(d,J=16.00Hz,1H),5.94(s,1H),3.12(td,J=1.47,5.87Hz,1H),2.93(dt,J=5.62,9.54Hz,1H),2.74(td,J=1.71,5.75Hz,1H),2.13(d,J=9.29Hz,1H),1.59(s,3H),1.02(s,3H);
13C−NMR(CDCl3,75MHz);d204.13,164.23,135.99,134.96,129.15,128.88,127.42,127.35,122.66,58.23,52.87,43.76,40.03,26.78,22.16;
HRMS計算値C17H18O(M+H)239.1436,測定値239.1426;
HPLC分析結果:(方法1)95.0%(tR=4.82分)
2a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色ゲル状の(1S,5R)−4−(4−フルオロスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4b)を収得して、下記の実験例の試料として用いた(収率92%)
[a]20 D−33.2°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d7.46−7.51(m,2H),7.04−7.09(m,2H),6.90(d,J=17.00Hz,1H),6.86(d,J=16.50Hz,1H),5.93(s,1H),3.10(td,J=1.35,5.81Hz,1H),2.92(dt,J=5.62,9.29Hz,1H),2.74(td,J=1.71,5.75Hz,1H),2.12(d,J=9.29Hz,1H),1.59(s,3H),1.02(s,3H);
13C−NMR(CDCl3,75MHz);d204.04,164.03,162.13,133.62,132.21,129.04,127.15,122.61,116.02,58.17,52.83,43.72,39.99,26.73,22.12;
HRMS計算値C17H17FO(M+H)257.1342,測定値257.1343;
HPLC分析結果:(方法1)90.6%(tR=4.52分)
2a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色固体状の(1S,5R)−4−(4−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4c)[(1S,5R)−4−(4−methoxystyryl)−6,6−dimethylbicyclo[3.1.1]hept−3−en−2−one(4c)]を収得して、下記の実験例の試料として用いた(収率90%)
mp138−140℃;
[a]20 D−172.0°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d7.46(d,J=8.80Hz,2H),6.91(d,J=9.05Hz,2H),6.90(d,J=15.90Hz,1H),6.84(d,J=16.50Hz,1H),5.90(s,1H),3.85(s,3H),3.12(td,J=1.35,5.81Hz,1H),2.92(dt,J=5.53,9.48Hz,1H),2.73(td,J=1.71,5.75Hz,1H),2.13(d,J=9.54Hz,1H),1.59(s,3H),1.03(s,3H);
13C−NMR(CDCl3,75MHz);d204.17,164.63,160.50,134.64,128.83,128.78,125.25,121.66,114.35,58.17,55.34,52.74,43.76,39.99,26.76,22.15;
HRMS計算値C18H20O2(M+H)269.1542,測定値269.1549;
HPLC分析結果:(方法1)100%(tR=4.58分)
2a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色固体状の(1S,5R)−4−(2−(ビフェニル−4−イル)ビニール)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4d)[(1S,5R)−4−(2−(biphenyl−4−yl)vinyl)−6,6−dimethylbicyclo[3.1.1]hept−3−en−2−one(4d)]を収得して、下記の実験例の試料として用いた(収率92%)
mp148−150℃;
[a]20 D−152.4°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d7.55−7.65(m,6H),7.45(t,J=7.58Hz,2H),7.34−7.39(m,1H),7.01(d,J=16.50Hz,1H),6.96(d,J=16.50Hz,1H),5.95(s,1H),3.14(t,J=5.75Hz,1H),2.94(dt,J=5.50,9.54Hz,1H),2.75(t,J=5.62Hz,1H),2.14(d,J=9.29Hz,1H),1.60(s,3H),1.03(s,3H);
13C−NMR(CDCl3,75MHz);d204.12,164.23,141.86,140.23,134.99,134.50,128.87,127.84,127.69,127.51,127.38,126.94,122.65,58.24,52.86,43.77,40.02,26.79,22.18;
HRMS計算値C23H22O(M+H)315.1749,測定値315.1737;
HPLC分析結果:(方法1)100%(tR=6.35分)
2a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色固体状の(1S,5R)−4−(4−(1H−ピロール−1−イル)スチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4e)[(1S,5R)−4−(4−(1H−pyrrol−1−yl)styryl)−6,6−dimethylbicyclo[3.1.1]hept−3−en−2−one(4e)]を収得して、下記の実験例の試料として用いた(収率41%)
mp146−148℃;
[a]20 D−142.4°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d7.55(d,J=8.56Hz,2H),7.39(d,J=8.56Hz,2H),7.12(t,J=2.20Hz,2H),6.95(d,J=16.00Hz,1H),6.91(d,J=16.00Hz,1H),6.36(t,J=2.20Hz,2H),5.94(s,1H),3.12(t,J=5.75Hz,1H),2.93(td,J=5.59,9.35Hz,1H),2.74(dt,J=1.71,5.75Hz,1H),2.13(d,J=9.29Hz,1H),1.59(s,3H),1.03(s,3H);
13C−NMR(CDCl3,75MHz);d203.97,164.03,140.92,133.78,133.21,128.57,127.14,122.61,120.25,118.95,110.94,58.19,25.79,43.72,39.97,26.75,22.14;
HRMS計算値C21H21NO(M+H)304.1701,測定値304.1691;
HPLC分析結果:(方法1)94.7%(tR=5.10分)
2a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色ゲル状の(1S,5R)−4−(3,4−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4f)を収得して、下記の実験例の試料として用いた(収率92%)
[a]20 D−111.2°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d7.02−7.09(m,2H),6.89(d,J=16.00Hz,1H),6.86(d,J=7.00Hz,1H),6.83(d,J=16.50Hz,1H),5.91(s,1H),3.93(s,3H),3.91(s,3H),3.11(t,J=5.75Hz,1H),2.91(dtd,J=1.47,5.56,9.41Hz,1H),2.72(tt,J=1.74,5.72Hz,1H),2.11(d,J=9.29Hz,1H),1.58(s,3H),1.02(s,3H);
13C−NMR(CDCl3,75MHz);d204.03,164.46,150.28,149.30,134.89,129.10,125.42,121.75,111.24,109.29,58.19,55.94,52.69,43.82,39.96,26.76,22.15;
HRMS計算値C19H22O3(M+H)299.1647,測定値299.1657;
HPLC分析結果:(方法2)97.9%(tR=9.19分)
2a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色ゲル状の(1S,5R)−4−(3,5−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4g)を収得して、下記の実験例の試料として用いた(収率90%)
[a]20 D−94.2°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d6.93(d,J=16.00Hz,1H),6.85(d,J=16.00Hz,1H),6.65(d,J=2.20Hz,2H),6.45(t,J=2.20Hz,1H),5.94(s,1H),3.82(s,6H),3.10(t,J=5.75Hz,1H),2.92(dt,J=5.62,9.54Hz,1H),2.74(td,J=1.59,5.69Hz,1H),2.12(d,J=9.29Hz,1H),1.58(s,3H),1.02(s,3H);
13C−NMR(CDCl3,75MHz);d204.04,163.03,161.03,137.88,134.93,127.83,122.81,105.32,101.51,58.19,55.40,52.82,43.73,39.99,26.73,22.12;
HRMS計算値C19H22O3(M+H)299.1647,測定値299.1662;
HPLC分析結果:(方法1)100%(tR=4.58分)
2a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色ゲル状の(1S,5R)−4−(2,5−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4h)を収得して、下記の実験例の試料として用いた(収率93%)
[a]20 D−94.8°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d7.29(d,J=16.38Hz,1H),7.11(d,J=2.69Hz,1H),6.95(d,J=16.14Hz,1H),6.81−6.88(m,2H),5.92(s,1H),3.84(s,3H),3.81(s,3H),3.16(dt,J=1.50,6.00Hz,1H),2.91(td,J=5.62,9.29Hz,1H),2.72(dt,J=1.71,5.75Hz,1H),2.11(d,J=9.29Hz,1H),1.58(s,3H),1.02(s,3H);
13C−NMR(CDCl3,75MHz);d204.16,164.83,153.74,152.04,129.50,127.74,125.62,122.37,115.85,112.34,111.85,58.24,56.13,52.76,43.76,40.03,26.76,22.15;
HRMS計算値C19H22O3(M+H)299.1647,測定値299.1650;
HPLC分析結果:(方法1)96.4%(tR=4.69分)
2a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色ゲル状の(1S,5R)−4−(5−ブロモ−2−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4i)を収得して、下記の実験例の試料として用いた(収率97%)
[a]20 D−71.6°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d7.66(s,1H),7.36(dd,J=2.45,8.80Hz,1H),7.20(d,J=16.38Hz,1H),6.95(d,J=16.14Hz,1H),6.77(d,J=8.80Hz,1H),5.93(s,1H),3.87(s,3H),3.12(t,J=5.62Hz,1H),2.91(dt,J=5.35,9.60Hz,1H),2.73(t,J=5.14Hz,1H),2.11(d,J=9.29Hz,1H),1.58(s,3H),1.01(s,3H);
13C−NMR(CDCl3,75MHz);d203.97,164.31,156.40,132.53,129.53,128.69,128.09,127.04,122.89,113.28,112.75,58.22,55.77,52.76,43.71,39.98,26.73,22.11;
HRMS計算値C18H19BrO2(M+H)347.0647,測定値347.0651;
HPLC分析結果:(方法1)99.0%(tR=6.23分)
アルドール縮合反応で(1S)−(−)−ベルベノンからジエン体を得るために、(1S)−(−)−ベルベノン(1,200mg、1.33mmol)を2−ピリジンカルボキシアルデヒド(171mg、1.60mmol)とMeOH(7mL)で撹はんしてNaOCH3(MeOH中25wt.%溶液、108mg、2.00mmol)で処理した。反応混合物を6時間60℃で撹はんして室温で冷却させた。少量の水を添加して混合物を24時間室温で放置した。前記混合物を減圧濃縮して茶色の産物を得て、これをシリカゲルカラムクロマトグラフィーで精製して、下記の物性値を示す黄色シロップ状の(1S,5R)−6,6−ジメチル−4−((E)−2−(ピリジン−2−イル)ビニール)ビシクロ[3.1.1]ヘプト−3−エン−2−オン(5a)[(1S,5R)−6,6−dimethyl−4−((E)−2−(pyridin−2−yl)vinyl)bicyclo[3.1.1]hept−3−en−2−one(5a)]を収得して、下記の実験例の試料として用いた(258mg、収率81%)
[a]20 D−102.0000°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d8.60(dd,J=4.77,0.61Hz,1H),7.67(td,J=7.70,1.71Hz,1H),7.45(d,J=15.90Hz,1H),7.39(d,J=7.83Hz,1H),7.19(ddd,J=7.52,4.83,0.86Hz,1H),6.96(d,J=15.89Hz,1H),6.02(s,1H),3.08−3.14(m,1H),2.87−2.95(m,1H),2.73(td,J=5.69,1.59Hz,1H),2.11(d,J=9.29Hz,1H),1.57(s,3H),1.00(s,3H);
13C−NMR(CDCl3,75MHz);d203.92,163.51,154.33,149.96,136.65,133.90,131.15,124.29,123.13,58.27,52.90,43.86,39.97,26.71,22.12;
HRMS計算値C16H17NO(M+H)240.1388,測定値240.1392;
HPLC分析結果:(方法1)98.4%(tR=4.28分)
5a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色固体状の(1S,5R)−6,6−ジメチル−4−((E)−2−(ピリジン−3−イル)ビニール)ビシクロ[3.1.1]ヘプト−3−エン−2−オン(5b)を収得して、下記の実験例の試料として用いた(収率77%)
5a化合物の製造方法と類似する方法を利用して、下記の物性値を示す黄色ゲル状の(1S,5R)−6,6−ジメチル−4−((E)−2−(ピリジン−4−イル)ビニール)ビシクロ[3.1.1]ヘプト−3−エン−2−オン(5c)を収得して、下記の実験例の試料として用いた(収率80%)
[a]20 D−152.0°(c1.0,MeOH);
1H−NMR(CDCl3,500MHz);d8.62(d,J=5.87Hz,2H),7.35(d,J=5.87Hz,2H),7.13(d,J=16.14Hz,1H),6.84(d,J=16.14Hz,1H),6.01(s,1H),3.10(t,J=5.87Hz,1H),2.95(td,J=5.62,9.54Hz,1H),2.77(dt,J=1.59,5.69Hz,1H),2.13(d,J=9.54Hz,1H),1.60(s,3H),1.02(s,3H);
13C−NMR(CDCl3,75MHz);d203.57,162.78,150.42,143.12,131.89,131.57,124.62,121.23,58.24,52.90,43.68,39.95,26.70,22.11;
HRMS計算値C16H17NO(M+H)240.1338,測定値240.1378;
HPLC分析結果:(方法1)98.4%(tR=4.29分)
実験動物の準備
SDラット(260−270グラム雄)をチャールスリバー社(Charles River Laboratories,Seoul,Korea、韓国)から供給を受けて12時間明暗/循環周期を維持して、飲料水(食水)に自由に接近可能にして、実験前環境に馴染ませて使用し、NIH基準(NIH Guide for the Care and Use of Laboratory Animals)及び委員会(Korea University Institutional Animal Care & Use Committee)承認下実行された。
統計処理
データはmeans±S.E.M.で処理してone−way analysis of variance (ANOVA)で統計的有意性を検定して、多重比較法でpost−hoc bonferroni testで判定してP値<0.05を有意的に判断して、ANOVA分析前に分散の同質性(Equality of Variances)に対する試験法(Levene’s Test)のP値を確定した(P>0.05)。必要時には前記データをKruskal−Wallis test後Mann−Whitney testを行って再分析した。
前記実施例で収得した試料の興奮細胞毒性に及ぼす効果を確認するために、文献に開示された方法を応用して下記のように実験を行った(Ju C. et al., BBRC, 431(3), 484-489, 2013)。
皮質神経細胞(neuron)(5×105cells/mL)は、胎児16〜17日SDラットから収得した。すなわち、脳皮質を切断して緩衝液(Hanks’ Balanced Salt Solution,HBSS)でピペット(Pasteur pipette)を利用して繰り返された滴定(trituration)で細胞を分離させた。細胞懸濁液(1.8×103cells/mm2)をプレート(poly−D−lysine(100mg/mL)/laminin(4 mg/mL)−予備処置プレート)上に分株した。細胞を初期に10%FBS−添加NBM培地に位置させて、37℃で加湿された96%空気/5%CO2大気下で維持させた。試験は、前記培養物の培養後15〜16日に行った。
試験管低酸素性−虚血性症状を誘導するために、培養された細胞を嫌気性チャンバー(酸素部分圧<2mmHg)に位置させて、前記培養物を残存酸素を除去するために、30分間嫌気性ガス混合物(95%N2、5%CO2)でバブルリング(bubbling)するブドウ糖−除去培地(glucose−free DMEM)に取り替えて培養して、酸素欠乏(oxygen deprivation)のために、90分間37℃で培養した。90分後、前記露出溶液を酸素化25mmol/Lブドウ糖含有DMEM培地に取り替えてOGD反応を中断させて、細胞を正常酸素条件に回復させた。OGDに露出しなかった対照細胞を好気性混合ガス(95%air、5%CO2)を提供するブドウ糖(25mmol/L)−含有DMEM培地で維持させた。OGD/再酸素化(re−oxygenation)30分前から細胞を試料で処置して全実験期間中維持した。
プレートに15−18日間静置した後、皮質神経細胞を溶液(Mg2+−除去Earle’s balanced salt solution (EBSS);1.8mM CaCl2及び10mM glycine含有)で10分間NMDA(100mM)に露出させた。前記露出後に、細胞をMgSO4含有EBSS溶液で洗浄して37℃で5%CO2条件下で培養器で25mmol/Lグルコース含有DMEM培地で培養した。細胞をNMDA処置30分前から試料(10mM)で処置した。
細胞損傷または細胞死滅は、培地で分泌されるLDH量を細胞生存率測定キット(Sigma−Aldrich,St.Louis,MO)を利用して測定して、細胞生存率は、冷凍されて実験後で溶かした姉妹培養物(sister cultures)で測定された、全体細胞LDH水準に対するLDHの百分率で表示した。
興奮細胞毒性は、虚血症−誘導神経細胞死、特に初期段階脳虚血症で重要な因子中一つである。OGDは、培養された皮質神経細胞を利用して、虚血症での血流供給及びエネルギー消費の急激な破壊現象を模倣した実験モデルであって、OGDによって細胞損傷を誘導してLDHのようなタンパク質の培養液での分泌を促してこれを測定して細胞膜損傷及び神経細胞損傷を測定することができる。試験結果、化合物(3a、3c及び3f)が、既知のNMDA受容体拮抗剤であるMK801と相応する程度で、神経細胞損傷を有意的に減少させることを確認し細胞毒性は示さないことを確認した(図1)。
前記実施例で収得した試料の直接的な坑酸化活性を確認するために、文献に開示された方法を応用して下記のように実験を行った(Ju c. et al., BBRC, 431(3), 484-489, 2013; Huang D. et al., J. Agric. Food Chem., 53, 1841-1856, 2005.)
試料の直接的ラジカル消去活性を確認するために、再酸素化1時間後に、細胞内酸化力ストレスを測定するのに広範囲に利用されるH2DCF−DA(2,7−dihydroichlorofluorescein diacetate)蛍光指示薬で染色して、2時間後細胞を25mM Glucose、1.8mM CaCal2、1.2mM MgSO4及び2.5mM probenecid(pH7.4)含有EBSS緩衝液で洗浄してDCFの蛍光度を判読機器で(fluorescence microplate reader、SpectraMax GeminiEM;Ex=485nm、Em=530nm)またはデジタルカメラ(DFC420C、Leica、Wetzlar Germany)付顕微鏡(fluorescence microscope;DM IL HC Fluo、Leica、Wetzlar、Germany)で測定した。蛍光強度は、自動蛍光度で補正(すなわち、H2DCF−DAで積載されなかった細胞の蛍光度)した。
本実験結果、化合物3c及び3fはOGD−誘導細胞内酸化的ストレスを減少させることを確認した(図3)。
試料をDPPH(23.6μg/mL、in ethanol)で混合して37℃、暗所で30分間培養した。試料によって減少するDPPH吸光度を517nmで測定した。ビタミンC(Vit.C;Sigma−Aldrich,St.Louis,MO)を対照群で使って、DPPH%阻害率(inhibition value)は、下記の式(1)によって計算した。
消去活性(%)=[Absmax(Vit.C)−Abssample]/[Absmax(Vit.C)−Absmin(Vit.C)]×100 …(1)
ORACアッセイ法を文献に開示されたとおりに実験を下記のように行った(Huang, D. et al., J. Agric. Food Chem., 53, 1841-56, 2005)。
AUC=(0.5+f1/f0+f2/f0+f3/f0+・・・+fn−2/f0+fn−1/f0+fn/f0)×5 …(2)
(ここで、f0は、0分及び時間(time)Iでの最初蛍光度である。)
ネット(net)AUC=AUCsample−AUCblank …(3)
試料のトロロックス等量(TE;troloxequivalents)=[netAUCsample at25mM]/[net AUCtrolox at25mM] …(4)
フェニル基のメタ(meta)及びパラ(para)位のヒドロキシ基の導入は、遊離ラジカル消去活性を増進させることを確認した。
前記実施例で収得した試料の局所脳虚血症実験での効果を確認するために、文献に開示された方法を応用して下記のように実験を行った(Belayev L. et al., Stroke, 27, 1616-1622, 1996; discussion 1623)。
ラットをマスクを利用してN2O及びO2(70:30v/v)混合物中3.0%イソフルラン(isoflurane)から始めて2%イソフルランを維持させて麻酔した。全実験期間中麻酔から充分に回復するまで術後期間まで体温は、直腸用温度計及び温熱パッドを利用して37℃±0.3℃で調節及び維持させた。局所脳虚血症は、右側血管内MCAOに誘導した。要約すれば、3−0 heat−blunted単繊維性ナイロン縫合糸(monofilament nylon suture;Ethicon,Johnson−Johnson,Brussels,Belgium)をMCA小孔を閉塞させようと、右側外部頚動脈の切開部分内腔に挿入して、内側頚動脈に17.5mmに進入させた。前記縫合を動物が回復するように1時間半後に除去した。手術−対照群をMCAOを除いて同じ手術法で行った。生理学的数値はMCAO15分前及び再灌流15分後に測定して、平均血圧は血圧器(MicroMed,Lousville,KY)で5分間測定した。血中pH、PaO2、PaCO2及び血糖数値は分析器(Ciba Corning Diagnostics Corp.,Medfield,MA)で測定した。DMSOで溶解させて10%クレモフォール(cremophore)及び滅菌食塩水で希釈した(5%)試料(3f誘導体)は、MCAO誘導後2時間からラットの腹腔内に投与した(100mg/kg)。
再灌流後ラットを抱水クロラール(3.5% chloral hydrate、5mL/kg、腹腔注射)で麻酔させた後、頚椎脱臼させた。マトリックス(rat brain matrix,Ted Pella,Redding,CA)を利用して切断した脳動脈切片(2mm)を試薬(2%トリフェニルテトラゾリウム塩酸、シグマ−アルドリッチ、St.Louis,MO)で30分間37℃で染色した。4%パラホルムアルデヒド(pH7.4)で固定して、連続的に2日間、4℃で30%スクロースで凍結保護させた。
全体脳梗塞体積(mm3)=直接測定法(direct measurement)による同側性体積(IVd)×[(反側性体積(Vc))/反側性体積(Vc)] …(5)
浮腫体積(edema volume)(%)=[(同側性体積(V1)−反側性体積(Vc))/反側性体積(Vc)]×100 …(6)
以後に組織を冷凍させて切断機(Leica3050;Leica,Nussloch,Germany)で10または30mm頚動脈切片で切断して−20℃で保存した。
神経学的欠損は、虚血後24時間後に測定して、文献(Stroke, 17, 472-476, 1986)に開示された通り、4点スケールで測定する(0:神経学的欠損なし、1:前足を曲げる、2:前足曲げ及び側面を押す力に対する減少した抵抗性、回転しない、3:2と同様であるが回転する)。
前記方法のとおり準備した脳組織切片を非特異的抗体結合を抑制させるために5%血清が含まれた緩衝液で1時間常温で処理する。適正な濃度に希釈した1次抗体(MPO抗体及びED−1−抗体、各々1:100;Nitrotyrosine抗体、1:50;IL−1a、IL−1b、TNF−a抗体各々1:100)を加えて、4℃で一夜染色する。結合されなかった1次抗体を洗浄で除去した後、蛍光マーカーが重合された2次抗体で常温で1時間染色する。結合されなかった2次抗体を洗浄で除去した後、Hoechst 33258染色液で20分間核を染色して洗浄してガラススライドに取り付けた後、共焦点蛍光顕微鏡(Zeiss LSM510;Zeiss,Oberkochen,ドイツ)を用いて観察した。
染色液(エバンスブルー染色液、2%)は、静脈内注射時血清内アルブミンに直ちに結合して正常血液脳関門を透過できない高分子物質に変換されるが、脳虚血症を誘導したラット脳組織では、血液脳関門が損傷してエバンスブルーの透過性が増加して、染色量が増加する。前記方法とおりに局所脳虚血症を誘発したラットを200mLの生理食塩水で心臓灌流させる。脳組織を摘出して重さを測った後、試薬(トリクロロ酢酸、60%)に漬けて4℃で24時間処理する。組織を粉砕した後、10,000rpmで15分間遠心分離させ分離した上澄み液を取って脳組織内に残存したエバンスブルー染色液の吸光度を610nmで測定して定量してグラム組織当たり染色液量として算出する。
前記方法のとおり局所脳虚血症を誘発したラットを手術前と同じ条件で手術後3週間にかけて生存率及び神経学的欠損を測定する。
ラット(体重270−300g)を70%N2Oと30%O2(v/v)混合ガスに混合された3%イソフルランガスを用いて吸入麻酔させた後、3%イソフルランを利用して維持する。直腸温度計を挿入して、これと連結された自動ヒートパッドを用いて手術期間中ラットの体温を37.0〜37.9℃に維持させる。首に正中線を切開した後、右側内頸動脈(common carotid artery:CCA)と右側外側頸動脈(external carotid artery:ECA)と右側内頸動脈(internal carotid artery:ICA)を分離して、外側頸動脈と頸動脈を縛る。曲がった微細血管クリップを用いて内頸動脈を一時的に引き締める。外頚動脈と内頸動脈の分枝が始まる部分を小さく切開して血管注入が容易になるように注入口が外径0.3mmに減らされた外径0.58mmのPE−50カテーテルを利用して生理食塩水が入った100ulハミルトンシリンジで35mm塞栓を内頸動脈内に注入する。微細血管クリップを除去して、カテーテルを注意深く内頸動脈内に16−17mmまで前進させて、中脳大動脈の開始点から約2mmまで移動させる。カテーテルの塞栓を内頸動脈で注入する(10ul)。塞栓注入5分後、カテーテルを取り除く。内頸動脈分枝点で縛って、切開部位を縫い合わせた後、ラットが麻酔から覚めるように放置して置く。実験に用いられる塞栓は、ドナーマウスから取った大腿動脈血を迅速にPE−50チューブに注入して常温で2時間、4℃で22時間放置して血栓を生成させる。実験前にチューブを切って、生理食塩水が入った23G注射針が付き1mLシリンジを用いてPE−10チューブを介して変形されたPE−50カテーテルに移す。前記実験結果、一時的虚血誘導ラットモデル試験で、試料(3f、50mg/kg)の虚血後処置(Post−ischemic Treatment;腹腔注射;脳梗塞後2時間及び7時間合わせて2回投与時)で虚血性損傷、脳浮腫及び神経学的欠損を有意的に減少させることを確認した(図4)。また、試料を投与したラットから得た脳組織切片でのニトロチロシンに対する免疫組織学的染色を介して組織内坑酸化活性を測定した結果、試料投与群で脳組織内坑酸化活性が有意的に増加したことを確認した(図5)。
化合物3f 200mg
乳糖 100mg
タルク 10mg
前記成分を混合して気密包に充填して散剤を製造する。
化合物3c 200mg
コーンスターチ 100mg
乳糖 100mg
ステアリン酸マグネシウム 2mg
前記成分を混合した後、通常の錠剤の製造方法に従って打錠して錠剤を製造する。
RW 200mg
結晶性セルロース 3mg
ラクトース 14.8mg
ステアリン酸マグネシウム 0.2mg
通常のカプセル剤製造方法に従って前記成分を混合してゼラチンカプセルに充電してカプセル剤を製造する。
化合物4e 200mg
マンニトール 180mg
注射用滅菌蒸留水 2974mg
Na2HPO4、12H2O 26mg
通常の注射剤の製造方法に従って、1アンプル当たり(2mL)前記の成分含有量で製造する。
化合物5a 200mg
異性化糖 10g
マンニトール 5g
精製水 適量
通常の液剤の製造方法に従って、精製数にそれぞれの成分を加えて溶解させてレモンの香りを適量加えた後、前記成分を混合した後、精製水を加えて全体を100mLに調節した後、茶色のビンに充填して滅菌させて液剤を製造する。
化合物3a 1000mg
ビタミン混合物 適量
ビタミンAアセテート 70μg
ビタミンE 1.0mg
ビタミンB1 0.13mg
ビタミンB 0.15mg
ビタミンB6 0.5mg
ビタミンB12 0.2μg
ビタミンC 10mg
Biotin 10μg
ニコチン酸アミド 1.7mg
葉酸 50μg
パントテン酸カルシウム 0.5mg
無機質混合物 適量
硫酸第一鉄 1.75mg
酸化亜鉛 0.82mg
炭酸マグネシウム 25.3mg
第一リン酸カリウム 15mg
第二リン酸カルシウム 55mg
クエン酸カリウム 90mg
炭酸カルシウム 100mg
塩化マグネシウム 24.8mg
前記ビタミン及びミネラル混合物の組成比は、比較的健康食品に適合した成分を好ましい実施例として混合組成したが、その配合比を任意に変形実施しても構わなく、通常の健康食品製造方法に従って前記成分を混合した後、顆粒を製造して、通常の方法に従って健康食品組成物製造に用いてもよい。
化合物3f 1000mg
クエン酸 1000mg
オリゴ糖 100g
梅濃縮液 2g
タウリン 1g
精製水を加えて 全体900mL
通常の健康飲料製造方法に従って、前記成分を混合した後、約1時間85℃で撹はん加熱した後、作られた溶液をろ過して滅菌された2L容器に取得して密封滅菌した後、冷蔵保管した後、本発明の健康飲料組成物製造に用いる。
Claims (14)
- 下記一般式(1)の構造を持つベルベノン誘導体または薬学的に許容可能なその塩を有効成分として含有する退行性脳疾患の予防または治療用薬学組成物:
R1、R2、R3、R4、及びR5は、それぞれ独立して水素原子、F、Cl、Br及びIから選択されたハロゲン原子、ヒドロキシ基、C1〜C3アルキル基、C1〜C3アルコキシ基、アミノ基、C1〜C3アルキルアミン基、C1〜C3アルキルジアミン基、炭素数5〜8の芳香環、炭素数5〜8のシクロ環、及び炭素数5〜8のヘテロ芳香環で構成された群から選択された一つ以上の置換基であり、
X、Y及びZは、それぞれ独立して炭素原子またはN、O及びS原子で構成された群から選択された一つ以上のヘテロ原子であり、
は、二重結合または単一結合を意味する。 - 前記R1、R2、R3、R4、及びR5はそれぞれ独立して水素原子、F、Cl、Br及びIから選択されたハロゲン原子、ヒドロキシ基、メチル基、エチル基、メトキシ基、エトキシ基、アミノ基、炭素数5〜6の芳香環、炭素数5〜6のシクロ環、及び炭素数5〜6のヘテロ芳香環で構成された群から選択された一つ以上の置換基であることを特徴とする請求項1に記載の薬学組成物。
- 前記R1、R2、R3、R4、及びR5はそれぞれ独立してF、Cl、Br及びIから選択されたハロゲン原子、ヒドロキシ基、メチル基、メトキシ基、フェニル基、ピロール基、及びピリジン基で構成された群から選択された一つ以上の置換基であることを特徴とする請求項2に記載の薬学組成物。
- 前記X、Y及びZはそれぞれ独立して炭素原子及びN原子で構成された群から選択された一つ以上の原子であることを特徴とする請求項1に記載の薬学組成物。
- 前記薬学組成物は、次のような化合物群から選択される化合物を含むことを特徴とする請求項1に記載の薬学組成物:
(1S,5R)−4−(4−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3a);
(1S,5R)−4−(4−ヒドロキシ−2−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3b);
(1S,5R)−4−(3,4−ジヒドロキシスチリル)−6,6−ジメチルビシクルロ[3.1.1]ヘプト−3−エン−2−オン(3c);
(1S,5R)−4−(3−ブロモ−4−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3d);
(1S,5R)−4−(4−ヒドロキシ−2,6−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3e);
(1S,5R)−4−(3,4−ジヒドロキシ−5−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3f);
(1S,5R)−4−(3−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3g);
(1S,5R)−4−(2−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3h);
(1S,5R)−4−(2−ヒドロキシ−4−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3i);
(1S,5R)−6,6−ジメチル−4−スチリルビシクルロ[3.1.1]ヘプト−3−エン−2−オン(4a);
(1S,5R)−4−(4−フルオロスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4b);
(1S,5R)−4−(4−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4c);
(1S,5R)−4−(2−(ビフェニル−4−イル)ビニール)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4d);
(1S,5R)−4−(4−(1H−ピロール−1−イル)スチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4e);
(1S,5R)−4−(3,4−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4f);
(1S,5R)−4−(3,5−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4g);
(1S,5R)−4−(2,5−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4h);
(1S,5R)−4−(5−ブロモ−2−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4i);
(1S,5R)−6,6−ジメチル−4−((E)−2−(ピリジン−2−イル)ビニール)ビシクロ[3.1.1]ヘプト−3−エン−2−オン(5a);
(1S,5R)−6,6−ジメチル−4−((E)−2−(ピリジン−3−イル)ビニール)ビシクロ[3.1.1]ヘプト−3−エン−2−オン(5b);及び
(1S,5R)−6,6−ジメチル−4−((E)−2−(ピリジン−4−イル)ビニール)ビシクロ[3.1.1]ヘプト−3−エン−2−オン(5c)。 - 前記退行性脳疾患は、脳卒中、中風、痴呆、アルツハイマー疾患、パーキンソン疾患、またはハンチントン疾患であることを特徴とする請求項1に記載の薬学組成物。
- 前記退行性脳疾患は、脳卒中であることを特徴とする請求項1に記載の薬学組成物。
- 下記一般式(1)の構造を持つベルベノン誘導体または薬学的に許容可能なその塩を有効成分として含有する退行性脳疾患の予防または改善用健康機能食品:
R1、R2、R3、R4、及びR5は、それぞれ独立して水素原子、F、Cl、Br及びIから選択されたハロゲン原子、ヒドロキシ基、C1〜C3アルキル基、C1〜C3アルコキシ基、アミノ基、C1〜C3アルキルアミン基、C1〜C3アルキルジアミン基、炭素数5〜8の芳香環、炭素数5〜8のシクロ環、及び炭素数5〜8のヘテロ芳香環で構成された群から選択された一つ以上の置換基であり、
X、Y及びZは、それぞれ独立して炭素原子またはN、O及びS原子で構成された群から選択された一つ以上のヘテロ原子であり、
は、二重結合または単一結合を意味する。 - 前記R1、R2、R3、R4、及びR5はそれぞれ独立して水素原子、F、Cl、Br及びIから選択されたハロゲン原子、ヒドロキシ基、メチル基、エチル基、メトキシ基、エトキシ基、アミノ基、炭素数5〜6の芳香環、炭素数5〜6のシクロ環、及び炭素数5〜6のヘテロ芳香環で構成された群から選択された一つ以上の置換基であることを特徴とする請求項8に記載の健康機能食品。
- 前記R1、R2、R3、R4、及びR5はそれぞれ独立してF、Cl、Br及びIから選択されたハロゲン原子、ヒドロキシ基、メチル基、メトキシ基、フェニル基、ピロール基、及びピリジン基で構成された群から選択された一つ以上の置換基であることを特徴とする請求項9に記載の健康機能食品。
- 前記X、Y及びZはそれぞれ独立して炭素原子及びN原子で構成された群から選択された一つ以上の原子であることを特徴とする請求項8に記載の健康機能食品。
- 前記健康機能食品は、次のような化合物群から選択される化合物を含むことを特徴とする請求項8に記載の健康機能食品:
(1S,5R)−4−(4−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3a);
(1S,5R)−4−(4−ヒドロキシ−2−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3b);
(1S,5R)−4−(3,4−ジヒドロキシスチリル)−6,6−ジメチルビシクルロ[3.1.1]ヘプト−3−エン−2−オン(3c);
(1S,5R)−4−(3−ブロモ−4−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3d);
(1S,5R)−4−(4−ヒドロキシ−2,6−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3e);
(1S,5R)−4−(3,4−ジヒドロキシ−5−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3f);
(1S,5R)−4−(3−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3g);
(1S,5R)−4−(2−ヒドロキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3h);
(1S,5R)−4−(2−ヒドロキシ−4−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(3i);
(1S,5R)−6,6−ジメチル−4−スチリルビシクルロ[3.1.1]ヘプト−3−エン−2−オン(4a);
(1S,5R)−4−(4−フルオロスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4b);
(1S,5R)−4−(4−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4c);
(1S,5R)−4−(2−(ビフェニル−4−イル)ビニール)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4d);
(1S,5R)−4−(4−(1H−ピロール−1−イル)スチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4e);
(1S,5R)−4−(3,4−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4f);
(1S,5R)−4−(3,5−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4g);
(1S,5R)−4−(2,5−ジメトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4h);
(1S,5R)−4−(5−ブロモ−2−メトキシスチリル)−6,6−ジメチルビシクロ[3.1.1]ヘプト−3−エン−2−オン(4i);
(1S,5R)−6,6−ジメチル−4−((E)−2−(ピリジン−2−イル)ビニール)ビシクロ[3.1.1]ヘプト−3−エン−2−オン(5a);
(1S,5R)−6,6−ジメチル−4−((E)−2−(ピリジン−3−イル)ビニール)ビシクロ[3.1.1]ヘプト−3−エン−2−オン(5b);及び
(1S,5R)−6,6−ジメチル−4−((E)−2−(ピリジン−4−イル)ビニール)ビシクロ[3.1.1]ヘプト−3−エン−2−オン(5c)。 - 前記退行性脳疾患は、脳卒中、中風、痴呆、アルツハイマー疾患、パーキンソン疾患、またはハンチントン疾患であることを特徴とする請求項8に記載の健康機能食品。
- 前記退行性脳疾患は、脳卒中であることを特徴とする請求項13に記載の健康機能食品。
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