JP2006501285A - ヒドロキシフェニルウンデカン誘導体、その製法、及びその使用 - Google Patents
ヒドロキシフェニルウンデカン誘導体、その製法、及びその使用 Download PDFInfo
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- JP2006501285A JP2006501285A JP2004540640A JP2004540640A JP2006501285A JP 2006501285 A JP2006501285 A JP 2006501285A JP 2004540640 A JP2004540640 A JP 2004540640A JP 2004540640 A JP2004540640 A JP 2004540640A JP 2006501285 A JP2006501285 A JP 2006501285A
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Classifications
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Abstract
【化1】
Description
「a」が一重結合の場合は、Rは−OH又は−OC(O)CH3であり、および
「a」が二重結合の場合は、Rは存在しない、
は、UK特許出願GB2327674において、HIVインテグラーゼ阻害剤として記載されている。
R1及びR2は、それぞれ独立に、H又はSO3Hであり、
及び/又は生理学的に許容され得るそれらの塩及び/又は自明な化学的均等物に関するものである。
付けた。
能力をもっている。この適応能力が観察される生理的可変性の原因となる。表現型の適応には一個体の全ての細胞が関与する。このタイプの変化は、遺伝的には条件付けられては
いない。異なる条件下においては可逆的であるという変異である(H. Stolp著「微生物の生態:微生物体、棲息、活動」(Microbial ecology: organisms, habitats, activities.)Cambridge University Press, Cambridge, GB, Seite 180, 1988)。
a) 保存培地
構成成分を加熱して完全に溶解させた後に、得られた溶液を121℃で20分間滅菌し、そしてペトリデッシュ(デッシュ当たり15mL)に分配した。固化後に、ペトリデッシュに初期培養菌株を接種し、25 ℃で良好な生育が観察されるまで培養した。よく生育した培養菌株を以下の保存用に使用した。
保存培地:
麦芽エキス 2.00 %
酵母エキス 1.00 %
グルコース 1.00 %
(NH4)2HPO4 0.05 %
寒天 2.00 %
b) −135 ℃での保存:
滅菌した10% DMSO溶液1.5mLを2mLのクリオバイアル(cryo vials)に注入した。保存用寒天培地から、2cm2の寒天小片を取り出して、DMSO溶液に加えて、−135 ℃で保存した。
c) 液体窒素中での保存:
50%グリセロール溶液1.5mLを2mLのクリオバイアルに注入した。保存用寒天培地から、2cm2の寒天小片を取り出して、グリセロール溶液に加えて、液体窒素中で保存した。
a) 振とうフラスコ中での種培養の調製
種培養の培地を300mLの振とうフラスコ中に、100mL量ずつ分配し、121℃で30分間滅菌した。フラスコを室温で冷却した後、6日目の寒天培地から2cm2の寒天小片を取り出して接種するか、又は、保存バイアル(−135 ℃での保存又は液体窒素中での保存)の一本分で接種した。培養は、ロータリー式振とう培養機上で、140 rpm、25 ℃、72時間行なった。
種培養培地:
麦芽エキス 2.00 %
酵母エキス 0.20 %
グルコース 1.00 %
(NH4)2HPO4 0.05 %
pH6
生産条件:
生産培地:
コーンステイープリカー 0.50 %
トマトペースト 4.00 %
オートミール 1.00 %
微量元素溶液 1.00 mL
微量元素溶液:
FeSO4×7H2O 0.1000 %
MnSO4×H2O 0.1000 %
CuCl2×2H2O 0.0025 %
CaCl2×2H2O 0.0100 %
H3BO3 0.0056 %
(NH4)6Mo7O24×4H2O 0.0019 %
ZnSO4×7H2O 0.0200 %
振とうフラスコ中での種培養の調製
種培養の培地を2Lのエーレンマイヤーフラスコ(Erlenmeyer flask)中に、500mL量ずつ分配し、121℃で30分間滅菌した。種培養は、これらのフラスコ中で、実施例2に記載のようにして生育させた。
生産培地8Lを、12Lのファーメンター中に、消泡剤として1ml/1 Lのデスモフェン(Desmophen(R))と共に添加し、そのままの状態で(in situ)、121 ℃で45分間滅菌した後、25 ℃ (±1 ℃)に冷却し、そして上記種培養0.5L(12Lファーメンターの6.25%)を接種した。
温度: 25 ℃
撹拌: 200 rpm
通気: 0.5 vvm
収穫時間: 96 時間目
スピノサルフェートの生成は、実施例8及び9に記載したように、阻害を検定することにより測定した。実施例4及び6に記載した方法により、培養液を回収して遠心分離し、そして培養濾液及び菌糸体から化合物スピノサルフェートA及びBを単離して精製した。
培養液(7.5L)を遠心分離し、培養濾液及び菌糸体をそれぞれ別々に凍結乾燥した。菌糸体の凍結乾燥物をメタノール(7L)で抽出し、活性抽出物を集めて減圧下で濃縮し、そして凍結乾燥して、38gの粗抽出物を得た。この粗抽出物を下記の条件下で、分取用HPLCにより精製した。
カラム: MCI(R) Gel CHP−20P (260×50 mm; Kronlab)
溶離液: A) H2O
B) MeOH
勾配: 分 %A %B
0 90 10
50.1 80 20
65.1 60 40
95.1 40 60
125.1 20 80
162.6 0 100
193 0 100
流速: 20 mL/分
検出: 210 nm
活性画分は、125分後に溶離した。当該画分を集めて減圧下で濃縮し、そして凍結乾燥した。
カラム: Luna(R) C18 (2) (5μm, 250×21 mm; Phenomenex, Inc.)
溶離液: A) 100%H2O
B) 100%CH3CN
勾配: 分 %A %B
0 70 30
10 70 30
45 5 95
流速: 30 mL/分
検出: 210 nm
活性画分は、HPLC及びLC−MS分析により測定した。スピノサルフェートA(MW: 730 Da)を含んでいる画分は、18分後に溶離した(A)。当該画分を集めて減圧下で濃縮し、そして凍結乾燥した。7.5Lの培養液からの総収量は35mgであった。
スピノサルフェートAの物理化学特性
外観: 無色油状
溶解性: メタノール、DMSO
LC−MS: カラム:Purospher(R)STAR RP.18e (30×2mm, 3μm;Merck KgaA, Darmstadt)
溶離液: CH3CN/ 10mMNH4Ac(pH 4.5)
勾配 : 時 % CH 3 CN
0.00 5.0
6.00 100.0
7.50 5.0
9.00 100.0
10.50 5.0
13.00 5.0
流速: 0.25 mL/分
温度: 40 ℃
検出: 210 nm, 230, 250, 320, 400 (UV); 100−2000 amu (MS)
溶離時間: 6.5 分
ESI−MS: 729.5 amu (M-H)-
HR−ESI−MS: 729.2987 [C35H53O12S2の計算値:729.2984 (M-H)-]
分子式: C35H54O12S2
MSn−実験: FTICR 分析機器、Bruker APEX III, 7T
備品:外部 ESI−線源
ESI-: 729amu (M-H)-〜649amu (-SO3), 649amu〜369amu, 359amu, (-C18H26O3), 341 (-C18H28O4), 307amu (-C17H26O5S), 289amu (-C17H28O6S)
培養液(22L)を分離し、菌糸体(310g)を、最初はメタノール(9L)で抽出し、その後酢酸エチル(4L)で抽出した。酢酸エチル画分を集めて凍結乾燥し、9.4gの粗抽出物を得た。HPLC及びLC−MS分析の結果、酢酸エチル抽出が活性物質のほとんどを含んでいることが分かり、そこでそれを下記の条件下で分取用HPLCにより精製した。
カラム: MCI(R) Gel CHP-20P (260×50 mm; Kronlab)
溶離液: A) H2O
B) イソプロパノール
勾配: 分 %A %B
0 80 20
15.1 60 40
45.1 40 60
75.1 20 80
113 0 100
142.5 0 100
流速: 20 mL/分
検出: 210 nm
活性画分は、100分後に溶離した。当該画分をHPLC及びLC−MSで分析した。スピノサルフェートを含んでいる画分を集めて減圧下で濃縮し、そして凍結乾燥した。
カラム: Luna(R) C18 (2) (5μ, 250×21.20 mm; Phenomenex, Inc.)
溶離液: A) 0.05% TFA水溶液
B) CH3CN
勾配: 分 %A %B
0 95 5
30 50 50
75 0 100
123 0 100
流速: 25 mL/分
検出: 210 nm
活性画分は、LC−MSで分析した。スピノサルフェートBを含んでいる画分は、160分後に溶離した。当該画分を集めて減圧下で濃縮し、そして凍結乾燥した。22Lの培養液からの総収量は60mgであった。
外観、溶解性及びLC−MSは、実施例5に記載したものと同一である。
保持時間: 8.5 分
ESI−MS: 569.3 amu (M-H)-
HR−ESI−MS: 571.39885 [C35H55O6の計算値: 571.39932 (M-H)-]
分子式: C35H54O6
MSn−実験: FTICR 分析機器、Bruker APEX III, 7T
備品:外部 ESI−線源
ESI-: 569amu (M-H)-〜289amu, 245amu, 91amu; 289amu〜245amu.
検定は、384−穴プレートフォーマト中で、シビオ ピペット システム(Cybio pipetting system)を用いて行なった。最終検定容量は、30 μlで、プローブ(検定すべき抽出物又は純粋物質)10 μl、酵素−基質混合物(JNK−3/GST−ATF2) 10 μl、及びATP溶液10 μlを含んでいる。37 ℃で20分間インキュベートした後、HTRF抗体混合物(XL665−抗−GST/(Eu) クリプテート 抗−P−ATF2) 50 μlを添加した。665及び615nmにおけるそれぞれのエネルギー転移及びEuの放射強度を、室温で、120分後に、また、Victor2(R)(Wallac) 中340 nmにおけるプローブの励起で測定した。
25 mM HEPES, pH 7.5
100 μM MgCl2
0.03% TRITON X 100
10 mM DTT
5% グリセロール
HTRF試薬希釈用緩衝液II:
100 mM HEPES, pH 7.0
100 mM KF
133 mM EDTA
1g/L BSA
その他の試薬:
JNK3 キナーゼ Biotech, Vitry 8 ng /穴
GST−ATF2 Biotech, Vitry 88 ng /穴
ATP溶液 Sigma, A7699 15 μM
抗−GST−XL665 CisBio 125 ng /穴
抗−P−ATF2−(Eu)クリプテート NEB/CisBio 6 ng /穴
各プレートは、16個の陽性対照(最大エネルギー転移、プローブの代わりに緩衝液I)8個のブランク対照(最小エネルギー転移、ATPの代わりに緩衝液II)及び200 μM ED
TA溶液を含んでいる8穴を含む。
シグナル配分比率:
SR = (強度(665nm) /強度(615nm))
ブランク補正:
デルタF (%) = (SR(プローブ)−SR(min)) / (SR(min)×100)
阻害:
阻害 (%) = 100×[1−(デルタF(プローブ) /デルタF(最大))]
スピノサルフェートA及びBに対する次のIC50値が測定された。
スピノサルフェートA:IC50 = 0.5 μM、
スピノサルフェートB:IC50 = 10 μM。
検定は、384−穴プレートフォーマト中で、シビオ ピペット システム(Cybio pipetting system)を用いて行なった。最終検定容量は、55μlであった。
エリーザ高結合プレート(greiner)をスピノフィリン(10μg/ml)の30μlを各穴に添加して被覆した。低結合対照には、代わりとしてBSA(1%)の30μlを与えた。4℃で一晩インキュベートした後、プレートは、検定に用いる前にTBS洗浄用緩衝液(20mM TRIS/HCl, pH 7.5, 500 mM NaCl)で3回洗浄した。
TBS緩衝液(1.25μg/ml)で希釈したGST−pp1の50μlを被覆したプレートの各穴に添加した。適当に希釈した検定用標品(或いは、高対照及び低対照のTBS)の5μlを添加した後、プレートを室温で3時間インキュベートした。洗浄工程(80μl TBS/穴で3回)の後、Eu標識抗体(Eu−W 1024−抗−GST−抗体、0.5 % BSA補強デルフィア(Delfia)検定緩衝液中において0.1μg/mL)の30μlを各穴に添加した。更にインキュベートを続けて(室温で1時間)、そして洗浄した後(3×80μl TBS/穴)、エンハンサー溶液(Wallac) を各穴に添加した。続いて、TRFシグナルをビクターワラック(Victor Wallac)プレート読取器を用いて615 nmで読み取る前に、プレートを室温で30分間インキュベートした。
100× [1−(標品の615nmにおけるTRFシグナルの平均値)/(対照の615nmにおけるTRFシグナルの平均値)]
スピノサルフェートAに対するIC50値は34μMと決定され、そしてスピノサルフェートBに対するIC50値は10μMと決定された。
Claims (11)
- R1及びR2がSO3Hである請求項1に記載の式(I)で表される化合物。
- R1及びR2がHである請求項1に記載の式(I)で表される化合物。
- クリフォネクトリア パラシチカ(Cryphonectria parasitica) DSM 14453菌株又はその変異株もしくは突然変異株の1つの培養によって得られる、請求項1〜3のいずれかに記載の式(I)で表される化合物又はそれらの生理学的に許容され得る塩及び/又は自明な化学的均等物。
- 式C35H54O12S2で表される化合物であって、更に1H−NMRデータ(δ単位ppm) 0.85, 0.88, 1.23, 1.23-1.32, 1.25, 1.31, 1.45, 1.50, 1.57, 1.59, 2.45, 2.55, 5.04, 6.12, 6.14, 6.72, 6.75, 9.75, 10.48 及び 13C NMR データ (δ単位 ppm) 13.74, 13.87, 18.07, 22.00, 24.82, 28.60, 28.80-28.99, 29.13, 30.81, 31.20, 31.33, 33.58, 34.41, 35.23, 35.76, 74.23, 100.38, 108.63, 109.02, 110.23, 114.85, 142.54, 144.32, 153.56, 159.71, 160.21, 169.25によって特徴付けられる化合物。
- 式C35H54O6で表される化合物であって、更に1H−NMRデータ(δ単位 ppm) 0.84, 0.88,
1.25, 1.26, 1.33/1.29, 1.39/1.33, 1.45, 1.46, 1.56, 1.58, 2.34, 2.55, 5.05, 6.00, 6.12, 6.14 及び13C NMR データ (δ単位 ppm) 13.75, 13.87, 18.08, 22.02, 24.84, 28.91-28.62, 28.91-28.62, 29.19, 30.67, 31.22, 31.39, 33.59, 34.49, 35.25, 35.78, 74.19, 99.91, 100.39, 106.20, 108.75, 144.08, 144.43, 158.11, 159.89, 160.37, 169.31 によって特徴付けられる化合物。 - クリフォネクトリア パラシチカ(Cryphonectria parasitica)DSM 14453菌株又はその変異株もしくは突然変異株の1つを培養し、単離し、及び、場合によっては式(I)で表される化合物を精製し、及び、適当ならば生理学的に許容され得る塩及び/又は自明な化学的均等物へ変換することを特徴とする、請求項1〜3のいずれかに記載の式(I)で表される化合物又はそれらの生理学的に許容され得る塩及び/又は自明な化学的均等物の製造方法。
- 式(I)で表される化合物又はそれらの生理学的に許容され得る塩又は自明な化学的均等物のアルツハイマー病、パーキンソン病、ハンチントン病、卒中、精神病及び/又はうつ病の治療及び/又は予防のための医薬品製造のための使用。
- 請求項1〜3のいずれかに記載の式(I)で表される化合物又はそれらの生理学的に許容され得る塩又は自明な化学的均等物を少なくとも一つ、及び医薬品として許容され得る少なくとも一つの賦形剤を含む医薬品。
- 請求項1〜3のいずれかに記載の式(I)で表される化合物又はそれらの生理学的に許容され得る塩又は自明な化学的均等物の少なくとも一つを、医薬品として許容され得る少なくとも一つの賦形剤と共に適当な剤型に変換することを特徴とする、請求項9に記載の医薬品の製造方法。
- クリフォネクトリア パラシチカ(Cryphonectria parasitica) DSM 14453菌株。
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