JP5327744B2 - ジフェニルメタン誘導体を有効成分とする抗ウイルス剤 - Google Patents
ジフェニルメタン誘導体を有効成分とする抗ウイルス剤 Download PDFInfo
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- JP5327744B2 JP5327744B2 JP2009061577A JP2009061577A JP5327744B2 JP 5327744 B2 JP5327744 B2 JP 5327744B2 JP 2009061577 A JP2009061577 A JP 2009061577A JP 2009061577 A JP2009061577 A JP 2009061577A JP 5327744 B2 JP5327744 B2 JP 5327744B2
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- 239000003443 antiviral agent Substances 0.000 title claims abstract description 18
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Xは、炭素原子又はケイ素原子であり、
Y及びZは、同一又は異なり、酸素原子又はNR5(ここで、R5は水素原子又は置換若しくは非置換のアルキル基である)であり、
A及びBは、同一又は異なり、水素原子又は直鎖C1-5-アルキル基であり、
R1及びR2は、同一若しくは異なり、直鎖若しくは分岐のC1-5-アルキル基であるか、又は一緒になって環状構造を形成するものであり、
R3及びR4は、同一又は異なり、水素原子、置換若しくは非置換のアルキル基、又はCO-R6若しくはCO-NR7R8(ここで、R6、R7及びR8は、同一又は異なり、水素又は置換若しくは非置換のアルキル基である)である]
で示される化合物又はその薬学的に許容される塩を含有する抗ウイルス剤に関する。当該抗ウイルス剤が対象とするウイルスとしては、フラビウイルス科に属するウイルスが挙げられる。
A及びBは、同一又は異なり、水素原子又は直鎖C1-5-アルキル基であり、
R1及びR2は、同一若しくは異なり、直鎖若しくは分岐のC1-5-アルキル基であるか、又は一緒になって環状構造を形成するものであり、
R6は、水素又は置換若しくは非置換のアルキル基である]
で示される化合物又はその薬学的に許容される塩に関する。
前記式(I)において、直鎖C1-5-アルキル基としては、例えばメチル基、エチル基、n-プロピル基、n-ブチル基、n-ペンチル基等が挙げられる。
AとBとが異なる場合には、Hal1及びHal2の一方を塩素、他方を臭素とし、2工程により製造する]
以下、実施例を用いて本発明をより詳細に説明するが、本発明の技術的範囲はこれら実施例に限定されるものではない。
1. 化合物1:1-(N-ベンジル-N-(4-(3-(4-(3,3-ジメチル-2-オキソブチルヒドロキシ)-3-メチルフェニル)ペンタン-3-イル)-2-メチルフェニル)アミノ)-3,3-ジメチルブタン-2-オンの合成
(1) 1-(4-(3-(4-アミノ-3-メチルフェニル)ペンタン-3-イル)-2-メチルフェノキシ)-3,3-ジメチルブタン-2-オンの合成
1H-NMR: 6.93 (s, 1H), 6.91 (dd, J = 8.5, 2.6 Hz, 1H), 6.82-6.80 (m, 2H), 6.56 (d, J = 8.1 Hz, 1H), 6.49 (d, J = 7.7 Hz, 1H), 4.82 (s, 2H), 3.47 (s, 2H), 2.23 (s, 3H), 2.12 (s, 3H), 1.99 (q, J = 7.3 Hz, 4H), 1.25 (s, 9H), 0.59 (t, J = 7.3 Hz, 6H); MS (FAB, M+): 381。
1H-NMR: 6.93-6.89 (m, 3H), 6.83 (s, 1H), 6.49 (d, J = 8.1 Hz, 1H), 6.39 (d, J = 8.1 Hz, 1H), 4.82 (s, 2H), 4.50 (s, 1H), 4.13 (d, J = 4.3 Hz, 2H), 2.23 (s, 3H), 2.16 (s, 3H), 1.99 (q, J = 7.3 Hz, 4H), 1.25 (s, 9H), 1.24 (s, 9H), 0.59 (t, J = 7.3 Hz, 6H); MS (FAB, [M+H]+) 480。
1H-NMR: 7.30-7.20 (m, 5H), 7.00 (d, J = 8.6 Hz, 1H), 6.91-6.87 (m, 4H), 6.49 (d, J = 9.4 Hz, 1H), 4.83 (s, 2H), 4.30 (s, 2H), 3.88 (s, 2H), 2.31 (s, 3H), 2.23 (s, 3H), 2.00 (q, J = 7.3 Hz, 4H), 1.25 (s, 9H), 0.99 (s, 9H), 0.57 (t, J = 7.3 Hz, 6H). MS (FAB, [M+H]+) 570。
以下のようにして、下記の表1に示す化合物9を製造した。
1H-NMR: 7.25 (s, 2H), 7.22 (d, J = 8.5 Hz, 2H), 6.59 (d, J = 8.5 Hz, 2H), 4.87 (s, 4H), 2.28 (s, 6H), 1.26 (s, 18H), 0.99-0.97 (m, 10H); MS (FAB, M+): 496。
(1)材料
ジフェニルメタン誘導体の抗ウイルス活性を調べるために、以下の材料を使用した。
2) ウイルス:ウシ下痢症ウイルス(Bovine viral diarrhea virus:以下、「BVDV」という)Nose株
3) 培地:100 unit/ml ペニシリンG、100μg/mlストレプトマイシン及び3%ウマ血清を添加したDulbecco's Modified Eagle Medium
4) 培養プレート:96穴平底マイクロタイタープレート
5) 測定用試薬又はキット:LDH cytotoxicity detection kit(Takara Biochemicals社)及び水溶性MTT液TetraColor One(登録商標)(Seikagaku Corporation社)
6) 化合物
試験化合物は、下記の表1に示す化合物1〜9である。化合物1〜9は、Hosoda, S., Tanatani, A., Wakabayashi, K., Makishima, M., Imai, K., Miyachi, H., Nagasawa, K., Hashimoto, Y.: Ligand with a 3,3-diphenylpentane skeleton for nuclear vitamin D and androgen receptors: dual activities and metabolic activation. Bioorg. Med. Chem., 14: 5489-5502 (2006)又はHosoda, S., Hashimoto, Y.: 3,3-Diphenylpentane skeleton as a steroid skeleton substitute: novel inhibitors of human 5α-reductase 1. Bioorg. Med. Chem. Lett., 17: 5414-5418 (2007)及びTagle, L. H., Terraza, C. A., Alvarez, P.: Synthesis and characterization of poly(carbonates) and poly(thiocarbonates) derived from diphenyls containing silicon as central atom. Phos. Sulf. Silicon, 181: 239-248 (2006)に記載の方法に準じて製造した。なお、化合物1及び9については、具体的な製造方法を実施例1において説明した。
以下に示す方法により、化合物1〜9の抗ウイルス活性を測定した(Baba, C. et al., Antiviral Chemistry & Chemotherapy, Vol. 16, No. 1, p. 33-39 (2005))。
この式において、各略称は以下の意味を示す。
(ODC)M:化合物非存在下におけるウイルス非感染細胞上清の吸光度(LDH活性)
(ODC)V:化合物非存在下におけるウイルス感染細胞上清の吸光度(LDH活性)
(ODC)M:化合物非存在下における非感染細胞培養液の吸光度(MTT活性)
さらに得られた細胞増殖抑制率から、50%の細胞増殖抑制率を付与する化合物の濃度(50%細胞毒性濃度:CC50)を求めた。
各化合物のEC50(μM)、CC50(μM)及び選択係数(CC50/EC50;SI)を表1に示す。なお、EC50(μM)及びCC50(μM)の数値は、少なくとも2回、別々に行われた実験からの平均値である。
実施例2に記載の感染及び培養方法に準じて、MDBK細胞(1×105細胞/ml)に、BVDVを感染多重度(multiplicity of infection;MOI)=0.01で感染させた。次いで、BVDV感染細胞を含む溶液を96穴平底マイクロタイタープレートの各穴(ウェル)に100μlずつ分注(1×104細胞/ウェル)し、同時に各種濃度の上記化合物9を添加し、37℃(5%CO2)で培養した。培養1日後、未感染のウイルスを含む培養上清を取り除き、同じ濃度の化合物9を含む新しい培養液を添加し、さらに2日間培養した。
Claims (3)
- 次式(I):
[式中、
Xは、炭素原子又はケイ素原子であり、
Y及びZは、同一又は異なり、酸素原子又はNR5(ここで、R5は水素原子、又はフェニル基、トリル基及びo-キシリル基から成る群より選択される芳香族基で置換されたアルキル基若しくは非置換のアルキル基である)であり、
A及びBは、同一又は異なり、水素原子又は直鎖C1-5-アルキル基であり、
R1及びR2は、同一若しくは異なり、直鎖若しくは分岐のC1-5-アルキル基であるか、又は一緒になって環状構造を形成するものであり、該環状構造は、シクロブチル基、シクロペンチル基及びシクロヘキシル基から成る群より選択されるC 4-6 -脂肪族環状アルキル基であり、
R3及びR4は、同一又は異なり、水素原子、置換若しくは非置換のアルキル基、又はCH 2 -CO-R 6 若しくはCO-NR7R8(ここで、R6、R7及びR8は、同一又は異なり、水素又は置換若しくは非置換のアルキル基である)であり、
ここで、R 3 、R 4 及びR 6 〜R 8 が置換のアルキル基である場合には、該アルキル基は水酸基及びオキソ基から成る群より選択される1以上の置換基で置換されたものである]
で示される化合物又はその薬学的に許容される塩を含有する抗ウイルス剤であって、該ウイルスがフラビウイルス科に属するウイルスである、前記抗ウイルス剤。 - 前記ウイルスが、黄熱病ウイルス(YFV)、デング熱ウイルス(DENV)、日本脳炎ウイルス(JEV)、西ナイルウイルス(WNV)、ウシ下痢症ウイルス(BVDV)及びC型肝炎ウイルス(HCV)から成る群より選択されるフラビウイルス科に属するウイルスである、請求項1記載の抗ウイルス剤。
- 次式(II):
[式中、
A及びBは、同一又は異なり、水素原子又は直鎖C1-5-アルキル基であり、
R1及びR2は、同一若しくは異なり、直鎖若しくは分岐のC1-5-アルキル基であるか、又は一緒になって環状構造を形成するものであり、該環状構造は、シクロブチル基、シクロペンチル基及びシクロヘキシル基から成る群より選択されるC 4-6 -脂肪族環状アルキル基であり、
R6は、水素又は置換若しくは非置換のアルキル基であり、ここで、R 6 が置換のアルキル基である場合には、該アルキル基は水酸基及びオキソ基から成る群より選択される1以上の置換基で置換されたものである]
で示される化合物又はその薬学的に許容される塩。
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