JPWO2008108323A1 - インフルエンザ治療剤 - Google Patents
インフルエンザ治療剤 Download PDFInfo
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- JPWO2008108323A1 JPWO2008108323A1 JP2009502568A JP2009502568A JPWO2008108323A1 JP WO2008108323 A1 JPWO2008108323 A1 JP WO2008108323A1 JP 2009502568 A JP2009502568 A JP 2009502568A JP 2009502568 A JP2009502568 A JP 2009502568A JP WO2008108323 A1 JPWO2008108323 A1 JP WO2008108323A1
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- influenza
- therapeutic
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- 206010022000 influenza Diseases 0.000 title description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 86
- 206010064097 avian influenza Diseases 0.000 claims abstract description 54
- 230000000069 prophylactic effect Effects 0.000 claims abstract description 43
- 239000004480 active ingredient Substances 0.000 claims abstract description 42
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 41
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
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- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 9
- 125000005843 halogen group Chemical group 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 60
- 239000003795 chemical substances by application Substances 0.000 claims description 53
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 52
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- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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Abstract
Description
で表される化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤、
(2)(1)において、Xが炭素数1乃至4個のアルコキシ基である化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤、
(3)(1)において、Xがメトキシ基である化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤、
(4)(1)乃至(3)のいずれかにおいて、R1が炭素数6乃至20個のアルカノイル基であり、R2が水素原子であり、R3が水素原子である化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤、
(5)(1)乃至(3)のいずれかにおいて、R1が炭素数6乃至18個のアルカノイル基であり、R2が水素原子であり、R3が水素原子である化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤、
(6)(1)乃至(3)のいずれかにおいて、R1がヘキサノイル、オクタノイル、デカノイル、ドデカノイル、テトラデカノイル、ヘキサデカノイルまたはオクタデカノイル基であり、R2が水素原子であり、R3が水素原子である化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤、
(7)(1)乃至(3)のいずれかにおいて、R1およびR2が水素原子であり、R3が炭素数8乃至20個のアルキル基である化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤、
(8)(1)乃至(3)のいずれかにおいて、R1およびR2が水素原子であり、R3がデシル、ドデシル、テトラデシル、ヘキサデシルまたはオクタデシル基である化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤、または、
(9)(1)において、下記の群から選択される化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤:
5-アセタミド-4-グアニジノ-9-O-ヘキサノイル-2、3、4、5-テトラデオキシ-7-O-メチル-D-グリセロ-D-ガラクト-ノン-2-エノピラソン酸、
5-アセタミド-4-グアニジノ-9-O-オクタノイル-2、3、4、5-テトラデオキシ-7-O-メチル-D-グリセロ-D-ガラクト-ノン-2-エノピラソン酸、
5-アセタミド-4-グアニジノ-9-O-デカノイル-2、3、4、5-テトラデオキシ-7-O-メチル-D-グリセロ-D-ガラクト-ノン-2-エノピラソン酸、
5-アセタミド-4-グアニジノ-9-O-ドデカノイル-2、3、4、5-テトラデオキシ-7-O-メチル-D-グリセロ-D-ガラクト-ノン-2-エノピラソン酸、および、
5-アセタミド-4-グアニジノ-9-O-テトラデカノイル-2、3、4、5-テトラデオキシ-7-O-メチル-D-グリセロ-D-ガラクト-ノン-2-エノピラソン酸。
で表される化合物の薬理学的に有効な量を脊椎動物に投与することによるH5N1型インフルエンザを治療または予防する方法。
で表される化合物の使用。
Xは、好適には、炭素数1乃至4個のアルコキシ基であり、最も好適には、メトキシ基である。
(I−1)Xが炭素数1乃至4個のアルコキシ基である化合物、
(I−2)Xがメトキシ基である化合物、
(I−3)R1が炭素数6乃至20個のアルカノイル基であり、R2が水素原子であり、Xが炭素数1乃至4個のアルコキシ基であり、R3が水素原子である化合物、
(I−4)R1が炭素数6乃至20個のアルカノイル基であり、R2が水素原子であり、Xがメトキシ基であり、R3が水素原子である化合物、
(I−5)R1が炭素数6乃至18個のアルカノイル基であり、R2が水素原子であり、Xがメトキシ基であり、R3が水素原子である化合物、
(I−6)R1がヘキサノイル、オクタノイル、デカノイル、ドデカノイル、テトラデカノイル、ヘキサデカノイルまたはオクタデカノイル基であり、R2が水素原子であり、Xがメトキシ基であり、R3が水素原子である化合物、
(I−7)R1およびR2が水素原子であり、Xがメトキシ基であり、R3が炭素数8乃至20個のアルキル基である化合物、または、
(I−8)R1およびR2が水素原子であり、Xがメトキシ基であり、R3がデシル、ドデシル、テトラデシル、ヘキサデシルまたはオクタデシル基である化合物。
5−アセタミド−4−グアニジノ−9−O−オクタノイル−2、3、4、5−テトラデオキシ−7−O−メチル−D−グリセロ−D−ガラクト−ノン−2−エノピラソン酸
1H核磁気共鳴スペクトル(400MHz, CD3OD)δppm: 5.88(1H, d, J=2.5 Hz), 4.45 (3H, m), 4.27 (1H, dd, J=10.0 Hz, 10.0 Hz), 4.15 (1H, m), 3.47 (2H, m), 3.42 (3H, s), 2.37 (2H, t, J=7.4 Hz), 2.10 (3H, s), 1.31 (2H, m), 1.20-1.40 (8H, m), 0.85-0.95 (3H, m).
13C核磁気共鳴スペクトル(100MHz, CD3OD)δppm: 176.5, 173.7, 164.7, 158.9, 146.7, 108.7, 80.1, 78.0, 69.3, 66.8, 61.4, 52.4, 35.1, 32.8, 30.2, 30.1, 26.0, 23.7, 22.8, 14.4.
(2)標記化合物は以下の方法によっても得られた。
5−アセタミド−4−グアニジノ−2、3、4、5−テトラデオキシ−7−O−メチル−D−グリセロ−D−ガラクト−ノン−2−エノピラソン酸
なお、製造例2の化合物は、製造例1の化合物が体内で代謝されて生成される化合物である。すなわち、製造例1の化合物は、製造例2の化合物のプロドラッグであり、製造例2の化合物は活性本体である。
(実施例1)ノイラミニダーゼ阻害活性試験
以下の試験は、Nature, 2005年,第437巻, p.1108に記載された方法に準じた方法に従って行われた。
オセルタミビル感受性株: A/Hanoi/30408/2005 (clone 7)
オセルタミビル耐性株: A/Hanoi/30408/2005 (clone 9)
(実施例2)ウイルス増殖阻害活性試験
H5N1型インフルエンザウイルスを一つのwellあたり50乃至100個のプラークを形成するようにMDCK細胞に接種し、37℃で1時間吸着させた後、0.1乃至1000nMの濃度の試験化合物を含む寒天培地を重層し、MDCK細胞を2日間培養した。その後、19%メタノールに溶解した0.1%クリスタルバイオレットにて固定染色し、プラーク数およびプラークの直径を測定した。面積を基として阻害率を算出するため、全プラークの直径の二乗の和を計算し、試験化合物が無添加である場合を100%としたときの各濃度での試験化合物の阻害率(%)を算出し、50%のウイルス増殖阻害活性を与える試験化合物の濃度(IC50)を算出した。結果を表2に示す。
オセルタミビル感受性株: A/Hanoi/30408/2005 (clone 7)
オセルタミビル耐性株: A/Hanoi/30408/2005 (clone 9)
(実施例3)マウス感染治療試験1
Balb/cマウスに生理食塩水のみまたは生理食塩水に溶解した種々の濃度の試験化合物を経鼻的に投与し、投与7日後に、H5N1型インフルエンザウイルスを経鼻的に接種して、感染させる。感染の1日、2日および3日後にマウスの肺を採取し、肺中に含まれるH5N1型インフルエンザウイルスを定量することにより、H5N1型インフルエンザウイルスの増殖抑制効果を調べる。
実施例3と同様にして試験化合物を投与し、H5N1型インフルエンザウイルスを接種したマウスの生存を感染の20日後まで観察する。
Claims (11)
- 請求項1において、Xが炭素数1乃至4個のアルコキシ基である化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤。
- 請求項1において、Xがメトキシ基である化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤。
- 請求項1乃至3のいずれかにおいて、R1が炭素数6乃至20個のアルカノイル基であり、R2が水素原子であり、R3が水素原子である化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤。
- 請求項1乃至3のいずれかにおいて、R1が炭素数6乃至18個のアルカノイル基であり、R2が水素原子であり、R3が水素原子である化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤。
- 請求項1乃至3のいずれかにおいて、R1がヘキサノイル、オクタノイル、デカノイル、ドデカノイル、テトラデカノイル、ヘキサデカノイルまたはオクタデカノイル基であり、R2が水素原子であり、R3が水素原子である化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤。
- 請求項1乃至3のいずれかにおいて、R1およびR2が水素原子であり、R3が炭素数8乃至20個のアルキル基である化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤。
- 請求項1乃至3のいずれかにおいて、R1およびR2が水素原子であり、R3がデシル、ドデシル、テトラデシル、ヘキサデシルまたはオクタデシル基である化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤。
- 請求項1において、下記の群から選択される化合物を有効成分として含有するH5N1型インフルエンザの治療剤または予防剤:
5-アセタミド-4-グアニジノ-9-O-ヘキサノイル-2、3、4、5-テトラデオキシ-7-O-メチル-D-グリセロ-D-ガラクト-ノン-2-エノピラソン酸、
5-アセタミド-4-グアニジノ-9-O-オクタノイル-2、3、4、5-テトラデオキシ-7-O-メチル-D-グリセロ-D-ガラクト-ノン-2-エノピラソン酸、
5-アセタミド-4-グアニジノ-9-O-デカノイル-2、3、4、5-テトラデオキシ-7-O-メチル-D-グリセロ-D-ガラクト-ノン-2-エノピラソン酸、
5-アセタミド-4-グアニジノ-9-O-ドデカノイル-2、3、4、5-テトラデオキシ-7-O-メチル-D-グリセロ-D-ガラクト-ノン-2-エノピラソン酸、および、
5-アセタミド-4-グアニジノ-9-O-テトラデカノイル-2、3、4、5-テトラデオキシ-7-O-メチル-D-グリセロ-D-ガラクト-ノン-2-エノピラソン酸。
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DK0823428T3 (da) * | 1996-07-22 | 2002-02-18 | Sankyo Co | Neuraminsyrederivater, deres fremstilling og deres medicinske anvendelse |
JP3209946B2 (ja) * | 1996-07-22 | 2001-09-17 | 三共株式会社 | ノイラミン酸誘導体 |
US6340702B1 (en) * | 1996-07-22 | 2002-01-22 | Sankyo Company, Limited | Neuraminic acid derivatives, their preparation and their medical use |
JP4151800B2 (ja) | 1996-08-13 | 2008-09-17 | 第一三共株式会社 | ノイラミン酸化合物 |
JP3920041B2 (ja) | 2000-04-25 | 2007-05-30 | 三共株式会社 | ノイラミン酸化合物の水和物及び結晶 |
TWI291462B (en) * | 2000-04-25 | 2007-12-21 | Daiichi Sankyo Co Ltd | Hydrate crystal of neuraminic acid compound |
ATE414215T1 (de) | 2005-08-22 | 2008-11-15 | Delphi Tech Inc | Nockenwellenversteller zur einstellung der phase zwischen einer nockenwelle und einem antriebsrad |
-
2008
- 2008-03-03 PL PL08721158T patent/PL2123271T3/pl unknown
- 2008-03-03 US US12/449,909 patent/US20100204314A1/en not_active Abandoned
- 2008-03-03 AT AT08721158T patent/ATE526960T1/de active
- 2008-03-03 KR KR1020097018422A patent/KR101473028B1/ko active IP Right Grant
- 2008-03-03 JP JP2009502568A patent/JP5286251B2/ja active Active
- 2008-03-03 SI SI200830440T patent/SI2123271T1/sl unknown
- 2008-03-03 ES ES08721158T patent/ES2372996T3/es active Active
- 2008-03-03 CN CN2008800149108A patent/CN101715343B/zh active Active
- 2008-03-03 WO PCT/JP2008/053738 patent/WO2008108323A1/ja active Application Filing
- 2008-03-03 EP EP08721158A patent/EP2123271B1/en not_active Not-in-force
- 2008-03-03 CA CA002680415A patent/CA2680415A1/en not_active Abandoned
- 2008-03-03 DK DK08721158.7T patent/DK2123271T3/da active
- 2008-03-03 PT PT08721158T patent/PT2123271E/pt unknown
- 2008-03-07 TW TW097107984A patent/TWI424841B/zh active
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2010
- 2010-04-21 HK HK10103858.3A patent/HK1137142A1/xx unknown
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2011
- 2011-11-21 HR HR20110861T patent/HRP20110861T1/hr unknown
- 2011-12-30 CY CY20111101293T patent/CY1112201T1/el unknown
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2013
- 2013-04-22 JP JP2013089202A patent/JP6012076B2/ja active Active
- 2013-08-27 US US14/010,784 patent/US20140018418A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
SI2123271T1 (sl) | 2012-05-31 |
WO2008108323A1 (ja) | 2008-09-12 |
ATE526960T1 (de) | 2011-10-15 |
TWI424841B (zh) | 2014-02-01 |
JP6012076B2 (ja) | 2016-10-25 |
JP5286251B2 (ja) | 2013-09-11 |
US20100204314A1 (en) | 2010-08-12 |
ES2372996T3 (es) | 2012-01-30 |
HRP20110861T1 (hr) | 2011-12-31 |
US20140018418A1 (en) | 2014-01-16 |
DK2123271T3 (da) | 2012-01-23 |
KR20090129414A (ko) | 2009-12-16 |
CN101715343B (zh) | 2012-09-26 |
HK1137142A1 (en) | 2010-07-23 |
JP2013139483A (ja) | 2013-07-18 |
KR101473028B1 (ko) | 2014-12-15 |
PT2123271E (pt) | 2011-12-20 |
EP2123271A1 (en) | 2009-11-25 |
TW200848018A (en) | 2008-12-16 |
CN101715343A (zh) | 2010-05-26 |
CA2680415A1 (en) | 2008-09-12 |
EP2123271A4 (en) | 2010-03-17 |
CY1112201T1 (el) | 2015-12-09 |
EP2123271B1 (en) | 2011-10-05 |
PL2123271T3 (pl) | 2012-03-30 |
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