JP2008524232A - ラパマイシン誘導体及び神経障害の治療におけるその使用 - Google Patents
ラパマイシン誘導体及び神経障害の治療におけるその使用 Download PDFInfo
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Abstract
Description
II.本発明の化合物を調製する方法
本発明の式Iのラパマイシン誘導体はラパマイシン系出発物質から調製される。1つの実施形態において、ラパマイシン系出発物質には、限定されないが、ラパマイシン、ノルラパマイシン、デオキソラパマイシン、デスメチルラパマイシン又はデスメトキシラパマイシン、あるいは、それらの医薬的に許容され得る塩、プロドラッグ又は代謝産物が含まれる。しかしながら、当業者は、本発明の新規なラパマイシン誘導体を調製するために利用することができる好適なラパマイシン系出発物質を容易に選択することができる。
III.本発明の化合物を使用する方法
本発明の式Iのラパマイシン誘導体(飽和度がより大きいラパマイシン誘導体及び飽和度がより低いラパマイシン誘導体を含む)は、神経障害に関連する適用を含めて様々な適用における用途を有する。本発明の化合物は、アルツハイマー病、筋萎縮性側索硬化症、てんかん、ハンチントン舞踏病、パーキンソン病、脳卒中、脊髄傷害、外傷性脳傷害、レヴィー小体認知症、多発性硬化症、ピック病、ニーマン・ピック病、アミロイド血管症、脳アミロイド血管症、全身性アミロイドーシス、ダッチ型のアミロイドーシスを伴う遺伝性脳出血、封入体筋炎、軽度認識障害及びダウン症候群(これらに限定されない)を含む神経障害を治療することにおいて有用であり、また、そのための医薬品の調製において有用である。ラパマイシン誘導体はまた、脳卒中、頭蓋骨損傷又は脊髄傷害、あるいは、脳、末梢神経系、中枢神経系又は神経筋系に対する他の傷害に起因する合併症を治療することにおいて有用であり、また、そのための医薬品の調製において有用である。
IV.ラパマイシン誘導体を含有する投与可能な組成物を調製する方法
1つの態様において、本発明は、本発明の1つ又は複数のラパマイシン誘導体を含有する医薬組成物を調製する方法を包含する。組成物はいくつかの異なる経路によって、被験対象の哺乳動物に投与することができ、望ましくは、固体形態又は液体形態で経口投与される。
V.本発明のキット
本発明はまた、ラパマイシン誘導体を含有するキット又は包装物を提供する。本発明のキットは、本発明のラパマイシン誘導体と、上記で議論されたような被験対象の哺乳動物への投与のために好適な担体とを含むことができる。キットはまた、本発明のラパマイシン誘導体を調製するために必要とされる試薬を含有することができ、また、ラパマイシン、場合により置換されたオレフィン、及び溶媒を含むことができる。
Claims (25)
- 式Iの化合物又はその医薬的に許容され得る塩:
R1及びR2は、同一又は異なって、CR16R17及びCR18R19からなる群より選択される;
R3及びR4は、
(a)独立して、H、OH、O(C1−C6アルキル)、O(C1−C6置換アルキル)、O(アシル)、O(アリール)、O(置換アリール)及びハロゲンからなる群より選択される;又は
(b)一緒になって、Oに対して二重結合を形成する;
R5、R6及びR7は、独立して、H、OH及びOCH3からなる群より選択される;
R8及びR9は、(i)単結合を介して連結し、かつ、CH2であるか、又は、(ii)二重結合を介して連結し、かつ、CHである;
R15は、C=O、CHOH及びCH2からなる群より選択される;
R16及びR17は、独立して、H、C1−C6アルキル、C1−C6置換アルキル、アリール、置換アリール、アシル、CF3、CN及びNO2からなる群より選択される;
R18及びR19は、独立して、H、C1−C6アルキル、C1−C6置換アルキル、アリール、置換アリール、アシル、CF3、CN及びNO2からなる群より選択される;又は
R17及びR18は、一緒になって、炭素型(carbon-based)又は複素環式の5員環〜7員環を形成する;
nは1又は2である。 - R17及びR18が、一緒になって、炭素型又は複素環式の5員環〜7員環を形成する、請求項1に記載の化合物。
- R8及びR9が単結合により結合する、請求項1又は請求項2に記載の化合物。
- R3又はR4がOHである、請求項1〜3のいずれか1項に記載の化合物。
- R3又はR4がO(アシル)である、請求項1〜3のいずれか1項に記載の化合物。
- R5、R6及びR7がOCH3である、請求項1〜6のいずれか1項に記載の化合物。
- nが2である、請求項1〜7のいずれか1項に記載の化合物。
- R15がC=Oである、請求項1〜8のいずれか1項に記載の化合物。
- 式Iaの化合物又はその医薬的に許容され得る塩:
R1及びR2は、同一又は異なって、CR16R17及びCR18R19からなる群より選択される;
R6は、H、OH及びOCH3からなる群より選択される;
R8及びR9は、(i)単結合を介して連結し、かつ、CH2であるか、又は、(ii)二重結合を介して連結し、かつ、CHである;
R16及びR17は、独立して、H、C1−C6アルキル、C1−C6置換アルキル、アリール、置換アリール、アシル、CF3、CN及びNO2からなる群より選択される;
R18及びR19は、独立して、H、C1−C6アルキル、C1−C6置換アルキル、アリール、置換アリール、アシル、CF3、CN及びNO2からなる群より選択される;又は
R18及びR19は、一緒になって、5員環〜7員環を形成する。 - 神経保護剤又は神経再生剤である、請求項1〜12のいずれかに記載の化合物。
- (i)請求項1〜12のいずれか1項において定義される化合物又はその医薬的に許容され得る塩と、(ii)医薬的に許容され得る担体とを、その必要性のある被験者に投与することを含む、神経変性障害を治療する方法。
- 前記神経変性障害が、アルツハイマー病、筋萎縮性側索硬化症、てんかん、ハンチントン舞踏病、パーキンソン病、脳卒中、脊髄傷害、外傷性脳傷害、レヴィー小体認知症、多発性硬化症、ピック病、ニーマン・ピック病、アミロイド血管症、脳アミロイド血管症、全身性アミロイドーシス、ダッチ型のアミロイドーシスを伴う遺伝性脳出血、封入体筋炎、軽度認識障害及びダウン症候群からなる群より選択される、請求項14に記載の方法。
- (i)請求項1〜12のいずれか1項において定義される化合物又はその医薬的に許容され得る塩と、(ii)医薬的に許容され得る担体とを、その必要性のある被験者に投与することを含む、脳卒中又は頭蓋骨損傷(head trauma)に起因する合併症を治療する方法。
- ラパマイシン又はそのアナログを式R16R17C=CR18R19のオレフィンと反応して、請求項1又は請求項10において定義される化合物(この場合、R8及びR9は二重結合を介して連結し、かつ、CHである)を得ること、及び、所望されるならば、水素化して、請求項1又は請求項10において定義される化合物(この場合、R8及びR9は単結合を介して連結し、かつ、CH2である)を得ること、及び、さらには、必要により、その医薬的に許容され得る塩として単離することを含む、請求項1又は請求項10において定義される化合物又はその医薬的に許容され得る塩を調製する方法。
- 前記ラパマイシンアナログが、ノルラパマイシン、デオキソラパマイシン又はデスメチルラパマイシンである、請求項17に記載の方法。
- 反応が高温において行われる、請求項17又は請求項18に記載の方法。
- 生成物が、クロマトグラフィーを使用して単離される、請求項17〜19のいずれか1項に記載の方法。
- 水素化が、Pd/C触媒及び水素ガスを使用して行われる、請求項17〜20のいずれか1項に記載の方法。
- 生成物が、R8及びR9が単結合を介して連結し、かつ、CH2である式Iを有するか、又は、その医薬的に許容され得る塩である、請求項17〜21のいずれか1項に記載の方法。
- その必要性のある被験者において神経変性障害を治療するための医薬品の調製における、請求項1〜12のいずれか1項において定義される化合物又はその医薬的に許容され得る塩の使用。
- 前記神経変性障害が、アルツハイマー病、筋萎縮性側索硬化症、てんかん、ハンチントン舞踏病、パーキンソン病、脳卒中、脊髄傷害、外傷性脳傷害、レヴィー小体認知症、多発性硬化症、ピック病、ニーマン・ピック病、アミロイド血管症、脳アミロイド血管症、全身性アミロイドーシス、ダッチ型のアミロイドーシスを伴う遺伝性脳出血、封入体筋炎、軽度認識障害及びダウン症候群からなる群より選択される、請求項23に記載の使用。
- その必要性のある被験者において脳卒中又は頭蓋骨損傷に起因する合併症を治療するための医薬品の調製における、請求項1〜12のいずれか1項において定義される化合物又はその医薬的に許容され得る塩の使用。
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PCT/US2005/045331 WO2006068905A2 (en) | 2004-12-20 | 2005-12-15 | Rapamycin derivatives and the uses thereof in the treatment of neurological disorders |
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US (3) | US7273874B2 (ja) |
EP (1) | EP1828203A2 (ja) |
JP (1) | JP2008524232A (ja) |
KR (1) | KR20070090931A (ja) |
CN (1) | CN101084226A (ja) |
AU (1) | AU2005319427B2 (ja) |
BR (1) | BRPI0519593A2 (ja) |
CA (1) | CA2590254A1 (ja) |
CR (1) | CR9149A (ja) |
IL (1) | IL183772A0 (ja) |
MX (1) | MX2007007409A (ja) |
NI (1) | NI200700156A (ja) |
NO (1) | NO20072665L (ja) |
RU (1) | RU2007119585A (ja) |
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- 2005-12-15 KR KR1020077013852A patent/KR20070090931A/ko not_active Application Discontinuation
- 2005-12-15 RU RU2007119585/04A patent/RU2007119585A/ru not_active Application Discontinuation
- 2005-12-15 WO PCT/US2005/045331 patent/WO2006068905A2/en active Application Filing
- 2005-12-15 EP EP05854115A patent/EP1828203A2/en not_active Withdrawn
- 2005-12-15 US US11/300,941 patent/US7273874B2/en not_active Expired - Fee Related
- 2005-12-15 AU AU2005319427A patent/AU2005319427B2/en not_active Ceased
- 2005-12-15 BR BRPI0519593-4A patent/BRPI0519593A2/pt not_active IP Right Cessation
- 2005-12-15 JP JP2007546876A patent/JP2008524232A/ja active Pending
- 2005-12-15 CN CNA2005800437050A patent/CN101084226A/zh active Pending
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- 2007-05-24 CR CR9149A patent/CR9149A/es not_active Application Discontinuation
- 2007-05-25 NO NO20072665A patent/NO20072665L/no not_active Application Discontinuation
- 2007-06-07 IL IL183772A patent/IL183772A0/en unknown
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- 2007-08-14 US US11/891,879 patent/US7476678B2/en not_active Expired - Fee Related
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CR9149A (es) | 2007-10-23 |
KR20070090931A (ko) | 2007-09-06 |
IL183772A0 (en) | 2007-09-20 |
US7476678B2 (en) | 2009-01-13 |
CA2590254A1 (en) | 2006-06-29 |
RU2007119585A (ru) | 2009-01-27 |
US20060135550A1 (en) | 2006-06-22 |
US20090088448A1 (en) | 2009-04-02 |
AU2005319427A1 (en) | 2006-06-29 |
AU2005319427B2 (en) | 2011-11-03 |
MX2007007409A (es) | 2007-07-12 |
BRPI0519593A2 (pt) | 2009-02-25 |
NO20072665L (no) | 2007-09-07 |
US20080027089A1 (en) | 2008-01-31 |
WO2006068905A3 (en) | 2006-12-07 |
NI200700156A (es) | 2008-06-17 |
CN101084226A (zh) | 2007-12-05 |
US7273874B2 (en) | 2007-09-25 |
EP1828203A2 (en) | 2007-09-05 |
WO2006068905A2 (en) | 2006-06-29 |
ZA200705123B (en) | 2010-01-27 |
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