JP2009505982A - O−ニトロ化合物、その医薬組成物および用途 - Google Patents
O−ニトロ化合物、その医薬組成物および用途 Download PDFInfo
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- JP2009505982A JP2009505982A JP2008526289A JP2008526289A JP2009505982A JP 2009505982 A JP2009505982 A JP 2009505982A JP 2008526289 A JP2008526289 A JP 2008526289A JP 2008526289 A JP2008526289 A JP 2008526289A JP 2009505982 A JP2009505982 A JP 2009505982A
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Abstract
Description
本発明は、O−ニトロ化合物、O−ニトロ化合物の医薬組成物、および異常細胞の増殖に関連する疾患を治療または予防するためにO−ニトロ化合物またはその医薬組成物を使用する方法を提供することによって、本要求および他の要求を満足する。
定義
「アルキル」はそれ自身または別の置換基の一部として、親のアルカン、アルケンまたはアルキンの1個の炭素原子からの1個の水素原子の除去によって派生する、飽和または不飽和の分枝、直鎖または環状の一価の炭化水素基を意味する。典型的なアルキル基は、メチル;エチル類、例えばエタニル、エテニル、エチニル;プロピル類、例えばプロパン−1−イル、プロパン−2−イル、シクロプロパン−1−イル、プロパ−1−エン−1−イル、プロパ−1−エン−2−イル、プロパ−2−エン−1−イル(アリル)、シクロプロパ−1−エン−1−イル、シクロプロパ−2−エン−1−イル、プロパ−1−イン−1−イル、プロパ−2−イン−1−イルなど;ブチル類、例えばブタン−1−イル、ブタン−2−イル、2−メチル−プロパン−1−イル、2−メチル−プロパン−2−イル、シクロブタン−1−イル、ブタ−1−エン−1−イル、ブタ−1−エン−2−イル、2−メチル−プロパ−1−エン−1−イル、ブタ−2−エン−1−イル、ブタ−2−エン−2−イル、ブタ−1,3−ジエン−1−イル、ブタ−1,3−ジエン−2−イル、シクロブタ−1−エン−1−イル、シクロブタ−1−エン−3−イル、シクロブタ−1,3−ジエン−1−イル、ブタ−1−イン−1−イル、ブタ−1−イン−3−イル、ブタ−3−エン−1−イルなど;などを含むが、これらに限定されない。
本発明は、O−ニトロ化合物、O−ニトロ化合物の医薬組成物、および異常細胞の増殖に関連する疾患を治療または予防するためのO−ニトロ化合物またはその医薬組成物を使用する方法を提供する。
O−ニトロ化合物および/またはその医薬組成物は、ヒト医学において有利に使用し得る。上記の4.2項目において記載する通り、O−ニトロ化合物および/またはその医薬組成物は、様々な疾患または障害の治療または予防に有用である。
本発明の医薬組成物は典型的に、治療学的に有効な量の1個以上のO−ニトロ化合物(純粋な形態が好ましい)を、適当な量の医薬的に許容し得るビヒクル(患者にとって適当な投与のための形態を供するため)と合わせて含む。患者に投与する場合には、該O−ニトロ化合物および医薬的に許容し得るビヒクルは滅菌することが好ましい。該O−ニトロ化合物を静脈内投与する場合には、水は好ましいビヒクルである。生理食塩水溶液、およびデキストロース水溶液およびグリセロール水溶液はまた、特に注射液剤のための液体ビヒクルとして使用し得る。適当な医薬的なビヒクルはまた賦形剤を含み、これは例えば、澱粉、グルコース、ラクトース、スクロース、セラチン、麦芽、米、小麦粉、粉乳、シリカゲル、ステアリン酸ナトリウム、グリセロールモノステアリン酸、タルク、塩化ナトリウム、乾燥脱脂乳、グリセロール、プロピレン、グリコール、水、エタノールなどを挙げられる。所望するならば、本発明の医薬組成物はまた、微量の湿潤剤もしくは乳化剤、またはpH緩衝化剤を含み得る。加えて、補助剤、安定化剤、増粘剤、滑沢剤、および、着色剤を使用し得る。
O−ニトロ化合物および/またはその医薬組成物は通常、意図する目的を達成するのに有効な量で使用する。上記の疾患または障害を治療または予防するための用途において、該O−ニトロ化合物および/またはその医薬組成物は、治療学的に有効な量で投与しまたは適用する。
ある実施態様において、O−ニトロ化合物および/またはその医薬組成物は、少なくとも1つの他の治療薬との併用療法で使用し得る。該O−ニトロ化合物および/またはその医薬組成物、並びに該治療薬は、相加的またはより好ましくは相乗的に作用し得る。ある実施態様において、O−ニトロ化合物および/またはその医薬組成物は、別の治療薬の投与と同時に投与する。他の実施態様において、O−ニトロ化合物および/またはその医薬組成物は、別の治療薬の投与の前または後に投与する。
本発明はまた、O−ニトロ化合物および/またはその医薬組成物を含有する治療キットを提供する。該治療キットはまた、他の化合物(例えば、化学療法薬、天然物、アポトーシス−誘発剤など)またはその医薬組成物を含み得る。
GLYNのシスプラチンとの組み合わせがSCC VII腫瘍の増殖に及ぼす化学増感効果
マウスを、マウス扁平上皮細胞癌腫であるSCC VII腫瘍細胞を用いて皮下インプラントした。腫瘍が100−150mm3にまで増殖した後に(インプラントの12日後)、腫瘍を有するマウスを、GLYN(100mg/kgまたは300mg/kg)、シスプラチン(CDDP、2または5mg/kg)の1回用量、またはそれらの組み合わせを用いて処置した。腫瘍を、処置の直前、および処置後の1週間当たり3回測定した。
GLYNおよびSGがSCC VII腫瘍増殖に及ぼす放射線増感効果
マウスを、SCC VII腫瘍細胞を用いて皮下インプラントした。腫瘍が100〜150mm3に達した後に、腫瘍を有するマウスを、GLYN(200mg/kg)、ナトリウム グリジシダゾール(SG、400mg/kg)、7Gyの放射線、またはそれらの組み合わせを用いて処置した。腫瘍を、処置の直前、および処置後の1週間当たり3回測定した。
GLYNによる腫瘍細胞中での一酸化窒素(NO)の産生
SCC VII腫瘍細胞を、96−ウェルプレート中、37℃で終夜増殖させた。蛍光プローブDAF−FM二酢酸塩を10μMの濃度で1時間かけて加え、次いでこのものを洗い流した。GLYNを、0.1mM、1mM、または10mMの濃度で該増殖培地中に加えた。該緑色蛍光を、マイクロプレート蛍光光度計(励起光495nmおよび発光515nm)を使用して、GLYNの添加の0分、10分、30分、1時間、2時間、6時間および24時間後に測定した(図4(a)および4(b)を参照)。
GLYNおよび放射線による腫瘍細胞中での一酸化窒素の産生
SCC VII腫瘍細胞を、96ウェルプレート中、37℃で終夜増殖させた。蛍光プローブDAF−FM二酢酸塩を10μMの濃度で1時間かけて加え、次いで洗い流した。GLYNを、0.1mM、1mM、または10mMの濃度で該増殖培地中に加えた。細胞を、2または10Gyの放射線量を用いて直ちに放射した。該緑色蛍光を、マイクロプレート蛍光光度計(励起光495nmおよび発光515nm)を使用して、GLYNの添加の0分、10分、30分、1時間、2時間、6時間、および24時間後に測定した。図5a〜dは、GLYNおよび放射線に曝露後の選んだ時間でのSCC VII細胞中での一酸化窒素の産生を示す。放射線の単独は、SCC VII腫瘍細胞中で低レベルのNOを産生した。GLYNと組み合わせた場合には、NOの細胞内レベルがわずかに増大した。
Claims (18)
- 処置が必要な患者に、治療学的に有効な量のO−ニトロ化合物またはその医薬的に許容し得る塩、水和物、もしくは溶媒和物を投与することを含む、癌を治療または予防するための方法。
- 癌は、乳癌、腎臓癌、脳癌、大腸癌、結腸直腸癌、前立腺癌、肺癌、いずれかの他の固形腫瘍、またはリンパ球造血系悪性腫瘍である、請求項1記載の方法。
- 該O−ニトロ化合物は、構造式R1−O−NO2(式中、R1は、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、シクロへテロアルキル、置換シクロへテロアルキル、へテロアルキル、置換へテロアルキル、縮合シクロアルキル、置換縮合シクロアルキル、置換シクロアルキル、縮合シクロアルキルシクロへテロアルキル、置換縮合シクロアルキルシクロへテロアルキル、キュビル、置換キュビル、アダマンチル、または置換アダマンチルである)を有する、請求項1記載の方法。
- O−ニトロ化合物またはその医薬的に許容し得る塩、水和物もしくは溶媒和物、および医薬的に許容し得るビヒクルを含有する医薬組成物。
- 処置が必要な患者に、治療学的に有効な量のO−ニトロ化合物またはその医薬的に許容し得る塩、水和物もしくは溶媒和物を投与することを含む、還元性の細胞内環境を用いて患者における腫瘍細胞を処置するための方法。
- 処置が必要な患者に、治療学的に有効な量のO−ニトロ化合物またはその医薬的に許容し得る塩、水和物もしくは溶媒和物を投与することを含む、患者における固形腫瘍を治療または予防するための方法。
- 処置が必要な患者に、治療学的に有効な量のO−ニトロ化合物またはその医薬的に許容し得る塩、水和物もしくは溶媒和物を投与することを含む、患者における炎症を治療または予防するための方法。
- 処置が必要な患者に、治療学的に有効な量のO−ニトロ化合物またはその医薬的に許容し得る塩、水和物もしくは溶媒和物を投与することを含む、患者における自己免疫疾患を治療または予防するための方法。
- 処置が必要な患者に、治療学的に有効な量のO−ニトロ化合物またはその医薬的に許容し得る塩、水和物もしくは溶媒和物を投与することを含む、患者における循環器系疾患を治療または予防するための方法。
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2006
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- 2006-08-14 KR KR1020087006017A patent/KR20090023327A/ko not_active Application Discontinuation
- 2006-08-14 EP EP06801465A patent/EP1924143A4/en not_active Withdrawn
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AU2006279678A1 (en) | 2007-02-22 |
US20070135380A1 (en) | 2007-06-14 |
CA2620611C (en) | 2017-01-03 |
US9133150B2 (en) | 2015-09-15 |
IL189438A0 (en) | 2008-08-07 |
EP1924143A2 (en) | 2008-05-28 |
CA2620611A1 (en) | 2007-02-22 |
WO2007022121A2 (en) | 2007-02-22 |
JP5241494B2 (ja) | 2013-07-17 |
AU2006279678B8 (en) | 2012-05-10 |
KR20090023327A (ko) | 2009-03-04 |
US20130309324A1 (en) | 2013-11-21 |
EP2433495A1 (en) | 2012-03-28 |
EP2433495B1 (en) | 2016-10-05 |
WO2007022121A3 (en) | 2007-07-19 |
US20120237615A1 (en) | 2012-09-20 |
US8530681B2 (en) | 2013-09-10 |
MX2008001982A (es) | 2008-09-26 |
AU2006279678B2 (en) | 2012-04-12 |
EP1924143A4 (en) | 2009-05-13 |
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