JP5666443B2 - オキサビシクロヘプタンおよびオキサビシクロヘプテン、その調製並びに使用 - Google Patents
オキサビシクロヘプタンおよびオキサビシクロヘプテン、その調製並びに使用 Download PDFInfo
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- JP5666443B2 JP5666443B2 JP2011521128A JP2011521128A JP5666443B2 JP 5666443 B2 JP5666443 B2 JP 5666443B2 JP 2011521128 A JP2011521128 A JP 2011521128A JP 2011521128 A JP2011521128 A JP 2011521128A JP 5666443 B2 JP5666443 B2 JP 5666443B2
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- Agricultural Chemicals And Associated Chemicals (AREA)
Description
レチノイド、ビタミンAの代謝産物は、神経膠腫を含む種々の腫瘍に対して治療的に試験されている(Yung et al.(1996))。核内受容体コリプレッサー(N−CoR)はレチノイドリセプターと密接に関係があり、リガンドがリセプターに結合する時に離される(Bastien et al. (2004))。プロテインホスファターゼ−1およびプロテインホスファターゼ−2Aの作用を防ぐことにより、抗ホスファターゼはN−CoRのリン酸化形態を高め、およびその続く細胞質移動を促進する(Hermanson et al.(2002))。
またはR3およびR4はそれぞれ異なり、それぞれOHまたは以下である
R7およびR8はそれぞれ独立してH、F、Cl、Br、SO2Ph、CO2CH3またはSR13であって、R13はH、アリールまたは置換若しくは未置換のアルキル、アルケニルまたはアルキニルである
またはこの化合物の塩、エナンチオマー若しくは双性イオンを提供する。
またはR3およびR4はそれぞれ異なり、それぞれOHまたは以下であり
R1およびR2はそれぞれ独立してH、O−またはOR9であって、R9はH、アルキル、置換アルキル、アルケニル、アルキニルまたはアリールである、
またはR1およびR2は=Oとなる;
R3およびR4はそれぞれ異なり、それぞれO(CH2)1−6R9またはOR10、または
R10は置換アルキル、置換アルケニル、置換アルキニル、または置換アリールである、
またはR3およびR4はそれぞれ異なり、それぞれOHまたは以下である
R7およびR8はそれぞれ独立してH、F、Cl、Br、SO2Ph、CO2CH3、またはSR13であって、R13はH、アリールまたは置換若しくは未置換のアルキル、アルケニルまたはアルキニルである
またはこの化合物の塩、エナンチオマー若しくは双性イオンを提供する。
R3はR9またはO(CH2)1−6R10であり
R9はアリールまたは置換エチルであり;
R10は置換フェニルであり、ここで置換基はパラ位に存在し;
R4は以下であり
各R11は独立してH、アルキル、ヒドロキシアルキル、置換C2−C12アルキル、アルケニル、置換C4−C12アルケニル、アルキニル、置換アルキニル、アリール、置換アリールであって置換基はクロロ以外である、
R12はアルキル、アルケニルまたはアルキニルであり、それぞれは置換されるか置換されず、またはHである;
またはR3はOHでありR4は以下である
R1およびR2は=Oとなり;
R3はOR9またはOR10またはO(CH2)1−2R9であって、
R9はアリールまたは置換エチルである;
R10は置換フェニルであって、ここで置換基はパラ位に存在する;
またはR3はOHでありR4は以下であり
R5およびR6は=Oとなり;および
R7およびR8はそれぞれ独立してHである。
R5およびR6は=Oとなり;および
R7およびR8はそれぞれ独立してHである。
各R11は独立してH、アルキル、ヒドロキシアルキル、置換C2−C12アルキル、アルケニル、置換C4−C12アルケニル、アルキニル、置換アルキニル、アリール、置換アリールであってR1およびR2が=Oとなるときは置換基はクロロ以外である、
R10は置換アルキル、置換アルケニル、置換アルキニル、または置換アリールである
またはR3およびR4はそれぞれ異なり、それぞれOHまたは以下であり
カンタリジンはヒトの肝臓癌(ヘパトーム)および上部消化管癌に対しての抗腫瘍活性を有するが、尿路に対して毒性がある(Wang, 1989)。ノルカンタリジン、脱メチル化カンタリジンである、はヘパトーム並びに胃癌および食道癌に対してカンタリジンの抗腫瘍活性を保つが、低い尿路毒性を有するか尿路毒性を有しない。また、ノルカンタリジンは患者およびマウスにおける白血球製造を促進するが,この現象は機構的に理解されていないが,抗癌剤としての薬理効果の潜在的利益を促進する(Wang et al., 1986; Wang, 1989)。
方法および材料
4.3−[4−(2−ヒドロキシエチル)−ピペラジン−1−カルボニル]−7−オキサ−ビシクロ[2.2.1]ヘプタン−2−カルボン酸ベンジルエステル(12,化合物−109):
工程1:7−オキサ−ビシクロ[2.2.1]ヘプタン−2,3−ジカルボン酸モノベンジルエステル(10):
工程1:3−(4−メチルピペラジン−1−カルボニル)−7−オキサ−ビシクロ[2,2,1]ヘプタン−2−カルボニルクロリド(1):
生体内実験
ヒト髄芽腫DAOY細胞をSCIDマウスの脇腹に皮下移植した。移植腫瘍細胞が6mmの平均直径を有する塊に達した7日後に、6匹の動物に0.12mgの化合物110を与え、6匹の動物に0.18gの化合物110を与え、および6匹の動物に添加剤(PBS)のみを与えた。2週間の治療後、すべての動物の治療をやめ、皮下腫瘍塊を切除し、その堆積を算出した。表1に示すように、化合物110の両投与は腫瘍成長の有意な抑制をもたらした。
化合物109の最も高い濃度では、3日後には細胞成長のわずかな抑制がある。より低い濃度では、7日に伸ばすと、化合物109はわずかな促進活性を有する(図2)。非常に低濃度での化合物100シリーズの他の化合物は、培養における細胞について中間から適度な促進活性を有し、これはより高い濃度では失われ、このとき薬剤は投与量に依存して抑制する(図3〜5を参照のこと)。化合物110、112、および113は投与量に依存して細胞成長を抑制した。
本明細書中に記載される化合物はAktを含むいくつかの調製タンパク質のリン酸化を高める。マウスに毒性のない低い投与量においては、これらの化合物は細胞増殖をわずかに促進し、SH−SY5Yを含む、試験したヒト癌細胞株におけるAktのリン酸化を高める。通常マウスに腹腔内に与えた場合には、化合物110、113および114は、本明細書の例において説明したように、試験した細胞株におけるAktリン酸化をも高めた。
の神経細胞内細胞活性を高めることとニューロンのヒストンのアセチル化を高めることに
よるものであろう。それぞれのこれら化合物は、腹腔内注入により与えられる場合には、
マウスニューロンにおけるリン酸化を高める。GSK−3βの高められたリン酸化はその
活性を低下させることが知られているため、本明細書に記載される化合物によるGSK
3βの長期抑制はタウのリン酸化を低下させるであろう。タウのリン酸化の低下は対らせ
ん状フィラメントの形成を、アルツハイマー病、パーキンソン病、筋萎縮性側索硬化症を
含むタウオパチーの進行を失うべき介入、およびタウ分子の異常な沈着により特徴付けられる他のより稀な神経変性疾患を減少させる。
本願発明の実施態様を以下に付記する。
1. 以下の構造を有する化合物
結合αは存在するか存在せず;
R 1 およびR 2 はそれぞれ独立してH、O − またはOR 9
R 9 はH、アルキル、置換アルキル、アルケニル、アルキニルまたはアリールである
またはR 1 およびR 2 は=Oとなり、
R 3 およびR 4 はそれぞれ異なり、それぞれO(CH 2 ) 1−6 R 9 またはOR 10 、ま
たは
各R 11 は独立してH、アルキル、ヒドロキシアルキル、置換C 2 −C 12 アルキル
、アルケニル、置換C 4 −C 12 アルケニル、アルキニル、置換アルキニル、アリール、
置換アリールであってR 1 およびR 2 が=Oの場合の置換基はクロロ以外のもの、
(R 12 ) 2 であって、各R 12 は独立してアルキル、アルケニルまたはアルキニルであ
って、それぞれは置換されるか置換されず、またはHであり、
R 10 は置換アルキル、置換アルケニル、置換アルキニル、または置換アリールである
、
またはR 3 およびR 4 はそれぞれ異なり、それぞれOHまたは
R 5 およびR 6 はそれぞれ独立してH、OH、またはR 5 および 6 は=Oとなり;並びに
R 7 およびR 8 はそれぞれ独立してH、F、Cl、Br、SO 2 Ph、CO 2 CH 3 また
はSR 13 であり、
ここでR 13 はH、アリールまたは置換若しくは未置換のアルキル、アルケニルまたは
アルキニルである
または前記化合物の塩、エナンチオマー若しくは双性イオン。
2. 前記化合物が以下の構造を有する1の化合物。
4. 結合αが存在しない1または2の化合物。
5. R 3 がR 9 またはO(CH 2 ) 1−6 R 10
R 9 はアリールまたは置換エチルであり;
R 10 は置換フェニルであり、ここで置換基はパラ位に存在し;
R 4 は以下であり
各R 11 は独立してH、アルキル、ヒドロキシアルキル、置換C 2 −C 12 アルキル
、アルケニル、置換C 4 −C 12 アルケニル、アルキニル、置換アルキニル、アリール、
置換アリールであって置換基はクロロ以外のもの、
+ (R 12 ) 2 である;
またはR 3 はOHでありR 4 は以下である
6. R 4 が以下である
またはR 4 は以下である
1ないし5のいずかの化合物。
7. R 1 およびR 2 は=Oとなり;
R 3 はOR 9 またはOR 10 またはO(CH 2 )1−2R 9 であって
R 9 はアリールまたは置換エチルである;
R 10 は置換フェニルであって、ここで置換基はパラ位に存在する;
またはR 3 はOHでありR 4 は以下であり
R 5 およびR 6 は=Oとなり;および
R 7 およびR 8 はそれぞれ独立してHである
1ないし6のいずれかの化合物。
8. R 1 およびR 2 は=Oとなり;
R 3 はOH、O(CH 2 )R 9 、またはR 10 であって
R 9 はフェニルである;
R 10 はCH 2 CCl 3 、
R 4 は以下であり
R 5 およびR 6 は=Oとなり;および
R 7 およびR 8 はそれぞれ独立してHである
1ないし7のいずれかの化合物。
9. R 3 はOR 10 であって、R 10 は(CH 2 ) 1−6 (CHNHBOC)CO 2 H、(
CH 2 ) 1−6 (CHNH 2 )CO 2 H、または(CH 2 ) 1−6 CCl 3 である1ないし8のいずれかの化合物。
10. R 10 がCH 2 (CHNHBOC)CO 2 Hである9の化合物。
11. R 10 がCH 2 (CHNH 2 )CO 2 Hである9の化合物。
12. R 10 がCH 2 CCl 3 である9の化合物。
13. R 3 がO(CH 2 ) 1−6 R 9 であって、R 9 がフェニルである1ないし9のいずれかの化合物。
14. R 3 がO(CH 2 )R 9 であって、R 9 がフェニルである1ないし9のいずれか
の化合物。
15. R 3 がOHであり、R 4 が
16. R 4 が以下である1ないし14のいずれかの化合物。
17. R 11 が−CH 2 CH 2 OHである16の化合物、
18. R 4 が以下である1ないし14の化合物。
19. R 11 が−CH 3 である18の化合物。
20. R 4 が以下である1ないし14のいずれかの化合物。
薬学組成物。
24. a)以下の構造の化合物
b)上記構造を有する無水物を少なくとも1種の求核試薬と反応させて以下の構造を有
する化合物を生じる
各R 11 は独立してH、アルキル、ヒドロキシアルキル、置換C 2 −C 12 アルキル
、アルケニル、置換C 4 −C 12 アルケニル、アルキニル、置換アルキニル、アリール、
置換アリールであってR 1 およびR 2 が=Oとなるときは置換基はクロロ以外である、
−CH 2 CN、−CH 2 CO 2 R 12 、−CH 2 COR 12 、−NHR 12 または−NH
+ (R 12 ) 2 であって、ここで各R 12 は独立してアルキル、アルケニル、またはアル
キニルであり、それぞれは置換されるか置換されておらず、またはHである;
R 10 は置換アルキル、置換アルケニル、置換アルキニル、または置換アリールである
またはR 3 およびR 4 はそれぞれ異なり、それぞれOHまたは以下であり
13 であって、ここでR 13 はH、アリールまたは置換若しくは未置換アルキル、アルケ
ニル若しくはアルキニルであることを含む1ないし22のいずれかの化合物の調製方法。
25. 前記求核試薬が少なくとも1つのヒドロキシル基を有する24の方法。
26. 前記求核試薬がO(CH 2 ) 1−6 R 9 またはOR 10 である25の方法。
27. 前記求核試薬が少なくとも1つの遊離アミン基を含む24の方法。
28. 前記求核試薬が以下である27の方法。
30. 望まない植物を制御する方法であって、前記植物またはその周囲を除草的に有効な量の1ないし22のいずれか1の前記化合物と接触させることを含む方法。
31. 植物ホスファターゼ活性を阻害する方法であって、前記植物またはその周囲を除草的に有効な量の1ないし22のいずれか1の前記化合物と接触させることを含む方法。
32. 対象における真菌感染症を予防するまたは治療する方法であって、前記対象に有効量の1ないし22のいずれか1の前記化合物を投与して、前記真菌感染症を治療する
ことを含む方法。
33. 乳癌、結腸癌、大細胞肺癌、肺腺癌、小細胞肺癌、胃癌、肝癌、卵巣腺癌、膵臓癌、前立腺癌、前骨髄球性白血病、慢性骨髄性白血病、または急性リンパ性白血病に苦しむ対象を治療する方法であって、前記対象に治療的に有効な量の1ないし22のいずれか
1の化合物を投与し、前記対象を治療する方法。
34. 神経変性疾患の対象を治療する方法であって、前記対象に有効量の1ないし22
の化合物のいずれかを投与し、前記対象を治療する方法。
35. 細胞内のGSK-3βの量を低減させる方法であって、前記細胞を有効量の1ないし22の化合物のいずれかと接触させることを含み前記細胞内のGSK-3βの量を低減させる方法。
36. 細胞内のリン酸化Aktの量を増加させる方法であって、神経系細胞を有効量の1ないし22の前記化合物のいずれかを接触させることを含み、細胞内のリン酸化Akt
の量を増加させる方法。
37.細胞内のTauのリン酸化を低下させる方法であって、前記細胞を有効量の1ない
し22の前記化合物のいずれかと接触させることを含み、前記細胞内のTauのリン酸化
を低下させる方法。
38. 細胞内のTauの凝集を低下させる方法であって、前記細胞を有効量の1ないし
22の前記化合物のいずれかと接触させることを含み、前記細胞内のTauのリン酸化を
低下させる方法。
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Claims (24)
- 以下の構造を有する化合物であって、
結合αは存在するか存在せず;
R1およびR2は=Oとなり、
R3は、O(CH2)1−6R9またはOR10であり、
ここで、R9は、置換C1−C12アルキルまたはアリールであり、
ここで、R10は、置換C1−C12アルキル、置換アリール、(CH2)1−6(CHNHBOC)CO2H、(CH2)1−6(CHNH2)CO2H、(CH2)1−6CCl3、
R4は、
ここでXは、NR11またはN+R11R11であり、
各R11は独立してH、C1−C12アルキル、ヒドロキシアルキルまたは置換C2−C12アルキルであり、
またはR3およびR4はそれぞれ異なり、それぞれOHまたは
R5およびR6は=Oとなり;並びに
R7およびR8はそれぞれ独立してHである化合物または前記化合物の塩、エナンチオマー若しくは双性イオン。 - 結合αが存在する請求項1ないし3のいずれか1項記載の化合物。
- 結合αが存在しない請求項1ないし3のいずれか1項記載の化合物。
- R3がO(CH2)1−6R9またはOR10であり;
R9はアリールまたは置換エチルであり;
R10は置換フェニルである請求項1記載の化合物。 - R3はOR10であって、R10は(CH2)1−6(CHNHBOC)CO2H、(CH2)1−6(CHNH2)CO2H、または(CH2)1−6CCl3である請求項1記載の化合物。
- R10がCH2(CHNHBOC)CO2Hである請求項11記載の化合物。
- R10がCH2(CHNH2)CO2Hである請求項11記載の化合物。
- R10がCH2CCl3である請求項11記載の化合物。
- R3がO(CH2)1−6R9であって、R9がフェニルである請求項1または4ないし6いずれか1項記載の化合物。
- R3がO(CH2)R9であって、R9がフェニルである請求項15記載の化合物。
- R11が−CH2CH2OHである請求項17記載の化合物、
- R11が−CH3である請求項19記載の化合物。
- 請求項1ないし22のいずれか1項記載の化合物および薬学的に許容できるキャリアを含む薬学組成物。
- 乳癌、結腸癌、大細胞肺癌、肺腺癌、小細胞肺癌、胃癌、肝癌、卵巣腺癌、膵臓癌、前立腺癌、前骨髄球性白血病、慢性骨髄性白血病、または急性リンパ性白血病を治療するための請求項1ないし22のいずれか1項記載の化合物を含む医薬組成物。
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JP2015044816A (ja) * | 2008-08-01 | 2015-03-12 | リクスト・バイオテクノロジー,インコーポレイテッド | オキサビシクロヘプタンおよびオキサビシクロヘプテン、その調製並びに使用 |
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US20120264764A1 (en) | 2012-10-18 |
US20100029484A1 (en) | 2010-02-04 |
WO2010014254A1 (en) | 2010-02-04 |
JP2011529883A (ja) | 2011-12-15 |
EA022311B1 (ru) | 2015-12-30 |
AU2009277031A1 (en) | 2010-02-04 |
CA2730489A1 (en) | 2010-02-04 |
US8541458B2 (en) | 2013-09-24 |
EA201170288A1 (ru) | 2011-12-30 |
CA2730489C (en) | 2017-11-28 |
EP2307344B1 (en) | 2015-07-29 |
MX2011001007A (es) | 2011-03-25 |
HK1151791A1 (en) | 2012-02-10 |
AU2009277031B2 (en) | 2015-01-29 |
EP2307344A1 (en) | 2011-04-13 |
JP2015044816A (ja) | 2015-03-12 |
CN102333752A (zh) | 2012-01-25 |
EP2307344A4 (en) | 2012-05-02 |
BRPI0911717A2 (pt) | 2019-09-24 |
US8227473B2 (en) | 2012-07-24 |
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