JP5606738B2 - 解離可能な連結を有する第ix因子部分−ポリマー共役体 - Google Patents
解離可能な連結を有する第ix因子部分−ポリマー共役体 Download PDFInfo
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- JP5606738B2 JP5606738B2 JP2009544104A JP2009544104A JP5606738B2 JP 5606738 B2 JP5606738 B2 JP 5606738B2 JP 2009544104 A JP2009544104 A JP 2009544104A JP 2009544104 A JP2009544104 A JP 2009544104A JP 5606738 B2 JP5606738 B2 JP 5606738B2
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Description
本出願は、2006年12月27日に出願された米国暫定特許出願第60/877,589号に対する優先権の利益を主張するものであり、参照することによりその全体が本願明細書に組み込まれる。
POLY1は、第1の水溶性ポリマーであり、
POLY2は、第2の水溶性ポリマーであり、
X1は、第1のスペーサ部分であり、
X2は、第2のスペーサ部分であり、
Hαは、イオン化水素原子であり、
R1は、Hまたは有機ラジカルであり、
R2は、Hまたは有機ラジカルであり、
(a)は、ゼロまたは1のいずれかであり、
(b)は、ゼロまたは1のいずれかであり、
Relは、存在する場合、第1の電子変化基であり、
Re2は、存在する場合、第2の電子変化基であり、
Y1は、OまたはSであり、
Y2は、OまたはSであり、
F9は、アミン含有の第IX因子部分の残基である。
例えば、本発明は、以下の項目を提供する。
(項目1)
以下の構造を有する化合物であって、
式中、
POLY 1 は、第1の水溶性ポリマーであり、
POLY 2 は、第2の水溶性ポリマーであり、
X 1 は、第1のスペーサ部分であり、
X 2 は、第2のスペーサ部分であり、
H α は、イオン化可能な水素原子であり、
R 1 は、Hまたは有機ラジカルであり、
R 2 は、Hまたは有機ラジカルであり、
(a)は、ゼロまたは1のいずれかであり、
(b)は、ゼロまたは1のいずれかであり、
R e1 は、存在する場合、第1の電子変化基であり、
R e2 は、存在する場合、第2の電子変化基であり、
Y 1 は、OまたはSであり、
Y 2 は、OまたはSであり、
(F9)は、アミン含有の第IX因子部分の残基である、である、化合物。
(項目2)
前記アミン含有の第IX因子部分は、組換え第IX因子である、項目1に記載の化合物。
(項目3)
前記組換え第IX因子は、ヒト組換え第IX因子である、項目2に記載の化合物。
(項目4)
前記第1の水溶性ポリマーは、ポリ(アルキレンオキシド)であり、前記第2の水溶性ポリマーは、ポリ(アルキレンオキシド)である、項目1に記載の化合物。
(項目5)
前記第1の水溶性ポリマーは、10,000ダルトンから85,000ダルトンの重量平均分子量を有し、前記第2の水溶性ポリマーは、10,000ダルトンから85,000ダルトンの重量平均分子量を有する、項目1に記載の化合物。
(項目6)
以下から成る群から選択される構造を有し、
各構造に対して、および各場合において、(n)は、独立して4から1500の整数であり、(F9)は、アミン含有の第IX因子部分の残基である、項目1に記載の化合物。
(項目7)
以下の構造を有し、
式中、(F9)は、アミン含有の第IX因子部分の残基であり、(n)は、各場合において、独立して4から1500である、項目1に記載の化合物。
(項目8)
以下の構造を有し、
式中、(F9)は、アミン含有の第IX因子部分の残基であり、(n)は、各場合において、独立して4から1500である、項目1に記載の化合物。
(項目9)
前記第IX因子部分は、ヒト組換え第IX因子である、項目7および項目8のうちの1項に記載の化合物。
(項目10)
ポリマー試薬をアミン含有の第IX因子部分に接触させるステップを含む方法であって、前記ポリマー試薬と前記生物活性薬剤との間の共有結合を形成するのに適切な条件下で行なわれ、前記ポリマー試薬は以下の構造を有し、
式中、
POLY 1 は、第1の水溶性ポリマーであり、
POLY 2 は、第2の水溶性ポリマーであり、
X 1 は、第1のスペーサ部分であり、
X 2 は、第2のスペーサ部分であり、
H α は、イオン化可能な水素原子であり、
R 1 は、Hまたは有機ラジカルであり、
R 2 は、Hまたは有機ラジカルであり、
(a)は、ゼロまたは1のいずれかであり、
(b)は、ゼロまたは1のいずれかであり、
R e1 は、存在する場合、第1の電子変化基であり、
R e2 は、存在する場合、第2の電子変化基であり、
(FG)は、活性薬剤のアミノ基と反応して、解離可能な連結を形成することが可能な官能基である、方法。
(項目11)
前記解離可能な連結は、カルバミン酸連結である、項目10に記載の方法。
(項目12)
前記ポリマー試薬は、以下から成る群から選択される構造を有し、
各構造に対して、および各場合において、(n)は、独立して4から1500の整数である、項目10に記載の方法。
(項目13)
第IX因子部分は、ヒト組換え第IX因子である、項目12に記載の方法。
(項目14)
項目1から9のいずれか一項に記載の化合物と、医薬的に許容される賦形剤とを含有する、組成物。
(項目15)
項目14に記載の組成物を、患者に投与するステップを含む、方法。
HO−CH2CH2O−(CH2CH2O)m’−CH2CH2−OH
式中、(m’)は、典型的にはゼロから約4,000、好ましくは約20から約1,000の範囲である。
−CH2CH2O−(CH2CH2O)m’−CH2CH2−
式中、(m’)は上記で定義される通りである。
CH3O−CH2CH2O−(CH2CH2O)m’−CH2CH2−
式中、(m’)は上述の通りである。
例えば、PEGは、構造
polyaおよびpolybは、(同一または異なる)メトキシポリ(エチレングリコール)等のPEG骨格であり、
R”は、H、メチル、またはPEG骨格等の非反応部分であり、
PおよびQは、非反応連結である。好ましい実施形態において、分岐PEGポリマーは、メトキシポリ(エチレングリコール)2置換リジンである。
−PEG−CO2−PEG−+H2O→−PEG−CO2H+HO−PEG−。
POLY1は、第1の水溶性ポリマーであり、
POLY2は、第2の水溶性ポリマーであり、
X1は、第1のスペーサ部分であり、
X2は、第2のスペーサ部分であり、
Hαは、イオン化水素原子であり、
R1は、Hまたは有機ラジカルであり、
R2は、Hまたは有機ラジカルであり、
(a)は、ゼロまたは1のいずれかであり、
(b)は、ゼロまたは1のいずれかであり、
Relは、存在する場合、第1の電子変化基であり、
Re2は、存在する場合、第2の電子変化基であり、
(FG)は、活性薬剤のアミノ基と反応して、カルバミン酸連結等の解離可能な連結を形成することのできる官能基である。
POLY1は、第1の水溶性ポリマーであり、
POLY2は、第2の水溶性ポリマーであり、
X1は、第1のスペーサ部分であり、
X2は、第2のスペーサ部分であり、
Hαは、イオン化水素原子であり、
R1は、Hまたは有機ラジカルであり、
R2は、Hまたは有機ラジカルであり、
(a)は、ゼロまたは1のいずれかであり、
(b)は、ゼロまたは1のいずれかであり、
Relは、存在する場合、第1の電子変化基であり、
Re2は、存在する場合、第2の電子変化基であり、
Y1は、OまたはSであり、
Y2は、OまたはSであり、
F9は、アミン含有の第IX因子部分の残基である。
本発明の実施は、特に明記しない限り、有機合成等の従来の技術を採用し、これは、当業者によって理解され、文献に説明されている。以下の実施例において、使用される数字(例えば、量、温度等)に関しては正確性を確保する努力がなされたが、ある程度の実験誤差および偏差を考慮すべきである。特に明記しない限り、温度は摂氏であり、圧力は、海面での大気圧またはその付近である。全ての試薬は、特に明記しない限り、商業的に取得した。全ての産生されたNMRは、Bruker(Billerica,MA)によって製造された300または400MHz NMR分光計から取得した。全ての処理は、ガラスまたはガラス裏打ち容器内で行い、金属含有容器または機器との接触を避ける。
SDS−PAGE ドデシル硫酸ナトリウムポリアクリルアミドゲル電気泳動
以下の実施例で使用される第IX因子は、組換え第IX因子のBENEFIX(登録商標)ブランド(Wyeth,Madison NJ)で販売される市販の調製物から単離される。単離されたタンパク質溶液は、低温で保存される。
実施例2
第IX因子共役体の調製
(20.000ダルトン総ポリマー重量平均分子量)
(「長解離」)
実施例3
薬物動態
(対照として第IX因子に加えて)それぞれ20,000ダルトンの総ポリマー重量平均分子量を有する、実施例1および2に従って調製された共役体の薬物動態を、従来の技術を使用して決定した。簡潔に述べると、雄のSDラットを使用し(180〜220グラム、6〜7週齢)、100μLの静脈注射を一回投与した。1群につき4匹の動物を使用し、注射後様々な時点(例えば0、1、2、3、6、12、24、36、48、72時間)で、血漿を収集した。
表1
共役体薬物動態値
Claims (14)
- 以下の構造を有する化合物であって、
POLY1は、第1の水溶性ポリマーであり、
POLY2は、第2の水溶性ポリマーであり、
X1は、第1のスペーサ部分であり、
X2は、第2のスペーサ部分であり、
Hαは、イオン化可能な水素原子であり、
R1は、Hまたは有機ラジカルであり、
R2は、Hまたは有機ラジカルであり、
(a)は、ゼロまたは1のいずれかであり、
(b)は、ゼロまたは1のいずれかであり、
Re1は、存在する場合、第1の電子変化基であり、
Re2は、存在する場合、第2の電子変化基であり、
Y1は、OまたはSであり、
Y2は、OまたはSであり、
(F9)は、アミン含有の第IX因子部分の残基であり、
該アミン含有の第IX因子部分は、組換え第IX因子である、
化合物。 - 前記組換え第IX因子は、ヒト組換え第IX因子である、請求項1に記載の化合物。
- 前記第1の水溶性ポリマーは、ポリ(アルキレンオキシド)であり、前記第2の水溶性ポリマーは、ポリ(アルキレンオキシド)である、請求項1に記載の化合物。
- 前記第1の水溶性ポリマーは、10,000ダルトンから85,000ダルトンの重量平均分子量を有し、前記第2の水溶性ポリマーは、10,000ダルトンから85,000ダルトンの重量平均分子量を有する、請求項1に記載の化合物。
- 前記第IX因子部分は、ヒト組換え第IX因子である、請求項6および請求項7のうちの1項に記載の化合物。
- ポリマー試薬をアミン含有の第IX因子部分に共有結合させるための方法であって、該ポリマー試薬を該アミン含有の第IX因子部分に接触させるステップを含み、該ポリマー試薬と該アミン含有の第IX因子部分との間の共有結合を形成するのに適切な条件下で行なわれ、該ポリマー試薬は以下の構造を有し、
POLY1は、第1の水溶性ポリマーであり、
POLY2は、第2の水溶性ポリマーであり、
X1は、第1のスペーサ部分であり、
X2は、第2のスペーサ部分であり、
Hαは、イオン化可能な水素原子であり、
R1は、Hまたは有機ラジカルであり、
R2は、Hまたは有機ラジカルであり、
(a)は、ゼロまたは1のいずれかであり、
(b)は、ゼロまたは1のいずれかであり、
Re1は、存在する場合、第1の電子変化基であり、
Re2は、存在する場合、第2の電子変化基であり、
(FG)は、アミン含有の第IX因子部分のアミノ基と反応して、解離可能な連結を形成することが可能な官能基であり、
該アミン含有の第IX因子部分は、組換え第IX因子である、
方法。 - 前記解離可能な連結は、カルバミン酸連結である、請求項9に記載の方法。
- 第IX因子部分は、ヒト組換え第IX因子である、請求項11に記載の方法。
- 請求項1から8のいずれか一項に記載の化合物と、医薬的に許容される賦形剤とを含有する、組成物。
- 出血性疾患を処置するための請求項13に記載の組成物。
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US60/877,589 | 2006-12-27 | ||
PCT/US2007/026425 WO2008082613A2 (en) | 2006-12-27 | 2007-12-27 | Factor ix moiety-polymer conjugates having a releasable linkage |
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BRPI0720619A2 (pt) | 2014-03-25 |
WO2008082613A3 (en) | 2009-04-09 |
US8507653B2 (en) | 2013-08-13 |
WO2008082613A2 (en) | 2008-07-10 |
US20080188414A1 (en) | 2008-08-07 |
JP2010514770A (ja) | 2010-05-06 |
CN101588819B (zh) | 2012-11-21 |
EP2097108B1 (en) | 2014-02-12 |
BRPI0720619B1 (pt) | 2022-04-05 |
CN101588819A (zh) | 2009-11-25 |
AU2007339238B2 (en) | 2013-06-20 |
EP2097108A2 (en) | 2009-09-09 |
CA2672021A1 (en) | 2008-07-10 |
CA2672021C (en) | 2014-02-11 |
NO342748B1 (no) | 2018-08-06 |
WO2008082613A9 (en) | 2008-08-21 |
MX2009007146A (es) | 2009-07-09 |
NO20092186L (no) | 2009-08-06 |
KR20090102785A (ko) | 2009-09-30 |
KR101442867B1 (ko) | 2014-09-25 |
AU2007339238A1 (en) | 2008-07-10 |
NZ577397A (en) | 2012-01-12 |
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