JP2009149903A - 化学的に異なる末端基を含むポリ(エチレングリコール) - Google Patents
化学的に異なる末端基を含むポリ(エチレングリコール) Download PDFInfo
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- JP2009149903A JP2009149903A JP2009036621A JP2009036621A JP2009149903A JP 2009149903 A JP2009149903 A JP 2009149903A JP 2009036621 A JP2009036621 A JP 2009036621A JP 2009036621 A JP2009036621 A JP 2009036621A JP 2009149903 A JP2009149903 A JP 2009149903A
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- aliphatic
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- nhc
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- ring
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
- C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
- C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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Abstract
【解決手段】本発明は、二官能PEG、その中間体および調製方法を提供する。このような官能基化PEGは、医薬分野および生物医学分野での種々の目的に有用である。このような使用としては、他の分子または基材をPEG化するプロセスで本発明の二官能PEGを使用することが挙げられる。したがって、本発明の別の実施形態は、本発明の化合物との分子接合体または基材接合体を提供する。
【選択図】なし
Description
この出願は、2006年4月27日に出願された米国仮特許出願第60/795,412号(この全体は、参考として本明細書に援用される)への優先権を主張する。
本発明は、ポリマー化学の分野に関し、より特定的には、官能基化ポリマー、その使用およびその中間体に関する。
特定の実施形態では、本発明は、式Iの化合物またはその塩を提供する:
nは10〜2500であり;
R1およびR2は、それぞれ独立して、水素、ハロゲン、NO2、CN、N3、−N=C=O、−C(R)=NN(R)2、−P(O)(OR)2、−P(O)(X)2、9〜30員のクラウンエーテルであるか、または脂肪族、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する3〜8員の飽和環、部分的に不飽和な環またはアリール環、窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する8〜10員の飽和二環、部分的に不飽和な二環またはアリール二環から選択される、任意に置換された基であるか、または検出可能な部分であり;
Xはそれぞれ独立してハロゲンであり;
Rはそれぞれ独立して、水素であるか、または脂肪族、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する3〜8員の飽和環、部分的に不飽和な環またはアリール環から選択される任意に置換された基であり;
L1およびL2は、それぞれ独立して、原子価結合であるか、または二価の飽和または不飽和の直鎖または分枝鎖のC1〜12炭化水素鎖であり、L1およびL2の0〜6個のメチレン単位は、独立して、−Cy−、−O−、−NR−、−S−、−OC(O)−、−C(O)O−、−C(O)−、−SO−、−SO2−、−NRSO2−、−SO2NR−、−NRC(O)−、−C(O)NR−、−OC(O)NR−または−NRC(O)O−で置き換えられており、ここで、
−Cy−はそれぞれ独立して、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する、任意に置換された3〜8員の二価の飽和環、部分的に不飽和な環またはアリール環であるか、または窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する、任意に置換された8〜10員の二価の飽和二環、部分的に不飽和な二環またはアリール二環である。
本発明は、例えば、以下を提供する:
(項目1)
式Iの化合物またはその塩:
〔式中、
nは10〜2500であり;
R1は、水素、ハロゲン、NO2、CN、N3、−N=C=O、−C(R)=NN(R)2、−P(O)(OR)2、−P(O)(X)2、9〜30員のクラウンエーテルまたは検出可能な部分であり;
Xはそれぞれ独立してハロゲンであり;
Rはそれぞれ独立して、水素であるか、または任意に置換された脂肪族基であり;
L1およびL2は、それぞれ独立して、原子価結合であるか、または二価の飽和または不飽和の直鎖または分枝鎖のC1〜12アルキレン鎖であり、ここでL1およびL2の0〜6個のメチレン単位は、独立して、−Cy−、−O−、−NR−、−S−、−OC(O)−、−C(O)O−、−C(O)−、−SO−、−SO2−、−NRSO2−、−SO2NR−、−NRC(O)−、−C(O)NR−、−OC(O)NR−または−NRC(O)O−で置き換えられており、ここで、
−Cy−はそれぞれ独立して、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する、任意に置換された3〜8員の二価の飽和環、部分的に不飽和な環またはアリール環であるか、または窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する、任意に置換された8〜10員の二価の飽和二環、部分的に不飽和な二環またはアリール二環であり;
R2は、t−ブチル、5−ノルボルネン−2−イル、オクタン−5−イル、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、N3であるか、フェニル、ピリジル、ナフチル、ピレニル、トリアゾリル、イミダゾリル、フタルイミド、テトラゾリル、フラニルまたはピラニルから選択される任意に置換された環、エポキシド環、クラウンエーテル、検出可能な部分、−P(O)(OR)2または−P(O)(X)2である〕。
(項目2)
R1は、水素、ハロゲン、NO2、CN、N3、−N=C=O、−CH=NN(R)2、−P(O)(OH)2、−P(O)(Cl)2、9〜30員のクラウンエーテルまたは検出可能な部分であり;
L1およびL2は、独立して、−O−、−S−、−NH−、−C(O)O−、−Cy−、−C(O)−、−C(O)NH−、−NHC(O)−、−NH−O−、−O−Cy−CH2NH−O−、−OCH2−、−OCH2C(O)−、−OCH2CH2C(O)−、−OCH2CH2O−、−OCH2CH2S−、−OCH2CH2C(O)O−、−OCH2CH2NH−、−OCH2CH2NHC(O)−、−OCH2CH2C(O)NH−、−NHC(O)CH2CH2C(O)O−、−OCH2CH2NHC(O)CH2CH2C(O)O−、−OCH2CH2NHC(O)CH2OCH2C(O)O−、−OCH2CH2NHC(O)CH2OCH2C(O)NH−、−CH2C(O)NH−、−CH2C(O)NHNH−または−OCH2CH2NHNH−であり;
R2は、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、N3、エポキシド環、クラウンエーテル、検出可能な部分、−P(O)(OH)2または−P(O)(Cl)2であるか、またはCN、N3、NO2、−CH3、−CH2N3、t−ブチル、5−ノルボルネン−2−イル、オクタン−5−イル、−CH=CH2、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、Cl、Br、I、F、−NH2、−OH、−SH、−CO2H、−C(O)H、−CH2NH2、−CH2OH、−CH2SH、−CH2CO2H、−CH2C(O)H、−C(O)(C1〜6脂肪族)、−NHC(O)(C1〜6脂肪族)、−NHC(O)NH−、−NHC(O)NH(C1〜6脂肪族)、−NHC(S)NH−、−NHC(S)N(C1〜6脂肪族)2、−NHC(O)O(C1〜6脂肪族)、−NHNH2、−NHNHC(O)(C1〜6脂肪族)、−NHNHC(O)NH2、−NHNHC(O)NH(C1〜6脂肪族)、−NHNHC(O)O(C1〜6脂肪族)、−C(O)NH2、−C(O)NH(C1〜6脂肪族)2、−C(O)NHNH2、−C(S)N(C1〜6脂肪族)2、−OC(O)NH(C1〜6脂肪族)、−C(O)C(O)(C1〜6脂肪族)、−C(O)CH2C(O)(C1〜6脂肪族)、−S(O)2(C1〜6脂肪族)、−S(O)2O(C1〜6脂肪族)、−OS(O)2(C1〜6脂肪族)、−S(O)2NH(C1〜6脂肪族)、−S(O)(C1〜6脂肪族)、−NHS(O)2NH(C1〜6脂肪族)、−NHS(O)2(C1〜6脂肪族)、−P(O)2(C1〜6脂肪族)、−P(O)(C1〜6脂肪族)2、−OP(O)(C1〜6脂肪族)2または−OP(O)(OC1〜6脂肪族)2で任意に置換されたフェニル環、ピリジル環、ナフチル環、ピレニル環、トリアゾリル環、イミダゾリル環、フタルイミド環、テトラゾリル環、フラニル環またはピラニル環である、項目1に記載の化合物。
(項目3)
R2が、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、N3、エポキシド環、クラウンエーテル、検出可能な部分、−P(O)(OH)2、−P(O)(Cl)2であるか、またはCN、N3、NO2、−CH3、−CH2N3、t−ブチル、5−ノルボルネン−2−イル、オクタン−5−イル、−CH=CH2、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、Cl、Br、I、F、−NH2、−OH、−SH、−CO2H、−C(O)H、−CH2NH2、−CH2OH、−CH2SH、−CH2CO2H、−CH2C(O)H、−C(O)(C1〜6脂肪族)、−NHC(O)(C1〜6脂肪族)、−NHC(O)NH−、−NHC(O)NH(C1〜6脂肪族)、−NHC(S)NH−、−NHC(S)N(C1〜6脂肪族)2、−NHC(O)O(C1〜6脂肪族)、−NHNH2、−NHNHC(O)(C1〜6脂肪族)、−NHNHC(O)NH2、−NHNHC(O)NH(C1〜6脂肪族)、−NHNHC(O)O(C1〜6脂肪族)、−C(O)NH2、−C(O)NH(C1〜6脂肪族)2、−C(O)NHNH2、−C(S)N(C1〜6脂肪族)2、−OC(O)NH(C1〜6脂肪族)、−C(O)C(O)(C1〜6脂肪族)、−C(O)CH2C(O)(C1〜6脂肪族)、−S(O)2(C1〜6脂肪族)、−S(O)2O(C1〜6脂肪族)、−OS(O)2(C1〜6脂肪族)、−S(O)2NH(C1〜6脂肪族)、−S(O)(C1〜6脂肪族)、−NHS(O)2NH(C1〜6脂肪族)、−NHS(O)2(C1〜6脂肪族)、−P(O)2(C1〜6脂肪族)、−P(O)(C1〜6脂肪族)2、−OP(O)(C1〜6脂肪族)2または−OP(O)(OC1〜6脂肪族)2で任意に置換されたフェニル環である、項目2に記載の化合物。
(項目4)
R1またはR2のいずれかが、
から選択される検出可能な基である、項目2に記載の化合物。
(項目5)
式Iの化合物またはその塩:
〔式中、
nは10〜2500であり;
R1は、Cl、Br、I、F、−NH2、−OH、−SH、−CO2H、−C(O)H、−C(O)(C1〜6脂肪族)、−NHC(O)(C1〜6脂肪族)、−NHC(O)NH2、−NHC(O)NH(C1〜6脂肪族)、−NHC(S)NH−、−NHC(S)N(C1〜6脂肪族)2、−NHC(O)O(C1〜6脂肪族)、−NHNH2、−NHNHC(O)(C1〜6脂肪族)、−NHNHC(O)NH2、−NHNHC(O)NH(C1〜6脂肪族)、−NHNHC(O)O(C1〜6脂肪族)、−C(O)NH2、−C(O)NH(C1〜6脂肪族)2、−C(O)NHNH2、−C(S)N(C1〜6脂肪族)2、−OC(O)NH(C1〜6脂肪族)、−C(O)C(O)(C1〜6脂肪族)、−C(O)CH2C(O)(C1〜6脂肪族)、−S(O)2(C1〜6脂肪族)、−S(O)2O(C1〜6脂肪族)、−OS(O)2(C1〜6脂肪族)、−S(O)2NH(C1〜6脂肪族)、−S(O)(C1〜6脂肪族)、−NHS(O)2NH(C1〜6脂肪族)、−NHS(O)2(C1〜6脂肪族)、−P(O)2(C1〜6脂肪族)、−P(O)(C1〜6脂肪族)2、−OP(O)(C1〜6脂肪族)2または−OP(O)(OC1〜6脂肪族)2から独立して選択される1個以上の置換基で任意に置換された脂肪族基であり;
L1およびL2は、それぞれ独立して、原子価結合であるか、または二価の飽和または不飽和の直鎖または分枝鎖のC1〜12アルキレン鎖であり、L1およびL2の0〜6個のメチレン単位は、独立して、−Cy−、−O−、−NR−、−S−、−OC(O)−、−C(O)O−、−C(O)−、−SO−、−SO2−、−NRSO2−、−SO2NR−、−NRC(O)−、−C(O)NR−、−OC(O)NR−または−NRC(O)O−で置き換えられており、ここで、
−Cy−はそれぞれ独立して、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する、任意に置換された3〜8員の二価の飽和環、部分的に不飽和な環またはアリール環であるか、または窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する、任意に置換された8〜10員の二価の飽和二環、部分的に不飽和な二環またはアリール二環であり;
R2は、t−ブチル、5−ノルボルネン−2−イル、オクタン−5−イル、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、N3であるか、フェニル、ピリジル、ナフチル、ピレニル、トリアゾリル、イミダゾリル、フタルイミド、テトラゾリル、フラニルまたはピラニルから選択される任意に置換された環、エポキシド環、クラウンエーテル、検出可能な部分、−P(O)(OR)2または−P(O)(X)2であり;
Xはそれぞれ独立してハロゲンであり;
Rはそれぞれ独立して、水素であるか、または任意に置換された脂肪族基である〕。
(項目6)
L1およびL2が、独立して、−O−、−S−、−NH−、−C(O)O−、−Cy−、−C(O)−、−C(O)NH−、−NHC(O)−、−NH−O−、−O−Cy−CH2NH−O−、−OCH2−、−OCH2C(O)−、−OCH2CH2C(O)−、−OCH2CH2O−、−OCH2CH2S−、−OCH2CH2C(O)O−、−OCH2CH2NH−、−OCH2CH2NHC(O)−、−OCH2CH2C(O)NH−、−NHC(O)CH2CH2C(O)O−、−OCH2CH2NHC(O)CH2CH2C(O)O−、−OCH2CH2NHC(O)CH2OCH2C(O)O−、−OCH2CH2NHC(O)CH2OCH2C(O)NH−、−CH2C(O)NH−、−CH2C(O)NHNH−または−OCH2CH2NHNH−であり;
R2は、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、N3、エポキシド環、クラウンエーテル、検出可能な部分、−P(O)(OH)2または−P(O)(Cl)2であるか、またはCN、N3、NO2、−CH3、−CH2N3、t−ブチル、5−ノルボルネン−2−イル、オクタン−5−イル、−CH=CH2、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、Cl、Br、I、F、−NH2、−OH、−SH、−CO2H、−C(O)H、−CH2NH2、−CH2OH、−CH2SH、−CH2CO2H、−CH2C(O)H、−C(O)(C1〜6脂肪族)、−NHC(O)(C1〜6脂肪族)、−NHC(O)NH−、−NHC(O)NH(C1〜6脂肪族)、−NHC(S)NH−、−NHC(S)N(C1〜6脂肪族)2、−NHC(O)O(C1〜6脂肪族)、−NHNH2、−NHNHC(O)(C1〜6脂肪族)、−NHNHC(O)NH2、−NHNHC(O)NH(C1〜6脂肪族)、−NHNHC(O)O(C1〜6脂肪族)、−C(O)NH2、−C(O)NH(C1〜6脂肪族)2、−C(O)NHNH2、−C(S)N(C1〜6脂肪族)2、−OC(O)NH(C1〜6脂肪族)、−C(O)C(O)(C1〜6脂肪族)、−C(O)CH2C(O)(C1〜6脂肪族)、−S(O)2(C1〜6脂肪族)、−S(O)2O(C1〜6脂肪族)、−OS(O)2(C1〜6脂肪族)、−S(O)2NH(C1〜6脂肪族)、−S(O)(C1〜6脂肪族)、−NHS(O)2NH(C1〜6脂肪族)、−NHS(O)2(C1〜6脂肪族)、−P(O)2(C1〜6脂肪族)、−P(O)(C1〜6脂肪族)2、−OP(O)(C1〜6脂肪族)2または−OP(O)(OC1〜6脂肪族)2で任意に置換されたフェニル環、ピリジル環、ナフチル環、ピレニル環、トリアゾリル環、イミダゾリル環、フタルイミド環、テトラゾリル環、フラニル環またはピラニル環である、項目5に記載の化合物。
(項目7)
R2が、
から選択される検出可能な部分である、項目6に記載の化合物。
(項目8)
R2が、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、N3、エポキシド環、クラウンエーテル、検出可能な部分、−P(O)(OH)2、−P(O)(Cl)2であるか、またはCN、N3、NO2、−CH3、−CH2N3、t−ブチル、5−ノルボルネン−2−イル、オクタン−5−イル、−CH=CH2、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、Cl、Br、I、F、−NH2、−OH、−SH、−CO2H、−C(O)H、−CH2NH2、−CH2OH、−CH2SH、−CH2CO2H、−CH2C(O)H、−C(O)(C1〜6脂肪族)、−NHC(O)(C1〜6脂肪族)、−NHC(O)NH−、−NHC(O)NH(C1〜6脂肪族)、−NHC(S)NH−、−NHC(S)N(C1〜6脂肪族)2、−NHC(O)O(C1〜6脂肪族)、−NHNH2、−NHNHC(O)(C1〜6脂肪族)、−NHNHC(O)NH2、−NHNHC(O)NH(C1〜6脂肪族)、−NHNHC(O)O(C1〜6脂肪族)、−C(O)NH2、−C(O)NH(C1〜6脂肪族)2、−C(O)NHNH2、−C(S)N(C1〜6脂肪族)2、−OC(O)NH(C1〜6脂肪族)、−C(O)C(O)(C1〜6脂肪族)、−C(O)CH2C(O)(C1〜6脂肪族)、−S(O)2(C1〜6脂肪族)、−S(O)2O(C1〜6脂肪族)、−OS(O)2(C1〜6脂肪族)、−S(O)2NH(C1〜6脂肪族)、−S(O)(C1〜6脂肪族)、−NHS(O)2NH(C1〜6脂肪族)、−NHS(O)2(C1〜6脂肪族)、−P(O)2(C1〜6脂肪族)、−P(O)(C1〜6脂肪族)2、−OP(O)(C1〜6脂肪族)2または−OP(O)(OC1〜6脂肪族)2で任意に置換されたフェニル環である、項目5に記載の化合物。
(項目9)
L1およびL2が、独立して、−O−、−S−、−NH−、−C(O)O−、−Cy−、−C(O)−、−C(O)NH−、−NHC(O)−、−NH−O−、−O−Cy−CH2NH−O−、−OCH2−、−OCH2C(O)−、−OCH2CH2C(O)−、−OCH2CH2O−、−OCH2CH2S−、−OCH2CH2C(O)O−、−OCH2CH2NH−、−OCH2CH2NHC(O)−、−OCH2CH2C(O)NH−、−NHC(O)CH2CH2C(O)O−、−OCH2CH2NHC(O)CH2CH2C(O)O−、−OCH2CH2NHC(O)CH2OCH2C(O)O−、−OCH2CH2NHC(O)CH2OCH2C(O)NH−、−CH2C(O)NH−、−CH2C(O)NHNH−または−OCH2CH2NHNH−である、項目8に記載の化合物。
(項目10)
式Iの化合物またはその塩:
〔式中、
nは10〜2500であり;
R1は、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する、任意に置換された3〜8員の飽和環、部分的に不飽和な環またはアリール環であるか、窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する8〜10員の飽和二環、部分的に不飽和な二環またはアリール二環であり;
L1およびL2は、それぞれ独立して、原子価結合であるか、または二価の飽和または不飽和の直鎖または分枝鎖のC1〜12アルキレン鎖であり、L1およびL2の0〜6個のメチレン単位は、独立して、−Cy−、−O−、−NR−、−S−、−OC(O)−、−C(O)O−、−C(O)−、−SO−、−SO2−、−NRSO2−、−SO2NR−、−NRC(O)−、−C(O)NR−、−OC(O)NR−または−NRC(O)O−で置き換えられており、ここで、
−Cy−はそれぞれ独立して、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する、任意に置換された3〜8員の二価の飽和環、部分的に不飽和な環またはアリール環であるか、または窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する、任意に置換された8〜10員の二価の飽和二環、部分的に不飽和な二環またはアリール二環であり;
R2は、t−ブチル、5−ノルボルネン−2−イル、オクタン−5−イル、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、N3であるか、フェニル、ピリジル、ナフチル、ピレニル、トリアゾリル、イミダゾリル、フタルイミド、テトラゾリル、フラニルまたはピラニルから選択される任意に置換された環、エポキシド環、クラウンエーテル、検出可能な部分、−P(O)(OR)2または−P(O)(X)2であり;
Xはそれぞれ独立してハロゲンであり;
Rはそれぞれ独立して、水素であるか、または任意に置換された脂肪族基である〕。
(項目11)
R1が、フェニル、ピリジル、ナフチル、ピレニル、トリアゾリル、イミダゾリル、フタルイミド、テトラゾリル、フラニルまたはピラニルから選択される、任意に置換された環である、項目10に記載の化合物。
(項目12)
R1が、CN、N3、NO2、−CH3、−CH2N3、t−ブチル、5−ノルボルネン−2−イル、オクタン−5−イル、−CH=CH2、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、Cl、Br、I、F、−NH2、−OH、−SH、−CO2H、−C(O)H、−CH2NH2、−CH2OH、−CH2SH、−CH2CO2H、−CH2C(O)H、−C(O)(C1〜6脂肪族)、−NHC(O)(C1〜6脂肪族)、−NHC(O)NH−、−NHC(O)NH(C1〜6脂肪族)、−NHC(S)NH−、−NHC(S)N(C1〜6脂肪族)2、−NHC(O)O(C1〜6脂肪族)、−NHNH2、−NHNHC(O)(C1〜6脂肪族)、−NHNHC(O)NH2、−NHNHC(O)NH(C1〜6脂肪族)、−NHNHC(O)O(C1〜6脂肪族)、−C(O)NH2、−C(O)NH(C1〜6脂肪族)2、−C(O)NHNH2、−C(S)N(C1〜6脂肪族)2、−OC(O)NH(C1〜6脂肪族)、−C(O)C(O)(C1〜6脂肪族)、−C(O)CH2C(O)(C1〜6脂肪族)、−S(O)2(C1〜6脂肪族)、−S(O)2O(C1〜6脂肪族)、−OS(O)2(C1〜6−脂肪族)、−S(O)2NH(C1〜6脂肪族)、−S(O)(C1〜6脂肪族)、−NHS(O)2NH(C1〜6脂肪族)、−NHS(O)2(C1〜6脂肪族)、−P(O)2(C1〜6脂肪族)、−P(O)(C1〜6脂肪族)2、−OP(O)(C1〜6脂肪族)2または−OP(O)(OC1〜6脂肪族)2で任意に置換されたフェニル環、ピリジル環、ナフチル環、ピレニル環、トリアゾリル環、イミダゾリル環、フタルイミド環、テトラゾリル環、フラニル環またはピラニル環である、項目11に記載の化合物。
(項目13)
L1およびL2が、独立して、−O−、−S−、−NH−、−C(O)O−、−Cy−、−C(O)−、−C(O)NH−、−NHC(O)−、−NH−O−、−O−Cy−CH2NH−O−、−OCH2−、−OCH2C(O)−、−OCH2CH2C(O)−、−OCH2CH2O−、−OCH2CH2S−、−OCH2CH2C(O)O−、−OCH2CH2NH−、−OCH2CH2NHC(O)−、−OCH2CH2C(O)NH−、−NHC(O)CH2CH2C(O)O−、−OCH2CH2NHC(O)CH2CH2C(O)O−、−OCH2CH2NHC(O)CH2OCH2C(O)O−、−OCH2CH2NHC(O)CH2OCH2C(O)NH−、−CH2C(O)NH−、−CH2C(O)NHNH−または−OCH2CH2NHNH−であり;
R2が、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、N3、エポキシド環、クラウンエーテル、検出可能な部分、−P(O)(OH)2または−P(O)(Cl)2であるか、またはCN、N3、NO2、−CH3、−CH2N3、t−ブチル、5−ノルボルネン−2−イル、オクタン−5−イル、−CH=CH2、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、Br、I、F、−NH2、−OH、−SH、−CO2H、−C(O)H、−CH2NH2、−CH2OH、−CH2SH、−CH2CO2H、−CH2C(O)H、−C(O)(C1〜6脂肪族)、−NHC(O)(C1〜6脂肪族)、−NHC(O)NH−、−NHC(O)NH(C1〜6脂肪族)、−NHC(S)NH−、−NHC(S)N(C1〜6脂肪族)2、−NHC(O)O(C1〜6脂肪族)、−NHNH2、−NHNHC(O)(C1〜6脂肪族)、−NHNHC(O)NH2、−NHNHC(O)NH(C1〜6脂肪族)、−NHNHC(O)O(C1〜6脂肪族)、−C(O)NH2、−C(O)NH(C1〜6脂肪族)2、−C(O)NHNH2、−C(S)N(C1〜6脂肪族)2、−OC(O)NH(C1〜6脂肪族)、−C(O)C(O)(C1〜6脂肪族)、−C(O)CH2C(O)(C1〜6脂肪族)、−S(O)2(C1〜6脂肪族)、−S(O)2O(C1〜6脂肪族)、−OS(O)2(C1〜6−脂肪族)、−S(O)2NH(C1〜6脂肪族)、−S(O)(C1〜6脂肪族)、−NHS(O)2NH(C1〜6脂肪族)、−NHS(O)2(C1〜6脂肪族)、−P(O)2(C1〜6脂肪族)、−P(O)(C1〜6脂肪族)2、−OP(O)(C1〜6脂肪族)2または−OP(O)(OC1〜6脂肪族)2で任意に置換されたフェニル環、ピリジル環、ナフチル環、ピレニル環、トリアゾリル環、イミダゾリル環、フタルイミド環、テトラゾリル環、フラニル環またはピラニル環である、項目12に記載の化合物。
(項目14)
R2が、
から選択される検出可能な部分である、項目13に記載の化合物。
(項目15)
上記化合物のPDIが約1.0〜約1.2である、項目1、5および10のいずれか1項に記載の化合物。
(項目16)
上記化合物のPDIが約1.02〜約1.05である、項目15に記載の化合物。
(項目17)
式IIaの化合物またはその塩:
〔式中、
mは10〜2500であり;
RXは、水素、ハロゲン、NO2、CN、N3、−N=C=O、−C(R)=NN(R)2、−P(O)(OR)2、−P(O)(X)2、9〜30員のクラウンエーテルであるか、または脂肪族、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する3〜8員の飽和環、部分的に不飽和な環またはアリール環、窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する8〜10員の飽和二環、部分的に不飽和な二環またはアリール二環から選択される、任意に置換された基であるか、または検出可能な部分であり;
Xはそれぞれ独立してハロゲンであり;
Rはそれぞれ独立して、水素であるか、または任意に置換された脂肪族基であり;
LXは、原子価結合であるか、または二価の飽和または不飽和の直鎖または分枝鎖のC1〜12アルキレン鎖であり、LXの0〜6個のメチレン単位は、独立して、−Cy−、−O−、−NR−、−S−、−OC(O)−、−C(O)O−、−C(O)−、−SO−、−SO2−、−NRSO2−、−SO2NR−、−NRC(O)−、−C(O)NR−、−OC(O)NR−または−NRC(O)O−で置き換えられており、ここで、
−Cy−はそれぞれ独立して、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する、任意に置換された3〜8員の二価の飽和環、部分的に不飽和な環またはアリール環であるか、または窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する、任意に置換された8〜10員の二価の飽和二環、部分的に不飽和な二環またはアリール二環である〕。
(項目18)
RXが、Cl、Br、I、F、−NH2、−OH、−SH、−CO2H、−C(O)H、−C(O)(C1〜6脂肪族)、−NHC(O)(C1〜6脂肪族)、−NHC(O)NH2、−NHC(O)NH(C1〜6脂肪族)、−NHC(S)NH−、−NHC(S)N(C1〜6脂肪族)2、−NHC(O)O(C1〜6脂肪族)、−NHNH2、−NHNHC(O)(C1〜6脂肪族)、−NHNHC(O)NH2、−NHNHC(O)NH(C1〜6脂肪族)、−NHNHC(O)O(C1〜6脂肪族)、−C(O)NH2、−C(O)NH(C1〜6脂肪族)2、−C(O)NHNH2、−C(S)N(C1〜6脂肪族)2、−OC(O)NH(C1〜6脂肪族)、−C(O)C(O)(C1〜6脂肪族)、−C(O)CH2C(O)(C1〜6脂肪族)、−S(O)2(C1〜6脂肪族)、−S(O)2O(C1〜6脂肪族)、−OS(O)2(C1〜6−脂肪族)、−S(O)2NH(C1〜6脂肪族)、−S(O)(C1〜6脂肪族)、−NHS(O)2NH(C1〜6脂肪族)、−NHS(O)2(C1〜6脂肪族)、−P(O)2(C1〜6脂肪族)、−P(O)(C1〜6脂肪族)2、−OP(O)(C1〜6脂肪族)2または−OP(O)(OC1〜6脂肪族)2のいずれかで任意に置換された脂肪族基である、項目17に記載の化合物。
(項目19)
RXが、CN、N3、NO2、−CH3、−CH2N3、t−ブチル、5−ノルボルネン−2−イル、オクタン−5−イル、−CH=CH2、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、Cl、Br、I、F、−NH2、−OH、−SH、−CO2H、−C(O)H、−CH2NH2、−CH2OH、−CH2SH、−CH2CO2H、−CH2C(O)H、−C(O)(C1〜6脂肪族)、−NHC(O)(C1〜6脂肪族)、−NHC(O)NH−、−NHC(O)NH(C1〜6脂肪族)、−NHC(S)NH−、−NHC(S)N(C1〜6脂肪族)2、−NHC(O)O(C1〜6脂肪族)、−NHNH2、−NHNHC(O)(C1〜6脂肪族)、−NHNHC(O)NH2、−NHNHC(O)NH(C1〜6脂肪族)、−NHNHC(O)O(C1〜6脂肪族)、−C(O)NH2、−C(O)NH(C1〜6脂肪族)2、−C(O)NHNH2、−C(S)N(C1〜6脂肪族)2、−OC(O)NH(C1〜6脂肪族)、−C(O)C(O)(C1〜6脂肪族)、−C(O)CH2C(O)(C1〜6脂肪族)、−S(O)2(C1〜6脂肪族)、−S(O)2O(C1〜6脂肪族)、−OS(O)2(C1〜6−脂肪族)、−S(O)2NH(C1〜6脂肪族)、−S(O)(C1〜6脂肪族)、−NHS(O)2NH(C1〜6脂肪族)、−NHS(O)2(C1〜6脂肪族)、−P(O)2(C1〜6脂肪族)、−P(O)(C1〜6脂肪族)2、−OP(O)(C1〜6脂肪族)2または−OP(O)(OC1〜6脂肪族)2で任意に置換されたフェニル環、ピリジル環、ナフチル環、ピレニル環、トリアゾリル環、イミダゾリル環、フタルイミド環、テトラゾリル環、フラニル環またはピラニル環である、項目17に記載の化合物。
(項目20)
LXが、−O−、−S−、−NH−、−C(O)O−、−Cy−、−C(O)−、−C(O)NH−、−NHC(O)−、−NH−O−、−O−Cy−CH2NH−O−、−OCH2−、−OCH2C(O)−、−OCH2CH2C(O)−、−OCH2CH2O−、−OCH2CH2S−、−OCH2CH2C(O)O−、−OCH2CH2NH−、−OCH2CH2NHC(O)−、−OCH2CH2C(O)NH−、−NHC(O)CH2CH2C(O)O−、−OCH2CH2NHC(O)CH2CH2C(O)O−、−OCH2CH2NHC(O)CH2OCH2C(O)O−、−OCH2CH2NHC(O)CH2OCH2C(O)NH−、−CH2C(O)NH−、−CH2C(O)NHNH−または−OCH2CH2NHNH−である、項目17に記載の化合物。
(項目21)
式IIbの化合物またはその塩:
〔式中、
mは10〜2500であり;
Xはそれぞれ独立してハロゲンであり;
RXは、水素、ハロゲン、NO2、CN、N3、−N=C=O、−C(R)=NN(R)2、−P(O)(OR)2、−P(O)(X)2、9〜30員のクラウンエーテルであるか、または脂肪族、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する3〜8員の飽和環、部分的に不飽和な環またはアリール環、窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する8〜10員の飽和二環、部分的に不飽和な二環またはアリール二環から選択される、任意に置換された基であるか、または検出可能な部分であり;
Rはそれぞれ独立して、水素であるか、または任意に置換された脂肪族基であり;
LXは、原子価結合であるか、または二価の飽和または不飽和の直鎖または分枝鎖のC1〜12アルキレン鎖であり、LXの0〜6個のメチレン単位は、独立して、−Cy−、−O−、−NR−、−S−、−OC(O)−、−C(O)O−、−C(O)−、−SO−、−SO2−、−NRSO2−、−SO2NR−、−NRC(O)−、−C(O)NR−、−OC(O)NR−または−NRC(O)O−で置き換えられており、ここで、
−Cy−はそれぞれ独立して、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する、任意に置換された3〜8員の二価の飽和環、部分的に不飽和な環またはアリール環であるか、または窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する、任意に置換された8〜10員の二価の飽和二環、部分的に不飽和な二環またはアリール二環である〕。
(項目22)
RXが、Cl、Br、I、F、−NH2、−OH、−SH、−CO2H、−C(O)H、−C(O)(C1〜6脂肪族)、−NHC(O)(C1〜6脂肪族)、−NHC(O)NH2、−NHC(O)NH(C1〜6脂肪族)、−NHC(S)NH−、−NHC(S)N(C1〜6脂肪族)2、−NHC(O)O(C1〜6脂肪族)、−NHNH2、−NHNHC(O)(C1〜6脂肪族)、−NHNHC(O)NH2、−NHNHC(O)NH(C1〜6脂肪族)、−NHNHC(O)O(C1〜6脂肪族)、−C(O)NH2、−C(O)NH(C1〜6脂肪族)2、−C(O)NHNH2、−C(S)N(C1〜6脂肪族)2、−OC(O)NH(C1〜6脂肪族)、−C(O)C(O)(C1〜6脂肪族)、−C(O)CH2C(O)(C1〜6脂肪族)、−S(O)2(C1〜6脂肪族)、−S(O)2O(C1〜6脂肪族)、−OS(O)2(C1〜6脂肪族)、−S(O)2NH(C1〜6脂肪族)、−S(O)(C1〜6脂肪族)、−NHS(O)2NH(C1〜6脂肪族)、−NHS(O)2(C1〜6脂肪族)、−P(O)2(C1〜6脂肪族)、−P(O)(C1〜6脂肪族)2、−OP(O)(C1〜6脂肪族)2または−OP(O)(OC1〜6脂肪族)2のいずれかで任意に置換された脂肪族基である、項目21に記載の化合物。
(項目23)
RXが、CN、N3、NO2、−CH3、−CH2N3、t−ブチル、5−ノルボルネン−2−イル、オクタン−5−イル、−CH=CH2、−C≡CH、−CH2C≡CH、−CH2CH2C≡CH、−CH2CH2CH2C≡CH、Br、I、F、−NH2、−OH、−SH、−CO2H、−C(O)H、−CH2NH2、−CH2OH、−CH2SH、−CH2CO2H、−CH2C(O)H、−C(O)(C1〜6脂肪族)、−NHC(O)(C1〜6脂肪族)、−NHC(O)NH−、−NHC(O)NH(C1〜6脂肪族)、−NHC(S)NH−、−NHC(S)N(C1〜6脂肪族)2、−NHC(O)O(C1〜6脂肪族)、−NHNH2、−NHNHC(O)(C1〜6脂肪族)、−NHNHC(O)NH2、−NHNHC(O)NH(C1〜6脂肪族)、−NHNHC(O)O(C1〜6脂肪族)、−C(O)NH2、−C(O)NH(C1〜6脂肪族)2、−C(O)NHNH2、−C(S)N(C1〜6脂肪族)2、−OC(O)NH(C1〜6脂肪族)、−C(O)C(O)(C1〜6脂肪族)、−C(O)CH2C(O)(C1〜6脂肪族)、−S(O)2(C1〜6脂肪族)、−S(O)2O(C1〜6脂肪族)、−OS(O)2(C1〜6−脂肪族)、−S(O)2NH(C1〜6脂肪族)、−S(O)(C1〜6脂肪族)、−NHS(O)2NH(C1〜6脂肪族)、−NHS(O)2(C1〜6脂肪族)、−P(O)2(C1〜6脂肪族)、−P(O)(C1〜6脂肪族)2、−OP(O)(C1〜6脂肪族)2または−OP(O)(OC1〜6脂肪族)2で任意に置換されたフェニル環、ピリジル環、ナフチル環、ピレニル環、トリアゾリル環、イミダゾリル環、フタルイミド環、テトラゾリル環、フラニル環またはピラニル環である、項目21に記載の化合物。
(項目24)
LXが、−O−、−S−、−NH−、−C(O)O−、−Cy−、−C(O)−、−C(O)NH−、−NHC(O)−、−NH−O−、−O−Cy−CH2NH−O−、−OCH2−、−OCH2C(O)−、−OCH2CH2C(O)−、−OCH2CH2O−、−OCH2CH2S−、−OCH2CH2C(O)O−、−OCH2CH2NH−、−OCH2CH2NHC(O)−、−OCH2CH2C(O)NH−、−NHC(O)CH2CH2C(O)O−、−OCH2CH2NHC(O)CH2CH2C(O)O−、−OCH2CH2NHC(O)CH2OCH2C(O)O−、−OCH2CH2NHC(O)CH2OCH2C(O)NH−、−CH2C(O)NH−、−CH2C(O)NHNH−または−OCH2CH2NHNH−である、項目21に記載の化合物。
(項目25)
以下の構造のいずれかから選択される化合物またはその塩:
〔式中、
nはそれぞれ独立して10〜2500であり;
R1およびR2は、それぞれ独立して、水素、ハロゲン、NO2、CN、N3、−N=C=O、−C(R)=NN(R)2、−P(O)(OR)2、−P(O)(X)2、9〜30員のクラウンエーテルであるか、または脂肪族、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する3〜8員の飽和環、部分的に不飽和な環またはアリール環、窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する8〜10員の飽和二環、部分的に不飽和な二環またはアリール二環から選択される、任意に置換された基であるか、または検出可能な部分であり;
Xはそれぞれ独立してハロゲンであり;
Rはそれぞれ独立して、水素であるか、または任意に置換された脂肪族基であり;
L1およびL2は、それぞれ独立して、原子価結合であるか、または二価の飽和または不飽和の直鎖または分枝鎖のC1〜12アルキレン鎖であり、L1およびL2の0〜6個のメチレン単位は、独立して、−Cy−、−O−、−NR−、−S−、−OC(O)−、−C(O)O−、−C(O)−、−SO−、−SO2−、−NRSO2−、−SO2NR−、−NRC(O)−、−C(O)NR−、−OC(O)NR−または−NRC(O)O−で置き換えられており、ここで、
−Cy−はそれぞれ独立して、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する、任意に置換された3〜8員の二価の飽和環、部分的に不飽和な環またはアリール環であるか、または窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する、任意に置換された8〜10員の二価の飽和二環、部分的に不飽和な二環またはアリール二環である〕。
(項目26)
一次または二次の標識、染料または別の検出可能な部分、生体分子、タンパク質治療薬、低分子薬物、ウイルス、治療担体、細胞または表面から選択される部分をPEG化する方法であって、該方法は、項目1、5、10、17、21または25のいずれか1項に記載の化合物を、該部分に共有結合またはイオン結合のいずれかで結合させる工程を含む、方法。
(項目27)
表1〜25に記載のいずれかの化合物から選択される化合物。
本発明の化合物は、上に一般的に記載された化合物を含み、本明細書に開示される実施形態、副次的な実施形態および種によってさらに説明される。本明細書で使用される場合、他に言及されない限り、以下の定義を適用する。本発明の目的のために、化学元素は、Periodic Table of the Elements,CASバージョン,Handbook of Chemistry and Physics,75th Edに従って同定される。さらに、有機化学の一般的な原理は、「Organic Chemistry」,Thomas Sorrell,University Science Books,Sausalito:1999および「March’s Advanced Organic Chemistry」,5th Ed.,編集:Smith,M.B.およびMarch,J.,John Wiley & Sons,New York:2001(これらの内容全体は、本明細書に参照によって組み込まれる)に記載されている。
上に一般的に定義されているように、式Iのn基は10〜2500である。特定の実施形態では、本発明は、上述のように、nが約225の式Iの化合物を提供する。他の実施形態では、nは約10〜約40である。他の実施形態では、nは約40〜約60である。他の実施形態では、nは約60〜約90である。さらに他の実施形態では、nは約90〜約150である。他の実施形態では、nは約150〜約200である。さらに他の実施形態では、nは約200〜約250である。他の実施形態では、nは約300〜約375である。他の実施形態では、nは約400〜約500である。さらに他の実施形態では、nは約650〜約750である。特定の実施形態では、nは、50±10から選択される。他の実施形態では、nは、80±10、115±10、180±10または225±10から選択される。
特定の実施形態では、R1は−P(O)(OR)2または−P(O)(ハロゲン)2である。一態様によれば、本発明は、R1が−P(O)(OH)2である式Iの化合物を提供する。別の態様によれば、本発明は、R1が−P(O)(Cl)2である式Iの化合物を提供する。
mは10〜2500であり;
RXは、水素、ハロゲン、NO2、CN、N3、−N=C=O、−C(R)=NN(R)2、−P(O)(OR)2、−P(O)(X)2、9〜30員のクラウンエーテルであるか、または脂肪族、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する3〜8員の飽和環、部分的に不飽和な環またはアリール環、窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する8〜10員の飽和二環、部分的に不飽和な二環またはアリール二環から選択される、任意に置換された基であるか、または検出可能な部分であり;
Xはそれぞれ独立してハロゲンであり;
Rはそれぞれ独立して、水素であるか、または脂肪族、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する3〜8員の飽和環、部分的に不飽和な環またはアリール環から選択される、任意に置換された基であり;
LXは、原子価結合であるか、または二価の飽和または不飽和の直鎖または分枝鎖のC1〜12炭化水素鎖であり、LXの0〜6個のメチレン単位は、独立して、−Cy−、−O−、−NR−、−S−、−OC(O)−、−C(O)O−、−C(O)−、−SO−、−SO2−、−NRSO2−、−SO2NR−、−NRC(O)−、−C(O)NR−、−OC(O)NR−または−NRC(O)O−で置き換えられており、ここで、
−Cy−はそれぞれ独立して、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する、任意に置換された3〜8員の二価の飽和環、部分的に不飽和な環またはアリール環であるか、または窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する、任意に置換された8〜10員の二価の飽和二環、部分的に不飽和な二環またはアリール二環である。
mは10〜2500であり;
Xはそれぞれ独立してハロゲンであり;
RXは、水素、ハロゲン、NO2、CN、N3、−N=C=O、−C(R)=NN(R)2、−P(O)(OR)2、−P(O)(X)2、9〜30員のクラウンエーテルであるか、または脂肪族、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する3〜8員の飽和環、部分的に不飽和な環またはアリール環、窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する8〜10員の飽和二環、部分的に不飽和な二環またはアリール二環から選択される、任意に置換された基であるか、または検出可能な部分であり;
Rはそれぞれ独立して、水素であるか、または脂肪族、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する3〜8員の飽和環、部分的に不飽和な環またはアリール環から選択される、任意に置換された基であり;
LXは、原子価結合であるか、または二価の飽和または不飽和の直鎖または分枝鎖のC1〜12炭化水素鎖であり、LXの0〜6個のメチレン単位は、独立して、−Cy−、−O−、−NR−、−S−、−OC(O)−、−C(O)O−、−C(O)−、−SO−、−SO2−、−NRSO2−、−SO2NR−、−NRC(O)−、−C(O)NR−、−OC(O)NR−または−NRC(O)O−で置き換えられており、ここで、
−Cy−はそれぞれ独立して、窒素、酸素または硫黄から独立して選択される0〜4個のヘテロ原子を有する、任意に置換された3〜8員の二価の飽和環、部分的に不飽和な環またはアリール環であるか、または窒素、酸素または硫黄から独立して選択される0〜5個のヘテロ原子を有する、任意に置換された8〜10員の二価の飽和二環、部分的に不飽和な二環またはアリール二環である。
本発明の化合物は、一般的に、類似化合物について当業者に既知の合成方法および以下に示す一般的なスキームおよび実施例によって示されるような合成方法によって調製され得る。特定の実施形態では、本発明の化合物は、米国特許出願「Heterobifunctional poly(ethylene glycol)and Uses Thereof」(2005年10月24日出願、出願番号第11/256,735号)に詳細に記載される方法によって調製され、この内容は本明細書に参照により組み込まれる。
当業者は、表26、27および28に示した特定の末端基が、保護された官能基を含むことを理解するであろう。これらの保護基が、任意に除去され、本発明の化合物を生成することも理解されるであろう。官能基の脱保護方法は、当業者に周知であり、Greene(1999)に詳細に記載されるものが挙げられる。
上述のように、本発明は、二官能PEG、その中間体および調製方法を提供する。このような官能基化PEGは、医薬分野および生物医学分野での種々の目的に有用である。このような使用としては、他の分子または基材をPEG化するプロセスで本発明の二官能PEGを使用することが挙げられる。したがって、本発明の別の実施形態は、本発明の化合物との分子接合体または基材接合体を提供する。用語「PEG化」は、本明細書で使用される場合、用語「接合」と相互交換可能に使用される。したがって、PEG化生成物は、「接合体」として知られている。
一般的な方法
方法A:重合
開始剤(1mmol)の無水THF(100mL)溶液を攪拌し、この溶液に、カリウムナフタレニドのTHF溶液(0.2M、5mL、1mmol)を加えた。次いで、得られた溶液を0℃まで冷却した。Schlenk技術を用いてこのアルコキシド溶液にエチレンオキシド(10g、227mmol)を入れた。エチレンオキシドを加え終わったら、フラスコをアルゴンで満たしなおし、密閉し、室温で24時間攪拌した。この時点で、追加の停止剤を加えるか、または反応を水およびメタノールでクエンチした後、溶媒を減圧下で除去した。
所望のポリマーを含有する粘性液体をシリカゲル100gに置き、3% MeOH CHCl3溶液(1L)で洗浄し、次いで、10% MeOH CHCl3溶液(1L)で洗浄し、これにポリマー生成物が含まれていた。溶媒を除去し、得られた液体を少量のメタノールで希釈し、ジエチルエーテル中で沈殿させた。濾過後、白色粉末を単離した。
所望のポリマーを含有する粘性液体を水100mLに溶解し、CHCl3(4×300mL)で抽出した。合わせた有機層をMgSO4で乾燥し、濾過した。溶媒を除去し、得られた液体を少量のメタノールで希釈し、ジエチルエーテル中で沈殿させた。濾過後、白色粉末を単離した。
250mL丸底フラスコに、10%水酸化パラジウム/炭素(0.6g)およびメタノール(50mL)を加えた。ジベンジルアミノ−ポリエチレングリコール(10g)およびギ酸アンモニウム(2g)を加え、反応物を加熱して16時間環流させた。溶液を冷却し、クロロホルム(100mL)で希釈し、セライト濾過し、溶媒を除去した。得られた液体を1N水酸化ナトリウムに溶解し、方法Cにしたがって精製した。
250mL丸底フラスコに、アミノ−ポリエチレングリコール−アルコール(10g)およびメタノール(150mL)を加えた。ジ−t−ブチルジカーボネート(10当量)およびDMAP(1当量)を加え、得られた溶液を室温で攪拌した。溶媒を除去し、方法Bにしたがって精製した。
所望のPEG誘導体(1当量)をジクロロメタン(約10mL/gPEG)に溶解した。この溶液にトリフェニルホスフィン(4当量)を加え、次いで、所望のMitsunobu停止剤(5当量)を加え、次いでDIAD(3当量)を加え、8時間攪拌した。溶媒を除去し、方法Bにしたがって精製した。
所望のPEG誘導体(1当量)をCH2Cl2(約10mL/gPEG)に溶解し、0℃まで冷却した。塩化メタンスルホニル(2当量)を窒素下シリンジで滴下し、次いで、トリエチルアミン(2.5当量)を加えた。溶液を室温まで加温し、12時間攪拌した。溶媒を除去し、そのまま使用するか、または任意に、方法Bにしたがってさらに精製した。
所望のPEG誘導体(1当量)をエタノール(約10mL/gPEG)に溶解し、NaN3(10当量)を加えた。溶液を環流下で16時間攪拌し、冷却し、溶媒を蒸発させ、方法Bによって精製した。
所望のPEG(1g)を少量のTHF(2mL)に溶解し、室温で攪拌した。HClジオキサン溶液(4M、5mL)を加え、アルゴン下で溶液を6時間攪拌した。溶液を冷ジエチルエーテルに注ぎ、濾過後、ポリマー生成物を白色粉末として得た。
所望のPEG(1g)を3N HCl(aq)10mLに溶解し、環流下で4時間攪拌した。溶液を冷却し、方法Cにしたがって精製した。
所望のアミノ−PEG誘導体(1当量)をメタノール(約10mL/gPEG)に溶解した。トリフルオロ酢酸エチル(3当量)を加え、得られた溶液を室温で16時間攪拌した。溶媒を除去し、方法Bにしたがって精製した。
所望のPEG誘導体(1当量)をエタノール(約10mL/gPEG)に溶解し、ピリジニウム パラ−トルエンスルホネート(PPTS)(3当量)を加えた。この溶液を環流下で16時間攪拌し、冷却し、溶媒を蒸発させ、方法Cによって精製した。
所望のPEG誘導体をトルエン(約10mL/gPEG)に溶解し、4時間環流させた。この溶液を冷却した後、ポリマーをジエチルエーテル中で沈殿させた。濾過後、白色粉末を単離した。
Boc−PEG−アジド(5g)をメタノール(50mL)に溶解し、室温で均一になるまで攪拌した。無水HClを反応物に5分間バブリングし、反応物をさらに15分間攪拌した。溶媒を蒸発させ、飽和NaHCO3(30mL、水溶液)に溶解し、次いで生成物をジクロロメタン(3×60mL)で抽出した。合わせた有機層をMgSO4で乾燥し、濾過した。溶媒を除去し、得られた液体を最少量のメタノールで希釈し、ジエチルエーテル中で沈殿させた。濾過後、白色粉末(4.5g、収率90%)を単離した。
Claims (1)
- 本明細書中に記載されるような化合物。
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WO2005035727A2 (en) * | 2003-10-09 | 2005-04-21 | Ambrx, Inc. | Polymer derivatives |
US20060142506A1 (en) * | 2004-10-25 | 2006-06-29 | Kurt Breitenkamp | Heterobifunctional poly(ethylene glycol) and uses thereof |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US8658735B2 (en) | 2008-08-28 | 2014-02-25 | Tokyo University Of Science Educational Foundation Administrative Organization | Polymerizable monomer, graft copolymer, and surface modifier |
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CA2650035C (en) | 2015-02-03 |
EP2010477A2 (en) | 2009-01-07 |
US8207353B2 (en) | 2012-06-26 |
EP2010477A4 (en) | 2012-05-30 |
JP2009535462A (ja) | 2009-10-01 |
CA2650035A1 (en) | 2007-11-08 |
JP2011058001A (ja) | 2011-03-24 |
US20120226050A1 (en) | 2012-09-06 |
WO2007127473A3 (en) | 2008-07-24 |
US20100160645A1 (en) | 2010-06-24 |
US7893277B2 (en) | 2011-02-22 |
JP2011168799A (ja) | 2011-09-01 |
US20100280252A1 (en) | 2010-11-04 |
US20080207913A1 (en) | 2008-08-28 |
CA2861601A1 (en) | 2007-11-08 |
US8609857B2 (en) | 2013-12-17 |
WO2007127473A2 (en) | 2007-11-08 |
US7560588B2 (en) | 2009-07-14 |
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