JP6807900B2 - アミン含有トランスフェクション試薬ならびにそれを生成および使用するための方法 - Google Patents
アミン含有トランスフェクション試薬ならびにそれを生成および使用するための方法 Download PDFInfo
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- JP6807900B2 JP6807900B2 JP2018146564A JP2018146564A JP6807900B2 JP 6807900 B2 JP6807900 B2 JP 6807900B2 JP 2018146564 A JP2018146564 A JP 2018146564A JP 2018146564 A JP2018146564 A JP 2018146564A JP 6807900 B2 JP6807900 B2 JP 6807900B2
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Classifications
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- A—HUMAN NECESSITIES
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
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Description
本願は、35U.S.C.§119に基づき、2011年10月4日出願の米国仮出願番号61/543,242および2011年2月2日出願の米国仮出願番号61/438,903および2011年1月28日出願の米国仮出願番号61/437,503および2210年11月15日出願の米国仮出願番号61/413,905に対して優先権を主張するものである。上述の出願は、本願と共同所有されており、それらの全内容は、本明細書中に完全に示されたかのように、それらの全体が明確に参考として援用される。
本発明は、概して、生物学的に活性な物質のインビトロ送達およびインビボ送達のためのトランスフェクション試薬の分野に関する。より詳細には、本発明は、インビトロまたはインビボにおいて核酸または他の生物学的に活性な物質を細胞に導入するために使用され得る、生分解性および生体適合性の脂質ならびにそれらを使用して生成されたトランスフェクション複合体に関する。
[1]
一般構造Iを有する化合物またはその薬学的に許容可能な塩:
[化1]
式中:
X 1 およびX 2 の各々は、O、S、N−AおよびC−Aからなる群から独立して選択される部分であり、ここで、Aは、水素およびC 1 −C 20 炭化水素鎖からなる群から選択され;
YおよびZの各々は、C=O、C=S、S=O、CH−OHおよびSO 2 からなる群から独立して選択される部分であり;R 1 、R 2 およびR 3 、R 4 、R 5 、R 6 およびR 7 の各々は、水素、環式または非環式の置換または非置換の分枝状または非分枝状の脂肪族基、環式または非環式の置換または非置換の分枝状または非分枝状のヘテロ脂肪族基、置換または非置換の分枝状または非分枝状のアシル基、置換または非置換の分枝状または非分枝状のアリール基、置換または非置換の分枝状または非分枝状のヘテロアリール基からなる群から独立して選択される部分であり;
xは、1以上10以下の値を独立して有する整数であり;
nは、1以上3以下の値を独立して有する整数であり、mは、0以上20以下の値を独立して有する整数であり、pは、0または1の値を独立して有する整数であり、ここで、m=p=0である場合、R 2 は、水素であるが、
但しさらに、nまたはmの少なくとも1つが2という値を有する場合、R 3 および構造I中の窒素は、
[化2]
からなる群から選択される部分を形成し、式中、g、eおよびfの各々は、1以上6以下の値を独立して有する整数であり、「HCC」は、炭化水素鎖を表し、各 * は、構造I中の窒素原子を示す。
[2]
R 1 およびR 2 の各々が、3〜約20個の炭素原子および0〜4個の二重結合を有する、置換または非置換の分枝状または非分枝状のアルキルまたはアルケニル基からなる群から独立して選択される、[1]記載の化合物またはその薬学的に許容可能な塩。
[3]
R 1 およびR 2 の各々が、8〜約18個の炭素原子および0〜2個の二重結合を有する、置換または非置換の非分枝状のアルキルまたはアルケニル基からなる群から独立して選択される、[2]記載の化合物またはその薬学的に許容可能な塩。
[4]
nおよびmの各々が、独立して、1または3という値を有し、R 3 が、
[化3]
からなる群から選択され、式中、各「HCC」は、炭化水素鎖を表し、各 * は、構造I中の窒素原子に対するR 3 の潜在的な結合点を示し、ここで、任意の * 位における各Hは、構造I中の窒素原子への結合を達成するために置換され得る、[1]記載の化合物またはその薬学的に許容可能な塩。
[5]
xが、1〜6の値を有する、[1]記載の化合物またはその薬学的に許容可能な塩。
[6]
一般構造II:
[化4]
を有する[1]記載の化合物またはその薬学的に許容可能な塩。
[7]
少なくとも1つのX 1 が、NHである、[6]記載の化合物またはその薬学的に許容可能な塩。
[8]
少なくとも1つのX 1 が、Oである、[6]記載の化合物またはその薬学的に許容可能な塩。
[9]
各R 1 が、3〜約20個の炭素原子および0〜4個の二重結合を有する、置換または非置換の分枝状または非分枝状のアルキルまたはアルケニル基からなる群から独立して選択される、[6]記載の化合物またはその薬学的に許容可能な塩。
[10]
R 1 の各々が、8〜約18個の炭素原子および0〜2個の二重結合を有する、置換または非置換の非分枝状のアルキルまたはアルケニル基からなる群から独立して選択される、[9]記載の化合物またはその薬学的に許容可能な塩。
[11]
nおよびmの各々が、独立して、1または3という値を有し、R 3 が、
[化5]
からなる群から選択され、式中、各「HCC」は、炭化水素鎖を表し、各 * は、構造II中の窒素原子に対するR 3 の潜在的な結合点を示し、ここで、任意の * 位における各Hは、構造II中の窒素原子への結合を達成するために置換され得る、[6]記載の化合物またはその薬学的に許容可能な塩。
[12]
xが、1〜6の値を有する、[6]記載の化合物またはその薬学的に許容可能な塩。
[13]
化合物1〜87またはそれらの異性体:
[化6−1]
[化6−2]
[化6−3]
[化6−4]
[化6−5]
[化6−6]
[化6−7]
[化6−8]
[化6−9]
[化6−10]
[化6−11]
[化6−12]
[化6−13]
[化6−14]
[化6−15]
[化6−16]
[化6−17]
[化6−18]
[化6−19]
[化6−20]
[化6−21]
[化6−22]
[化6−23]
[化6−24]
[化6−25]
[化6−26]
[化6−27]
[化6−28]
[化6−29]
[化6−30]
[化6−31]
[化6−32]
[化6−33]
[化6−34]
[化6−35]
[化6−36]
[化6−37]
[化6−38]
[化6−39]
[化6−40]
からなる群から選択される、[1]記載の化合物またはその薬学的に許容可能な塩。
[14]
以下の工程を含む、構造Iを有する化合物またはその薬学的に許容可能な塩を合成するための方法:
[化7]
(a)構造R 1 −X 1 −Y−(CR 4 R 5 ) n −Brを有する第1中間体および構造R 2 −X 2 −Z−(CR 6 R 7 ) m −Brを有する第2中間体からなる群から選択される少なくとも2つの化合物を含む1当量以上の不飽和成分であって、式中、該構造の(CR 4 R 5 ) n および(CR 6 R 7 ) m 部分において、各R 4 は、同じであるかまたは異なり、各R 5 は、同じであるかまたは異なり、各R 6 は、同じであるかまたは異なり、各R 7 は、同じであるかまたは異なり、該第1中間体および該第2中間体は、同じであるかまたは異なる、1当量以上の不飽和成分を
(b)第一級アミンNH 2 −R 3 、ジアミン、ポリアミンまたはそれらの組み合わせを含む1当量のアミノ成分と
反応させる工程であって、それにより、構造Iを有する化合物を得る、工程、
式中:
X 1 およびX 2 の各々は、O、S、N−AおよびC−Aからなる群から独立して選択される部分であり、ここで、Aは、水素およびC 1 −C 20 炭化水素鎖からなる群から選択され;
YおよびZの各々は、C=O、C=S、S=O、CH−OHおよびSO 2 からなる群から独立して選択される部分であり;R 1 、R 2 およびR 3 、R 4 、R 5 、R 6 およびR 7 の各々は、水素、環式または非環式の置換または非置換の分枝状または非分枝状の脂肪族基、環式または非環式の置換または非置換の分枝状または非分枝状のヘテロ脂肪族基、置換または非置換の分枝状または非分枝状のアシル基、置換または非置換の分枝状または非分枝状のアリール基、置換または非置換の分枝状または非分枝状のヘテロアリール基からなる群から独立して選択される部分であり;
xは、1以上10以下の値を独立して有する整数であり;
nは、1以上3以下の値を独立して有する整数であり、mは、0以上20以下の値を独立して有する整数であり、pは、0または1の値を独立して有する整数であり、ここで、m=p=0である場合、R 2 は、水素であるが、
但しさらに、nまたはmの少なくとも1つが2という値を有する場合、R 3 および構造I中の窒素は、
[化8]
からなる群から選択される部分を形成し、式中、g、eおよびfの各々は、1以上6以下の値を独立して有する整数であり、「HCC」は、炭化水素鎖を表し、各 * は、構造I中の窒素原子を示す。
[15]
R 1 およびR 2 の各々が、3〜約20個の炭素原子および0〜4個の二重結合を有する、置換または非置換の分枝状または非分枝状のアルキルまたはアルケニル基からなる群から独立して選択される、[14]記載の方法。
[16]
R 1 およびR 2 の各々が、3〜約20個の炭素原子および0〜4個の二重結合を有する、置換または非置換の分枝状または非分枝状のアルキルまたはアルケニル基からなる群から独立して選択される、[14]記載の方法。
[17]
R 1 およびR 2 の各々が、8〜約18個の炭素原子および0〜2個の二重結合を有する、置換または非置換の非分枝状のアルキルまたはアルケニル基からなる群から独立して選択される、[16]記載の方法。
[18]
nおよびmの各々が、独立して、1または3という値を有し、前記第一級アミンNH 2 −R 3 が、
[化9]
からなる群から選択され、式中、各「HCC」は、炭化水素鎖を表し、各 * は、該第一級アミンNH 2 −R 3 中のアミノ基に対するR 3 の潜在的な結合点を示し、ここで、任意の * 位における各Hは、該第一級アミンNH 2 −R 3 中の窒素原子への結合を達成するために置換され得る、[14]記載の方法。
[19]
前記アミノ成分が、第一級アミンNH 2 −R 3 であり、前記不飽和成分と該第一級アミンとのモル比が、約1:1〜約6:1である、[14]記載の方法。
[20]
R 4 、R 5 、R 6 およびR 7 の各々が、水素であり、YおよびZの各々が、C=Oである、[14]記載の方法。
[21]
各R 1 が、3〜約20個の炭素原子および0〜4個の二重結合を有する、置換または非置換の分枝状または非分枝状のアルキルまたはアルケニル基からなる群から独立して選択される、[20]記載の方法またはその薬学的に許容可能な塩。
[22]
R 1 の各々が、8〜約18個の炭素原子および0〜2個の二重結合を有する、置換または非置換の非分枝状のアルキルまたはアルケニル基からなる群から独立して選択される、[21]記載の方法またはその薬学的に許容可能な塩。
[23]
一般構造Iを有するアミン含有トランスフェクション試薬またはその薬学的に許容可能な塩を含む、トランスフェクション複合体:
[化10]
式中:
X 1 およびX 2 の各々は、O、S、N−AおよびC−Aからなる群から独立して選択される部分であり、ここで、Aは、水素およびC 1 −C 20 炭化水素鎖からなる群から選択され;
YおよびZの各々は、C=O、C=S、S=O、CH−OHおよびSO 2 からなる群から独立して選択される部分であり;R 1 、R 2 およびR 3 、R 4 、R 5 、R 6 およびR 7 の各々は、水素、環式または非環式の置換または非置換の分枝状または非分枝状の脂肪族基、環式または非環式の置換または非置換の分枝状または非分枝状のヘテロ脂肪族基、置換または非置換の分枝状または非分枝状のアシル基、置換または非置換の分枝状または非分枝状のアリール基、置換または非置換の分枝状または非分枝状のヘテロアリール基からなる群から独立して選択される部分であり;
xは、1以上10以下の値を独立して有する整数であり;
nは、1以上3以下の値を独立して有する整数であり、mは、0以上20以下の値を独立して有する整数であり、pは、0または1の値を独立して有する整数であり、ここで、m=p=0である場合、R 2 は、水素であるが、
但しさらに、nまたはmの少なくとも1つが2という値を有する場合、R 3 および構造I中の窒素は、
[化11]
からなる群から選択される部分を形成し、式中、g、eおよびfの各々は、1以上6以下の値を独立して有する整数であり、「HCC」は、炭化水素鎖を表し、各 * は、構造I中の窒素原子を示す。
[24]
R 1 およびR 2 の各々が、3〜約20個の炭素原子および0〜4個の二重結合を有する、置換または非置換の分枝状または非分枝状のアルキルまたはアルケニル基からなる群から独立して選択される、[23]記載のトランスフェクション複合体またはその薬学的に許容可能な塩。
[25]
R 1 およびR 2 の各々が、8〜約18個の炭素原子および0〜2個の二重結合を有する、置換または非置換の非分枝状のアルキルまたはアルケニル基からなる群から独立して選択される、[24]記載のトランスフェクション複合体またはその薬学的に許容可能な塩。
[26]
nおよびmの各々が、独立して、1または3という値を有し、R 3 が、
[化12]
からなる群から選択され、式中、各「HCC」は、炭化水素鎖を表し、各 * は、構造I中の窒素原子に対するR 3 の潜在的な結合点を示し、ここで、任意の * 位における各Hは、構造I中の窒素原子への結合を達成するために置換され得る、[23]記載のトランスフェクション複合体またはその薬学的に許容可能な塩。
[27]
xが、1〜6の値を有する、[23]記載のトランスフェクション複合体またはその薬学的に許容可能な塩。
[28]
前記アミン含有トランスフェクション試薬が、一般構造II:
[化13]
を有する、[23]記載のトランスフェクション複合体またはその薬学的に許容可能な塩。
[29]
少なくとも1つのX 1 が、NHである、[28]記載のトランスフェクション複合体またはその薬学的に許容可能な塩。
[30]
少なくとも1つのX 1 が、Oである、[28]記載のトランスフェクション複合体またはその薬学的に許容可能な塩。
[31]
各R 1 が、3〜約20個の炭素原子および0〜4個の二重結合を有する、置換または非置換の分枝状または非分枝状のアルキルまたはアルケニル基からなる群から独立して選択される、[28]記載のトランスフェクション複合体またはその薬学的に許容可能な塩。
[32]
R 1 の各々が、8〜約18個の炭素原子および0〜2個の二重結合を有する、置換または非置換の非分枝状のアルキルまたはアルケニル基からなる群から独立して選択される、[31]記載のトランスフェクション複合体またはその薬学的に許容可能な塩。
[33]
nおよびmの各々が、独立して、1または3という値を有し、R 3 が、
[化14]
からなる群から選択され、式中、各「HCC」は、炭化水素鎖を表し、各 * は、構造II中の窒素原子に対するR 3 の潜在的な結合点を示し、ここで、任意の * 位における各Hは、構造II中の窒素原子への結合を達成するために置換され得る、[28]記載のトランスフェクション複合体またはその薬学的に許容可能な塩。
[34]
xが、1〜6の値を有する、[28]記載のトランスフェクション複合体またはその薬学的に許容可能な塩。
[35]
前記化合物が、化合物1〜87またはそれらの異性体:
[化15−1]
[化15−2]
[化15−3]
[化15−4]
[化15−5]
[化15−6]
[化15−7]
[化15−8]
[化15−9]
[化15−10]
[化15−11]
[化15−12]
[化15−13]
[化15−14]
[化15−15]
[化15−16]
[化15−17]
[化15−18]
[化15−19]
[化15−20]
[化15−21]
[化15−22]
[化15−23]
[化15−24]
[化15−25]
[化15−26]
[化15−27]
[化15−28]
[化15−29]
[化15−30]
[化15−31]
[化15−32]
[化15−33]
[化15−34]
[化15−35]
[化15−36]
[化15−37]
[化15−38]
[化15−39]
[化15−40]
からなる群から選択される、[23]記載のトランスフェクション複合体またはその薬学的に許容可能な塩。
[36]
少なくとも1つのヘルパー脂質をさらに含む、[23]記載のトランスフェクション複合体。
[37]
前記ヘルパー脂質が、BMOP(N−(2−ブロモエチル)−N,N−ジメチル−2,3−ビス(9−オクタデセニルオキシ)−プロパンアミニウムブロミド)、DDPES(ジパルミトイルホスファチジルエタノールアミン5−カルボキシスペルミルアミド)、DSPC、CTAB:DOPE(臭化セチルトリメチルアンモニウム(CATB)とDOPEとの配合物)、POPC(1−パルミトイル−2−オレオイル−sn−グリセロ−3−ホスホコリン)、DOPE(ジオレオイルホスファチジルエタノールアミン)、DMG、DMAP(4−ジメチルアミノピリジン)、DMPE(ジミリストイルホスファチジルエタノールアミン)、DOMG、DMA、DOPC(ジオレオイルホスファチジルコリン)、DMPC(ジミリストイルホスファチジルコリン)、DPEPC(ジパルミトイルエチルホスファチジルコリン)、DODAC(ジオレオイルジメチルアンモニウムクロリド)、DOSPER(1,3−ジ−オレオイルオキシ−2−(6−カルボキシスペルミル)−プロピルアミド)、DOTMA(N−[1−(2,3−ジオレイルオキシ)プロピル]−n,n,n−トリメチルアンモニウムクロリド)、DDAB(ジデシルメチルアンモニウムブロミド)、DOTAP(N−[1−(2,3−ジオレオイルオキシ)プロピル]−N,N,N−トリメチル−アンモニウムメチルスルフェート)、DOTAP・Cl、DC−chol(3,β−N,(N',N'−ジメチルアミノエタン)−カルバモイル]コレステロール)、DOSPA(2−(スペルミンカルボキサミド)エチル)−N,N−ジメチル−アンモニウムトリフルオロアセテート)、DC−6−14(O,O'−ジテトラデカノイル−N−(アルファトリメチルアンモニオアセチル)ジエタノールアミンクロリド)、DCPE(ジカプロイルホスファチジルエタノールアミン)、DLRIE(ジラウリルオキシプロピル−3−ジメチルヒドロキシエチルアンモニウムブロミド)、DODAP(1,2−ジオレオイル−3−ジメチルアンモニウム−プロパン)、エチル−PC、DOSPA(2,3−ジオレオイルオキシ−N−[2−(スペルミンカルボキサミドエチル]−N,N−ジ−メチル−1−プロパンアミニウムトリフルオロアセテート)、DOGS(ジオクタデシルアミドグリシルカルボキシスペルミン)、DMRIE(N−[1−(2,3ジミリスチルオキシ)プロピル]−N,N−ジメチル−N−(2−ヒドロキシエチル)アンモニウムブロミド)、DOEPC(ジオレオイルエチル−ホスホコリン)、DOHME(N−[1−(2,3−ジオレオイルオキシ)プロピル]−N−[1−(2−ヒドロキシエチル)]−N,Nジメチルアンモニウムヨージド)、GAP−DLRIE:DOPE(N−(3−アミノプロピル)−N,N−ジメチル−2,3−ビス(ドデシルオキシ)−1−プロパンイミニウムブロミド/ジオレイルホスファチジルエタノールアミン)、DPPC(ジパルミトイルホスファチジルコリン)、DOPG(1,2−ジオレオイル−sn−グリセロ−3−[ホスホ−rac−(3−リシル(1−グリセロール))・Cl)、N−ラウロイルサルコシン、(R)−(+)−リモネン、レシチン類(およびそれらの誘導体);ホスホチジルエタノールアミン(およびその誘導体);ホスファチジルエタノールアミン類、ジオレオイルホスファチジルエタノールアミン)、DPhPE(ジフィタノイルホスファチジルエタノールアミン)、DPPEジパルミトイルホスファチジルエタノールアミン)、ジパルミトイルホスファチジルエタノールアミン、O−Chol(3ベータ[1−オルニチンアミドカルバモイル]コレステロール)、POPE(パルミトイルオレオイルホスファチジルエタノールアミン)およびジステアロイルホスファチジルエタノールアミン;ホスホチジルコリン;ホスファチジルコリン類、DPPC(ジパルミトイルホスファチジルコリン)POPC(パルミトイルオレオイルホスファチジルコリン)およびジステアロイルホスファチジルコリン;ホスファチジルグリセロール;ピペラジンベースの陽イオン性脂質、ホスファチジルグリセロール類、例えば、DOPG(ジオレオイルホスファチジルグリセロール)、DPPG(ジパルミトイルホスファチジルグリセロール)およびジステアロイルホスファチジルグリセロール;ホスファチジルセリン(およびその誘導体);ホスファチジルセリン類、例えば、ジオレオイル−またはジパルミトイルホスファチジルセリン;ジ第四級アンモニウム塩、例えば、N,N'−ジオレイル−N,N,N',N'−テトラメチル−1,2−エタンジアミン(TmedEce)、N,N'−ジオレイル−N,N,N',N'−テトラメチル−1,3−プロパンジアミン(PropEce)、N,N'−ジオレイル−N,N,N',N'−テトラメチル−1,6−ヘキサンジアミン(HexEce)およびそれらの対応するN,N'−ジセチル飽和アナログ(TmedAce、PropAceおよびHexAce)、ジホスファチジルグリセロール類;脂肪酸エステル類;一価陽イオン性トランスフェクション脂質、例えば、1−デオキシ−1−[ジヘキサデシル(メチル)アンモニオ]−D−キシリトール;1−デオキシ−1−[メチル(ジテトラデシル)アンモニオ]−Dアラビニトール;1−デオキシ−1−[ジヘキサデシル(メチル)アンモニオ]−D−アラビニトール;1−デオキシ−1−[メチル(ジオクタデシル)アンモニオ]−Dアラビニトール、グリセロールエステル類;スフィンゴ脂質;カルジオリピン;セレブロシド類;およびセラミド類;ならびにそれらの混合物からなるリストから選択され、中性脂質にはまた、コレステロールおよび他の3βOH−ステロールならびにそれらの誘導体のホスファチジルコリンまたは商業的に入手可能な陽イオン性脂質混合物、例えば、LIPOFECTIN(登録商標)CELLFECTIN(登録商標)(N,NI,NII,NIII−テトラメチル−N,NI,NII,NIII−テトラパルミチルスペルミン(TMTPS)とジオレオイルホスファチジルエタノールアミン(DOPE)との1:1.5(M/M)配合物、LIPOFECTACE(登録商標)、GS 2888 CYTOFECTIN(登録商標)、FUGENE 6(登録商標)、EFFECTENE(登録商標)およびLIPOFECTAMINE(登録商標)、LIPOFECTAMINE 2000(登録商標)、LIPOFECTAMINE PLUS(登録商標)、LIPOTAXI(登録商標)、POLYECT(登録商標)、SUPERFECT(登録商標)、TFXN(商標)、TRANSFAST(商標)、TRANSFECTAM(登録商標)、TRANSMESSENGER(登録商標)、ベクタミジン(3−テトラデシルアミノ−N−tert−ブチル−N'−テトラデシルプロピオンアミジン(ジC14−アミジン)、OLIGOFECTAMINE(登録商標)も含まれる、[36]記載のトランスフェクション複合体。
[38]
少なくとも1つのペグ化脂質をさらに含む、[23]記載のトランスフェクション複合体。
[39]
少なくとも1つの生理活性物質をさらに含む、[23]記載のトランスフェクション複合体。
[40]
前記生理活性物質が、DNA分子およびRNA分子、薬物のタンパク質である、[39]記載のトランスフェクション複合体。
[41]
前記RNA分子が、siRNA、shRNA、miRNAおよびstRNAまたはmRNAである、[40]記載のトランスフェクション複合体。
[42]
前記生理活性物質が、siRNA分子である、[39]記載のトランスフェクション複合体。
[43]
前記生理活性物質が、mRNA分子である、[39]記載のトランスフェクション複合体。
[44]
前記生理活性物質が、DNA分子である、[39]記載のトランスフェクション複合体。
[45]
標的化部分をさらに含む、[23]記載のトランスフェクション複合体。
[46]
ペプチド、改変されたペプチド、抗体、改変された抗体、レセプター分子、改変されたレセプター分子、一本鎖または二本鎖の核酸分子、改変された一本鎖または二本鎖の核酸分子、ペプチドアプタマーまたは核酸アプタマー、改変されたペプチドアプタマーまたは核酸アプタマー、有機分子、多糖からなるリストから選択される標的化部分をさらに含む、[23]記載のトランスフェクション複合体。
本発明のこれらおよび他の特徴は、以下の説明、図面および添付の請求項を参照することにより、よりよく理解されるようになるだろう。
本発明が、特定のデバイスまたは生体系に限定されないことが理解されるべきであり、本発明は、当然のことながら変化し得る。本明細書および添付の請求項において使用されるとき、単数形「a」、「an」および「the」は、その内容が明らかに他のことを表していない限り、単数および複数の指示対象を含むこともまた理解されるべきである。したがって、例えば、「脂質(a lipid)」への言及は、1つ以上の脂質を含む。本明細書中で使用される任意の用語が、特定の実施形態だけを説明する目的のものであって、限定すると意図されないことが、なおもさらに理解されるべきである。
アミン含有トランスフェクション化合物
本発明は、トランスフェクション試薬として有用な様々なアミン含有化合物およびそれを合成する方法を記載する。より詳細には、本発明のいくつかの実施形態によると、一般構造Iを有する化合物またはその薬学的に許容可能な塩が提供され:
生物学的に活性な化合物を、インビトロにおいて細胞もしくは組織にまたはインビボにおいて動物の細胞もしくは組織に送達するために製剤化される新規トランスフェクション複合体を提供することが、ここで開示される実施形態のさらなる目的である。本明細書中で企図されるような細胞または組織への生物学的に活性な物質の送達は、障害を処置するための治療様式を提供するためのものであり得るか、または科学研究を行う過程において(例えば、研究ツールとして)提供され得る。
本明細書中に記載されるさらなる実施形態は、インビボにおける組織特異的送達のために、多数のトランスフェクション化合物をスクリーニングする方法を提供する。そのような方法は、被験トランスフェクション化合物とともに、マーカーの検出を難なく容易にする化合物を含む複数のトランスフェクション複合体を調製する工程、その複数のトランスフェクション複合体の各々を被験動物に送達する工程、およびマーカーを検出する工程を包含し得る。
本発明はさらに、以下の実施例を考慮することによって明らかにされ得、その実施例は、純粋に本発明の例示であって、決してその範囲を限定しないと意図されている。
表題の2つの化合物の混合物を、4テイルの表題化合物(a)および5テイルの表題化合物(b)を示している以下の一般的な反応スキームに従って合成した。
表題の2つの化合物の混合物を、以下の一般的な反応スキームに従って合成した。
本発明のいくつかの脂質を、コレステロール、ポリ(エチレングリコール)(PEG)脂質、緩衝液およびエタノールも含む脂質組成物に製剤化した。動物起源非含有コレステロールを、Sigma−Aldrich(St Louis,MO)から購入し、1,2−ジパルミトイル−sn−グリセロ−3−ホスホエタノールアミン−N−[メトキシ(ポリエチレングリコール)−2000](アンモニウム塩)(C16 PEG2000 PE)および1,2−ジミリストイル−sn−グリセロ−3−ホスホエタノールアミン−N−[メトキシ(ポリエチレングリコール)−2000](アンモニウム塩)(C14 PEG2000 PE)を、Avanti Lipids(Alabaster,AL)から購入した。RNAiは、安定化化学修飾を伴った25塩基対の二本鎖RNAオリゴヌクレオチドを有するSTEALTH(商標)RNAiだった。STEALTH(商標)RNAiは、Invitrogen(Carlsbad,CA)から商業的に入手可能である。
(表1)脂質配合物
を有する第VII因子(FVII)マウス遺伝子に対するRNAiおよびネガティブコントロールのMedium GC含有量−RNAiを、先に記載したようなプレリポソームと複合体化し、インビボで試験した。マウス20gあたり200μlのリポプレックス(PBS中のFVIIまたはCTRL RNAiを含む)を、10mg/kgおよび2mg/kgの用量(siRNA用量)で低圧尾静脈注射によって注射した。尾静脈注射の36時間後、肝臓組織および血清を、それぞれmRNAおよびタンパク質のノックダウン解析のために回収した。
以下の実験セットを、以下の例外を伴って、本質的には実施例9において上に記載されたように行った。siRNA/リポプレックスの形成後に行われる透析工程は、行わなかった。さらに、IVF2.0、57NOおよび84NOサンプルの乾燥粉末の重量比は、37.8:10.4:51.8であり、57OPT、72OPTおよび84OPTサンプルの乾燥粉末の重量比は、60:7:33だった。生成された配合物を、表2に記載する。
(表2)脂質配合物
本発明のいくつかの脂質を、コレステロールまたはDOPE、緩衝液およびエタノールも含む脂質組成物に製剤化した。動物起源非含有コレステロールを、Sigma−Aldrich(St Louis,MO)から購入し、DOPEをAvanti Lipids(Alabaster,AL)から購入した。それぞれアンチセンス配列
を有する、Silencer(登録商標)Select CSNK2A1 siRNAおよびSilencer(登録商標)SelectネガティブコントロールsiRNA(cat#4390824 siRNA id#s3637およびcat#4390843)は、Life Technologies(Carlsbad,CA)から商業的に入手可能であり、それらを、ヌクレアーゼ非含有水で50μMのストック濃度に再懸濁し、それを下流の実験に適うようにさらに希釈した。
(表3)脂質配合物
トランスフェクション脂質の調製
陽イオン性脂質87(上に示された)は、本明細書中に記載される方法に従ってLife Technologies,Carlsbad,CAにおいて合成され;動物起源非含有コレステロールを、Sigma−Aldrich(StLouis)から購入し、1,2−ジパルミトイル−sn−グリセロ−3−ホスホエタノールアミン−N−[メトキシ(ポリエチレングリコール)−2000](アンモニウム塩)(C16PEG))をAvanti Lipids Alabasterから購入した。CB547、コレステロールおよびC16PEGを、40℃の100%エタノール中で希釈した。次いで、その脂質混合物を、27G針を備えた注射器を用いて、20ml/分の流速で200mM酢酸ナトリウム,pH5.2中で混合した。次いで、その配合物を4℃で貯蔵した。
前の工程において合成されたmRNAの濃度を、25%エタノールを含む水で0.3mg/mlに調整した。等体積のプレリポソームおよびmRNA溶液を混合することによって、リポプレックス(mRNAプレリポソーム複合体)を調製した。混合後、その複合体を、50℃で30分間インキュベートし、次いで、Spectra/Por(登録商標)Float−A−Lyzer(登録商標)G2 8kDaを用いて、1リットルのリン酸緩衝食塩水(PBS),pH7.4において2時間透析した。透析後、体積を測定し、所望のmRNA濃度までPBSで調整した。そのリポプレックスを、インビボ注射まで4℃で貯蔵した。
動物試験において用いたすべての手順は、Institutional Animal Care and Use Committee(IACUC)によって承認されたものであり、当てはまる地域、州および連邦の規制に一致していた。マウスをJackson laboratoriesから購入した(B6.129S4−Gt(ROSA)26Sortm3(CAG−luc)Tyj/J)。このマウスは、CMVプロモーターの支配下におけるloxP隣接終止コドンを有する、CMVによって駆動されるルシフェラーゼレポーター遺伝子を有する。Creリコンビナーゼの存在下において、このloxP部位は、組み換わることにより、その終止コドンを切り取り、それにより、ルシフェラーゼレポータータンパク質の翻訳が可能になる。
Claims (15)
- 一般構造Iを有する化合物またはその薬学的に許容可能な塩:
X1およびX2の各々は、O、N−AおよびC−Aからなる群から独立して選択される部分であり、ここで、Aは、水素およびC1−C20炭化水素鎖からなる群から選択され;
YおよびZの各々は、C=O、およびC=Sからなる群から独立して選択される部分であり;
R1の各々が、それぞれ3〜20個の炭素原子および0〜4個の二重結合を有する、置換または非置換の分枝状または非分枝状のアルキル基とアルケニル基からなる群から独立して選択され;
R2の各々が、
それぞれ3〜20個の炭素原子および0〜4個の二重結合を有する、置換または非置換の分枝状または非分枝状のアルキル基とアルケニル基、ならびに
水素(ただしm=p=0である場合に限る。)
からなる群から独立して選択され;
R4、R5、R6およびR7の各々は、水素と、環式または非環式の置換または非置換の分枝状または非分枝状の脂肪族基からなる群から独立して選択される部分であり;
xは、2であり;
nは、1以上3以下の値を独立して有する整数であり;
mは、0以上20以下の値を独立して有する整数であり;
pは、0または1の値を独立して有する整数であり;
R 3 は、
- R1およびR2の各々が、それぞれ8〜18個の炭素原子および0〜2個の二重結合を有する、置換または非置換の非分枝状のアルキル基とアルケニル基からなる群から独立して選択される、請求項1記載の化合物またはその薬学的に許容可能な塩。
- 請求項1〜3のいずれか一項に記載の化合物またはその薬学的に許容可能な塩を含む、トランスフェクション複合体。
- 少なくとも1つのヘルパー脂質をさらに含む、請求項4記載のトランスフェクション複合体。
- 前記少なくとも1つのヘルパー脂質が、中性脂質および陽イオン性脂質からなる群から選択される、請求項5記載のトランスフェクション複合体。
- 前記少なくとも1つのヘルパー脂質が、コレステロール、3βOH−ステロールおよびその誘導体、ホスファチジルコリン、BMOP(N−(2−ブロモエチル)−N,N−ジメチル−2,3−ビス(9−オクタデセニルオキシ)−プロパンアミニウムブロミド)、DDPES(ジパルミトイルホスファチジルエタノールアミン5−カルボキシスペルミルアミド)、DSPC、CTAB:DOPE(臭化セチルトリメチルアンモニウム(CATB)とDOPEとの配合物)、POPC(1−パルミトイル−2−オレオイル−sn−グリセロ−3−ホスホコリン)、DOPE(ジオレオイルホスファチジルエタノールアミン)、DMG、DMAP(4−ジメチルアミノピリジン)、DMPE(ジミリストイルホスファチジルエタノールアミン)、DOMG、DMA、DOPC(ジオレオイルホスファチジルコリン)、DMPC(ジミリストイルホスファチジルコリン)、DPEPC(ジパルミトイルエチルホスファチジルコリン)、DODAC(ジオレオイルジメチルアンモニウムクロリド)、DOSPER(1,3−ジ−オレオイルオキシ−2−(6−カルボキシスペルミル)−プロピルアミド)、DOTMA(N−[1−(2,3−ジオレイルオキシ)プロピル]−n,n,n−トリメチルアンモニウムクロリド)、DDAB(ジデシルメチルアンモニウムブロミド)、DOTAP(N−[1−(2,3−ジオレオイルオキシ)プロピル]−N,N,N−トリメチル−アンモニウムメチルスルフェート)、DOTAP・Cl、DC−chol(3,β−N,(N',N'−ジメチルアミノエタン)−カルバモイル]コレステロール)、DOSPA(2−(スペルミンカルボキサミド)エチル)−N,N−ジメチル−アンモニウムトリフルオロアセテート)、DC−6−14(O,O'−ジテトラデカノイル−N−(アルファトリメチルアンモニオアセチル)ジエタノールアミンクロリド)、DCPE(ジカプロイルホスファチジルエタノールアミン)、DLRIE(ジラウリルオキシプロピル−3−ジメチルヒドロキシエチルアンモニウムブロミド)、DODAP(1,2−ジオレオイル−3−ジメチルアンモニウム−プロパン)、エチル−PC、DOSPA(2,3−ジオレオイルオキシ−N−[2−(スペルミンカルボキサミドエチル]−N,N−ジ−メチル−1−プロパンアミニウムトリフルオロアセテート)、DOGS(ジオクタデシルアミドグリシルカルボキシスペルミン)、DMRIE(N−[1−(2,3ジミリスチルオキシ)プロピル]−N,N−ジメチル−N−(2−ヒドロキシエチル)アンモニウムブロミド)、DOEPC(ジオレオイルエチル−ホスホコリン)、DOHME(N−[1−(2,3−ジオレオイルオキシ)プロピル]−N−[1−(2−ヒドロキシエチル)]−N,Nジメチルアンモニウムヨージド)、GAP−DLRIE:DOPE(N−(3−アミノプロピル)−N,N−ジメチル−2,3−ビス(ドデシルオキシ)−1−プロパンイミニウムブロミド/ジオレイルホスファチジルエタノールアミン)、DPPC(ジパルミトイルホスファチジルコリン)、DOPG(1,2−ジオレオイル−sn−グリセロ−3−[ホスホ−rac−(3−リシル(1−グリセロール))・Cl)、N−ラウロイルサルコシン、(R)−(+)−リモネン、レシチン類(およびそれらの誘導体);ホスホチジルエタノールアミン(およびその誘導体);ホスファチジルエタノールアミン類、ジオレオイルホスファチジルエタノールアミン)、DPhPE(ジフィタノイルホスファチジルエタノールアミン)、DPPEジパルミトイルホスファチジルエタノールアミン)、ジパルミトイルホスファチジルエタノールアミン、O−Chol(3ベータ[1−オルニチンアミドカルバモイル]コレステロール)、POPE(パルミトイルオレオイルホスファチジルエタノールアミン)およびジステアロイルホスファチジルエタノールアミン;ホスホチジルコリン;ホスファチジルコリン類、DPPC(ジパルミトイルホスファチジルコリン)POPC(パルミトイルオレオイルホスファチジルコリン)およびジステアロイルホスファチジルコリン;ホスファチジルグリセロール;ピペラジンベースの陽イオン性脂質、ホスファチジルグリセロール類、例えば、DOPG(ジオレオイルホスファチジルグリセロール)、DPPG(ジパルミトイルホスファチジルグリセロール)およびジステアロイルホスファチジルグリセロール;ホスファチジルセリン(およびその誘導体);ホスファチジルセリン類、例えば、ジオレオイル−またはジパルミトイルホスファチジルセリン;ジ第四級アンモニウム塩、例えば、N,N'−ジオレイル−N,N,N',N'−テトラメチル−1,2−エタンジアミン(TmedEce)、N,N'−ジオレイル−N,N,N',N'−テトラメチル−1,3−プロパンジアミン(PropEce)、N,N'−ジオレイル−N,N,N',N'−テトラメチル−1,6−ヘキサンジアミン(HexEce)およびそれらの対応するN,N'−ジセチル飽和アナログ(TmedAce、PropAceおよびHexAce)、ジホスファチジルグリセロール類;脂肪酸エステル類;一価陽イオン性トランスフェクション脂質、例えば、1−デオキシ−1−[ジヘキサデシル(メチル)アンモニオ]−D−キシリトール;1−デオキシ−1−[メチル(ジテトラデシル)アンモニオ]−Dアラビニトール;1−デオキシ−1−[ジヘキサデシル(メチル)アンモニオ]−D−アラビニトール;1−デオキシ−1−[メチル(ジオクタデシル)アンモニオ]−Dアラビニトール、グリセロールエステル類;スフィンゴ脂質;カルジオリピン;セレブロシド類;およびセラミド類;ならびにそれらの混合物からなるリストから選択される、請求項5記載のトランスフェクション複合体。
- 少なくとも1つのペグ化脂質をさらに含む、請求項4記載のトランスフェクション複合体。
- 少なくとも1つの生理活性物質をさらに含む、請求項4記載のトランスフェクション複合体。
- 前記少なくとも1つの生理活性物質が、DNA分子、RNA分子、タンパク質、および薬物からなる群から選択される、請求項9記載のトランスフェクション複合体。
- 前記RNA分子が、siRNA、shRNA、miRNA、stRNA、およびmRNAからなる群から選択される、請求項10記載のトランスフェクション複合体。
- 前記少なくとも1つの生理活性物質が、siRNA分子である、請求項9記載のトランスフェクション複合体。
- 前記少なくとも1つの生理活性物質が、mRNA分子である、請求項9記載のトランスフェクション複合体。
- 前記少なくとも1つの生理活性物質が、DNA分子である、請求項9記載のトランスフェクション複合体。
- 請求項3記載の化合物のうちの少なくとも1つの化合物;
その薬学的に許容される塩;
少なくとも1つのヘルパー脂質;
DNA分子、RNA分子、およびタンパク質からなる群から選択される少なくとも1つの生理活性物質;ならびに
任意で少なくとも1つのペグ化脂質
を含むトランスフェクション複合体。
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