JPH08508295A - 細胞への浸透増進プロドラッグ - Google Patents
細胞への浸透増進プロドラッグInfo
- Publication number
- JPH08508295A JPH08508295A JP6521827A JP52182794A JPH08508295A JP H08508295 A JPH08508295 A JP H08508295A JP 6521827 A JP6521827 A JP 6521827A JP 52182794 A JP52182794 A JP 52182794A JP H08508295 A JPH08508295 A JP H08508295A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- group
- prodrug
- pharmaceutically active
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- 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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- 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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- 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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- A—HUMAN NECESSITIES
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.薬学的に活性な化合物と細胞内輸送補助剤との共有結合体である薬学的に許 容されるプロドラッグであり、細胞内の酵素活性に対して切断感受性である共有 結合が存在することを特徴とするプロドラッグ。 2.薬学的に活性な化合物が、薬学的に活性なカルボン酸であり、補助剤が、グ リセロール、C3-20脂肪酸モノグリセリド、C3-20脂肪酸ジグリセリド、C3-20 脂肪酸のヒドロキシ−C2-6−アルキルエステル、リゾホスファチド酸のヒドロ キシ−C2-6−アルキルエステル、リゾプラズマローゲン、リゾホスホリピッド 、リゾホスファチド酸アミド、グリセロリン酸、リゾ−ホスファチダルエタノー ルアミン、リゾ−ホスファチジルエタノールアミン並びに上記アミンのN−モノ −及びN,N−ジ−(C1-4)−アルキル体及び4級化誘導体から選択される少 なくとも一種の薬学的に許容されるアルコールを含む、請求の範囲1記載のプロ ドラッグ。 3.薬学的に活性なカルボン酸が、分岐鎖の脂肪族カルボン酸、サリチル酸、ス テロイドカルボン酸、モノ複素環式カルボン酸及びポリ複素環式カルボン酸から 選択される、請求の範囲2記載のプロドラッグ。 4.部分的に又は全体的にカルボン酸(a)をヒドロキシ化合物(b)でエステ ル化した化合物であり、(a)は、構造式 (HOOC−CH2−)2−N−A−N−(CH2−COOH)2 〔式中、Aは、飽和又は不飽和の脂肪族、芳香族又は複素環式結合基を表し、 二つの窒素原子の間の直鎖結合間に、2〜4の酸素原子を間に有していてもよい 2〜8炭素原子の連続鎖を有する(ただし、酸素原子は窒素原子に直接結合しな い)。〕を有する薬学的に許容されるカルシウムのキレート化剤であり、(b) は、3〜32炭素原子及び1〜3の水酸基を有する薬学的に許容されるアルコー ルであり、 かつ、前記部分的にエステル化されたカルボン酸のアルカリ金属塩、及び一種 以上の塩形成可能な窒素原子を含有する前記エステル化されたカルボン酸の酸付 加塩である、請求の範囲1記載のプロドラッグ。 5.薬学的に許容されるアルコールがC7-32の二級モノ水素アルコールである、 請求の範囲4記載のプロドラッグ。 6.薬学的に許容されるアルコールが3〜6の炭素原子及び1〜3の水酸基を有 する、請求の範囲5記載のプロドラッグ。 7.結合基Aが、−(CH2CH2)m−(m=1〜4、このうち2〜4の窒素に 接続していない炭素は酸素原子に置き換えてもよい。)及び−CR=CR−O− CH2CH2−O−CR′=CR′−(R−R基及びR′−R′基の各対基は、隣 接する−C=C−基と一緒に、5又は6の環原子を含む芳香環又は複素環を表し 、R−Rによる環と、R′−R′による環は同じでも異なっていてもよい。)か らなる群から選択される、請求の範囲4記載のエステル。 8.結合基Aが−CH2CH2−及び−CH2CH2−O−CH2CH2−O−CH2 CH2−からなる群から選択される、請求の範囲4記載のエステル。 9.結合基が、−CR=CR−O−CH2CH2−O−CR′=CR′−(R−R 基及びR′−R′基の各対基は、隣接する−C=C−基と一緒に、5又は6の環 原子を含む芳香環又は複素環を表し、該芳香環及び複素環がフラン、チオフェン 、ピロール、ピラゾール、イミダゾール、1,2,3−トリアゾール、オキサゾ ール、イソオキサゾール、1,2,3−オキサジアゾール、1,2,5−オキサ ジアゾール、チアゾール、イソチアゾール、1,2,3−チアジアゾール、1, 2,5−チアジアゾール、ベンゼン、ピリジン、ピリダジン、ピリミジン、ピラ ジン、1,2,3−トリアジン、1,2,4−トリアジン並びに1,2−、1, 3−及び1,4−オキサジン及び−チアジンからなる群から選択され、R−Rに よる環とR′−R′による環は同じでも異なっていてもよい)である、請求の範 囲4記載のエステル。 10.結合基Aが、−CR=CR−O−CH2CH2−O−CR′=CR′−〔R− R基及びR′−R′基の各対基は、隣接する−C=C−基と一緒に、非置換又は 置換ベンゼン環から選択された同じ又は異なる環を表すか(該置換ベンゼン環は 、C1-3アルキル、C1-3アルコキシ、フッ素、塩素、臭素、ヨウ素、及びCF3 からなる群から選択される1〜4置換基を有する)〕、又は−O−(CH2)n− O−(n=3)である単一の二価置換基である、請求の範囲9記載のエステル。 11.キレート化剤がエチレン−1,2−ジアミン−N,N,N′,N′−テトラ 酢酸、エチレン−1,2−ジオール−ビス−(2−アミノエチルエーテル)−N ,N,N′,N′−テトラ酢酸及び1,2−ビス−(2−アミノフェノキシ)エ タン−N,N,N′,N′−テトラ酢酸から選択される、請求の範囲4記載のエ ステル。 12.薬学的に許容されるアルコールが3〜6の炭素原子及び1〜3の水酸基を有 する、請求の範囲7〜11のいずれか一項に記載のエステル。 13.薬学的に許容されるアルコールが、グリセロール、C3-20脂肪酸モノグリセ リド、C3-20脂肪酸ジグリセリド、C3-20脂肪酸のヒドロキシ−C2-6−アルキ ルエステル、リゾホスファチド酸のヒドロキシ−C2-6−アルキルエステル、リ ゾプラズマローゲン、リゾホスホリピッド、リゾホスファチド酸アミド、グリセ ロリン酸、リゾ−ホスファチダルエタノールアミン、リゾ−ホスファチジルエタ ノールアミン並びに上記アミンのN−モノ−及びN,N−ジ−(C1-4)−アル キル体及び4級化誘導体から選択される少なくとも一種の基を有する、請求の範 囲12記載のエステル。 14.1,2−ビス−(2−アミノフェノキシ)エタン−N,N,N′,N′−テ トラ酢酸とヘプタノイル−sn−3−グリセロホスファチジルコリン又はオクタ ノイル−sn−3−グリセロホスホリルコリンのモノ−、ジ−、トリ−、及びテ トラ−エステルである、請求の範囲4記載のエステル。 15.薬学的に活性な化合物がプロテインキナーゼ阻害剤である、請求の範囲1記 載のプロドラッグ。 16.グリセロール、C3-20脂肪酸モノグリセリド、C3-20脂肪酸ジグリセリド、 C3-20脂肪酸のヒドロキシ−C2-6−アルキルエステル、リゾホスファチド酸の ヒドロキシ−C2-6−アルキルエステル、リゾプラズマローゲン、リゾホスホリ ピッド、リゾホスファチド酸アミド、グリセロリン酸、リゾ−ホスファチダルエ タノールアミン、リゾ−ホスファチジルエタノールアミン並びに上記アミンのN −モノ−及びN,N−ジ−(C1-4)−アルキル体及び4級化誘導体から選択さ れる少なくとも一種の基を有する薬学的に許容されるアルコールと、プロテイン キナーゼ阻害剤のカルボン酸とのエステル化合物である、請求の範 囲15記載のプロドラッグ。 17.プロテインキナーゼ阻害剤がノルカジオシス種(Nocardiopsis sp.)から得 られたプロテインキナーゼ阻害剤k252bである、請求の範囲16記載のプロ ドラッグ。 18.プロテインキナーゼ阻害剤が、置換可能なN−結合水素原子を有するアミノ 基を含有し、プロドラッグが該アミンの、グリセロリン酸、O−アシルグリセロ リン酸、エーテル化されたグリセロリン酸及びモノアシル化モノエーテル化グリ セロリン酸からなる群から選択されたリン酸誘導体のアミドである、請求の範囲 15記載のプロドラッグ。 19.プロテインキナーゼ阻害剤が、非環式又は複素環式アミノアルキル基により N−置換されたイソキノリン−5−スルホンアミドである、請求の範囲18記載 のプロドラッグ。 20.アミノアルキル基がNHCH2CH2NHCH3及び2−メチルピペラジン− 1−イルからなる群から選択される、請求の範囲19記載のプロドラッグ。 21.プロテインキナーゼ阻害剤が、少なくとも一種のフェノール性水酸基を含有 し、プロドラッグが該フェノール性水酸基の、グリセロリン酸、O−アシルグリ セロリン酸、エーテル化されたグリセロリン酸及びモノアシル化モノエーテル化 グリセロリン酸からなる群から選択されたリン酸誘導体とのエステル化合物であ る、請求の範囲15記載のプロドラッグ。 22.プロテインキナーゼ阻害剤が、4′,5,7−トリヒドロキシイソフラボン である請求の範囲21記載の阻害剤。 23.異常細胞内酵素活性に関連したヒトの病気又は症状を治療する方法であり、 薬学的に許容される細胞膜浸透性プロドラッグを、そのような症状又は病気を有 するヒトに、異常酵素活性を減少させるのに有効な量投与することを含み、該プ ロドラッグは、細胞膜非浸透性の薬学的に活性な化合物と細胞内輸送補助剤との 共有結合体で、細胞内の酵素活性に切断感受性である共有結合が存在することを 特徴とし、そのような結合はそのような活性で切断され、異常細胞内酵素活性を 有する細胞内で薬学的に活性な化合物が選択的に蓄積される、方法。 24.薬学的に活性な化合物が、薬学的に活性なカルボン酸であり、補助剤が、グ リセロール、C3-20脂肪酸モノグリセリド、C3-20脂肪酸ジグリセリド、C3-20 脂肪酸のヒドロキシ−C2-6−アルキルエステル、リゾホスファチド酸のヒドロ キシ−C2-6−アルキルエステル、リゾプラズマローゲン、リゾホスホリピッド 、リゾホスファチド酸アミド、グリセロリン酸、リゾ−ホスファチダルエタノー ルアミン、リゾ−ホスファチジルエタノールアミン並びに上記アミンのN−モノ −及びN,N−ジ−(C1-4)−アルキル体及び4級化誘導体から選択される少 なくとも一種の薬学的に許容されるアルコールを含む、請求の範囲23記載の方 法。 25.薬学的に活性なカルボン酸が、分岐鎖の脂肪族カルボン酸、サリチル酸、ス テロイドカルボン酸、モノ複素環式カルボン酸及びポリ複素環式カルボン酸から 選択される、請求の範囲24記載の方法。 26.異常酵素活性が細胞内の過剰のCa2+イオンに関連しており、薬学的に活性 な化合物がカルシウムキレート化剤である、請求の範囲23記載の方法。 27.プロドラッグが、部分的に又は全体的にキレート化剤(a)をアルコール化 合物(b)でエステル化した化合物であり、(a)は、構造式 (HOOC−CH2−)2−N−A−N−(CH2−COOH)2 〔式中、Aは、飽和又は不飽和の脂肪族、芳香族又は複素環式結合基を表し、 二つの窒素原子の間の直鎖結合間に、2〜4の酸素原子を間に有していてもよい 2〜8炭素原子の連続鎖を有する(ただし、酸素原子は窒素原子に直接結合しな い)。〕を有する薬学的に許容されるカルシウムのキレート化剤であり、(b) は、3〜32炭素原子及び1〜3の水酸基を有する薬学的に許容されるアルコー ルであり、 かつ、部分的にエステル化されたカルボン酸のアルカリ金属塩、及び一種以上 の塩形成可能な窒素原子を含有するエステル化されたカルボン酸の酸付加塩であ る、請求の範囲26記載の方法。 28.薬学的に許容されるアルコールがC7-32の二級モノ水素アルコールである、 請求の範囲27記載の方法。 29.薬学的に許容されるアルコールが3〜6の炭素原子及び1〜3の水酸基を有 する、請求の範囲27記載の方法。 30.結合基Aが、−(CH2CH2)m−(m=1〜4、このうち2〜4の窒素に 接続していない炭素は酸素原子に置き換えてもよい。)及び−CR=CR−O− CH2CH2−O−CR′=CR′−(R−R基及びR′−R′基の各対基は、隣 接する−C=C−基と一緒に、5又は6の環原子を含む芳香環又は複素環を表し 、R−Rによる環と、R′−R′による環は同じでも異なっていてもよい。)か らなる群から選択される、請求の範囲27記載の方法。 31.結合基Aが−CH2CH2−及び−CH2CH2−O−CH2CH2−O−CH2 CH2−からなる群から選択される、請求の範囲27記載の方法。 32.結合基が、−CR=CR−O−CH2CH2−O−CR′=CR′−(R−R 基及びR′−R′基の各対基は、隣接する−C=C−基と一緒に、5又は6の環 原子を含む芳香環又は複素環を表し、該芳香環及び複素環がフラン、チオフェン 、ピロール、ピラゾール、イミダゾール、1,2,3−トリアゾール、オキサゾ ール、イソオキサゾール、1,2,3−オキサジアゾール、1,2,5−オキサ ジアゾール、チアゾール、イソチアゾール、1,2,3−チアジアゾール、1, 2,5−チアジアゾール、ベンゼン、ピリジン、ピリダジン、ピリミジン、ピラ ジン、1,2,3−トリアジン、1,2,4−トリアジン並びに1,2−、1, 3−及び1,4−オキサジン及び−チアジンからなる群から選択され、R−Rに よる環とR′−R′による環は同じでも異なっていてもよい)である、請求の範 囲27記載の方法。 33.結合基Aが、−CR=CR−O−CH2CH2−O−CR′=CR′−〔R− R基及びR′−R′基の各対基は、隣接する−C=C−基と一緒に、非置換又は 置換ベンゼン環から選択された同じ又は異なる環を表すか(該置換ベンゼン環は 、C1-3アルキル、C1-3アルコキシ、フッ素、塩素、臭素、ヨウ素、及びCF3 からなる群から選択される1〜4置換基を有する)〕、又は−O−(CH2)n− O−(n=3)である単一の二価置換基である、請求の範囲32記載の方法。 34.キレート化剤がエチレン−1,2−ジアミン−N,N,N′,N′−テトラ 酢酸、エチレン−1,2−ジオール−ビス−(2−アミノエチルエーテル)−N ,N,N′,N′−テトラ酢酸及び1,2−ビス−(2−アミノフェノキシ) エタン−N,N,N′,N′−テトラ酢酸から選択される、請求の範囲27記載 の方法。 35.薬学的に許容されるアルコールが3〜6の炭素原子及び1〜3の水酸基を有 する、請求の範囲30〜34のいずれか一項に記載の方法。 36.薬学的に許容されるアルコールが、グリセロール、C3-20脂肪酸モノグリセ リド、C3-20脂肪酸ジグリセリド、C3-20脂肪酸のヒドロキシ−C2-6−アルキ ルエステル、リゾホスファチド酸のヒドロキシ−C2-6−アルキルエステル、リ ゾプラズマローゲン、リゾホスホリピッド、リゾホスファチド酸アミド、グリセ ロリン酸、リゾ−ホスファチダルエタノールアミン、リゾ−ホスファチジルエタ ノールアミン並びに上記アミンのN−モノ−及びN,N−ジ−(C1-4)−アル キル体及び4級化誘導体から選択される少なくとも一種の基を有する、請求の範 囲35記載の方法。 37.1,2−ビス−(2−アミノフェノキシ)エタン−N,N,N′,N′−テ トラ酢酸とヘプタノイル−sn−3−グリセロホスファチジルコリン又はオクタ ノイル−sn−3−グリセロホスホリルコリンのモノ−、ジ−、トリ−、及びテ トラ−エステルである、請求の範囲27記載の方法。 38.薬学的に活性な化合物がプロテインキナーゼ阻害剤である、請求の範囲23 記載の方法。 39.プロドラッグが、グリセロール、C3-20脂肪酸モノグリセリド、C3-20脂肪 酸ジグリセリド、C3-20脂肪酸のヒドロキシ−C3-20−アルキルエステル、リゾ ホスファチド酸のヒドロキシ−C2-6−アルキルエステル、リゾプラズマローゲ ン、リゾホスホリピッド、リゾホスファチド酸アミド、グリセロリン酸、リゾ− ホスファチダルエタノールアミン、リゾ−ホスファチジルエタノールアミン並び に上記アミンのN−モノ−及びN,N−ジ−(C1-4)−アルキル体及び4級化 誘導体から選択される少なくとも一種の基を有する薬学的に許容されるアルコー ルと、プロテインキナーゼ阻害剤のカルボン酸とのエステル化合物である、請求 の範囲38記載の方法。 40.プロテインキナーゼ阻害剤がノルカジオシス種から得られたプロテインキナ ーゼ阻害剤k252bである、請求の範囲39記載の方法。 41.プロテインキナーゼ阻害剤が、置換可能なN−結合水素原子を有するアミノ 基を含有し、プロドラッグが該アミンの、グリセロリン酸、O−アシルグリセロ リン酸、エーテル化されたグリセロリン酸及びモノアシル化モノエーテル化グリ セロリン酸からなる群から選択されたリン酸誘導体のアミドである、請求の範囲 38記載の方法。 42.プロテインキナーゼ阻害剤が、非環式又は複素環式アミノアルキル基により N−置換されたイソキノリン−5−スルホンアミドである、請求の範囲38記載 の方法。 43.アミノアルキル基がNHCH2CH2NHCH3及び2−メチルピペラジン− 1−イルからなる群から選択される、請求の範囲42記載の方法。 44.プロテインキナーゼ阻害剤が、少なくとも一種のフェノール性水酸基を含有 し、プロドラッグが該フェノール性水酸基の、グリセロリン酸、O−アシルグリ セロリン酸、エーテル化されたグリセロリン酸及びモノアシル化モノエーテル化 グリセロリン酸からなる群から選択されたリン酸誘導体とのエステル化合物であ る、請求の範囲38記載の方法。 45.プロテインキナーゼ阻害剤が、4′,5,7−トリヒドロキシイソフラボン である請求の範囲44記載の方法。 46.異常細胞内酵素活性に関連したヒトの病気又は症状を、そのような活性を有 する細胞内に細胞膜非浸透性の薬学的に活性な化合物を選択的に蓄積することに より治療する、薬学的に許容される細胞膜浸透性プロドラッグである薬剤の製造 のための使用であり、該プロドラッグは、薬学的に活性な化合物と細胞内輸送補 助剤との共有結合体で、細胞内の酵素活性に切断感受性である共有結合を有する ことを特徴とし、そのような結合はそのような活性で切断される。 47.プロドラッグが請求の範囲2〜22のいずれか一項で定義されたものである 、請求の範囲46記載の使用。 48.薬学的に活性な化合物が薬学的に活性な核酸又は薬学的に活性な核酸のフラ グメントである請求の範囲1記載のプロドラッグ。 49.薬学的に活性な化合物が薬学的に活性な核酸又は薬学的に活性な核酸のフラ グメントである請求の範囲23記載の方法。
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CA2227013A1 (en) * | 1995-07-14 | 1997-02-06 | Glycotech Corp. | Compounds and methods for treatment of egf receptor associated cancers and purification of the egf receptor |
US6350780B1 (en) * | 1995-07-28 | 2002-02-26 | Allergan Sales, Inc. | Methods and compositions for drug delivery |
US6576636B2 (en) | 1996-05-22 | 2003-06-10 | Protarga, Inc. | Method of treating a liver disorder with fatty acid-antiviral agent conjugates |
US5795909A (en) | 1996-05-22 | 1998-08-18 | Neuromedica, Inc. | DHA-pharmaceutical agent conjugates of taxanes |
ES2206891T3 (es) | 1997-02-11 | 2004-05-16 | The Victoria University Of Manchester | Conjugados bioreductivos para el direccionamiento de medicamentos. |
CA2284142C (en) * | 1997-03-19 | 2008-02-26 | Lxr Biotechnology Inc. | Compositions containing lysophosphotidic acids which inhibit apoptosis and uses thereof |
EP1240922B1 (en) * | 1997-08-08 | 2008-11-12 | Celmed Oncology (USA), Inc. | Methods and compositions for overcoming resistance to biologic and chemotherapy |
CN1307421C (zh) | 1997-08-08 | 2007-03-28 | 塞米得肿瘤学美国公司 | 克服生物及化学治疗抗性的方法与组合物 |
DE69900841T2 (de) * | 1998-01-23 | 2002-10-02 | Newbiotics Inc | Durch enzymkatalyse erhaltene therapeutische substanzen. |
US7462605B2 (en) | 1998-01-23 | 2008-12-09 | Celmed Oncology (Usa), Inc. | Phosphoramidate compounds and methods of use |
US7235583B1 (en) | 1999-03-09 | 2007-06-26 | Luitpold Pharmaceuticals, Inc., | Fatty acid-anticancer conjugates and uses thereof |
CN1391486A (zh) * | 1999-07-22 | 2003-01-15 | 新生物公司 | 治疗对治疗有抗性的肿瘤的方法 |
US6683061B1 (en) | 1999-07-22 | 2004-01-27 | Newbiotics, Inc. | Enzyme catalyzed therapeutic activation |
IL131887A0 (en) | 1999-09-14 | 2001-03-19 | Dpharm Ltd | Phospholipid prodrugs of anti-proliferative drugs |
US6670341B1 (en) | 1999-10-28 | 2003-12-30 | Wake Forest University Health Sciences | Compositions and methods for double-targeting virus infections and targeting cancer cells |
US7026469B2 (en) | 2000-10-19 | 2006-04-11 | Wake Forest University School Of Medicine | Compositions and methods of double-targeting virus infections and cancer cells |
CZ20022507A3 (cs) * | 2000-01-20 | 2003-01-15 | Omegatech, Inc. | Způsob chování králíků |
WO2001083492A1 (en) * | 2000-05-02 | 2001-11-08 | Newbiotics, Inc. | Improved beta-lactam antibiotics |
US7309696B2 (en) | 2000-10-19 | 2007-12-18 | Wake Forest University | Compositions and methods for targeting cancer cells |
CA2441350A1 (en) | 2001-01-19 | 2002-07-25 | Newbiotics, Inc. | Methods to treat autoimmune and inflammatory conditions |
AU2002305099A1 (en) | 2001-03-23 | 2002-10-08 | Protarga, Inc. | Fatty alcohol drug conjugates |
WO2002076402A2 (en) | 2001-03-23 | 2002-10-03 | Protarga, Inc. | Fatty amine drug conjugates |
WO2003068242A1 (en) | 2002-02-11 | 2003-08-21 | Vertex Pharmaceuticals Incorporated | Phospholipids as caspase inhibitor prodrugs |
US20050187191A1 (en) * | 2004-02-20 | 2005-08-25 | Kucera Louis S. | Methods and compositions for the treatment of respiratory syncytial virus |
USD692565S1 (en) * | 2010-06-03 | 2013-10-29 | Smith & Nephew, Inc. | Organ protection layer |
CA140188S (en) | 2010-10-15 | 2011-11-07 | Smith & Nephew | Medical dressing |
CA140189S (en) | 2010-10-15 | 2011-11-07 | Smith & Nephew | Medical dressing |
AU2014209028C1 (en) * | 2013-01-28 | 2019-08-29 | Hector L. Lopez | Methods of improving tolerability, pharmacodynamics, and efficacy of b-alanine and use therefor |
CN108659038B (zh) * | 2017-03-31 | 2022-01-11 | 江苏恩华药业股份有限公司 | 1-硬脂酰-2-丙戊酰-sn-甘油-3-磷脂酰胆碱的多晶型物及制备方法 |
CN110407867A (zh) * | 2018-04-28 | 2019-11-05 | 江苏恩华药业股份有限公司 | 丙戊酸磷脂衍生物的新晶型及其制备方法 |
CN111334369B (zh) * | 2020-03-11 | 2022-10-21 | 陕西科技大学 | 一种酶法制备卵磷脂型pufa的方法 |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR244F (ja) * | 1900-01-01 | |||
ATE7295T1 (de) * | 1980-01-16 | 1984-05-15 | Lacer, S.A. | 2-halo-pyridine, ihre herstellung und pharmazeutische zusammensetzungen. |
US5223263A (en) * | 1988-07-07 | 1993-06-29 | Vical, Inc. | Liponucleotide-containing liposomes |
IT1201149B (it) * | 1987-01-14 | 1989-01-27 | Indena Spa | Complessi di bioflavonoidi con fosfolipidi,loro preparazione,uso e composizioni farmaceutici e cosmetiche |
IT1201151B (it) * | 1987-01-14 | 1989-01-27 | Indena Spa | Complessi fosfolipidici con estratti da vitis vinifera,procedimento per la loro preparazione e composizioni che li cntengono |
WO1989005358A1 (en) * | 1987-11-30 | 1989-06-15 | University Of Iowa Research Foundation | Dna and rna molecules stabilized by modifications of the 3'-terminal phosphodiester linkage and their use as nucleic acid probes and as therapeutic agents to block the expression of specifically targeted genes |
DE3801587A1 (de) * | 1988-01-21 | 1989-08-03 | Hoechst Ag | Neue aminosaeureglyceride, verfahren zu ihrer herstellung, sie enthaltende arzneimittel und deren verwendung |
WO1990010448A2 (en) * | 1989-03-07 | 1990-09-20 | Genentech, Inc. | Covalent conjugates of lipid and oligonucleotide |
JPH03133987A (ja) * | 1989-10-18 | 1991-06-07 | Kowa Yakuhin Kogyo Kk | 2‐マイトマイシンc‐スクシニル‐1,3‐ジパルミトイルグリセロールおよびその製造法 |
JPH03275625A (ja) * | 1990-03-23 | 1991-12-06 | Nippon Oil & Fats Co Ltd | 制癌剤およびその製造法 |
WO1991016920A1 (en) * | 1990-05-07 | 1991-11-14 | Vical, Inc. | Lipid prodrugs of salicylate and nonsteroidal anti-inflammatory drugs |
CH679856A5 (ja) * | 1990-07-04 | 1992-04-30 | Lonza Ag | |
US5149794A (en) * | 1990-11-01 | 1992-09-22 | State Of Oregon | Covalent lipid-drug conjugates for drug targeting |
WO1992017185A1 (en) * | 1991-03-29 | 1992-10-15 | University Of Florida | Targeted drug delivery via mixed phosphate derivatives |
WO1993000910A1 (en) * | 1991-07-12 | 1993-01-21 | Vical, Inc. | Antiviral liponucleosides: treatment of hepatitis b |
US6015834A (en) * | 1992-10-20 | 2000-01-18 | Toronto Neuroprotection Group | In vivo treatment of mammalian cells with a cell membrane permeant calcium buffer |
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1993
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1994
- 1994-03-30 KR KR1019950704313A patent/KR100400075B1/ko not_active IP Right Cessation
- 1994-03-30 HU HU9502866A patent/HU221678B1/hu not_active IP Right Cessation
- 1994-03-30 AU AU63808/94A patent/AU682029B2/en not_active Ceased
- 1994-03-30 DE DE69433560T patent/DE69433560T2/de not_active Expired - Lifetime
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- 1994-03-30 AT AT94911239T patent/ATE259661T1/de not_active IP Right Cessation
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IL105244A (en) | 2003-07-31 |
AU682029B2 (en) | 1997-09-18 |
ATE259661T1 (de) | 2004-03-15 |
JP3900533B2 (ja) | 2007-04-04 |
AU6380894A (en) | 1994-10-24 |
EP0691852A1 (en) | 1996-01-17 |
CA2159610A1 (en) | 1994-10-01 |
EP0691852B1 (en) | 2004-02-18 |
NZ263208A (en) | 1997-06-24 |
KR100400075B1 (ko) | 2004-02-25 |
SG81890A1 (en) | 2001-07-24 |
DE69433560T2 (de) | 2004-12-16 |
HU221678B1 (hu) | 2002-12-28 |
IL105244A0 (en) | 1993-07-08 |
US6136796A (en) | 2000-10-24 |
WO1994022483A2 (en) | 1994-10-13 |
CA2159610C (en) | 2008-05-20 |
HUT73669A (en) | 1996-09-30 |
HU9502866D0 (en) | 1995-11-28 |
WO1994022483A3 (en) | 1994-12-22 |
DE69433560D1 (de) | 2004-03-25 |
US5985854A (en) | 1999-11-16 |
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