JP2015527373A - 活性剤を送達するためのフェノキシアルキルジエタノールアミンとジイソプロパノールアミン化合物 - Google Patents
活性剤を送達するためのフェノキシアルキルジエタノールアミンとジイソプロパノールアミン化合物 Download PDFInfo
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- JP2015527373A JP2015527373A JP2015528657A JP2015528657A JP2015527373A JP 2015527373 A JP2015527373 A JP 2015527373A JP 2015528657 A JP2015528657 A JP 2015528657A JP 2015528657 A JP2015528657 A JP 2015528657A JP 2015527373 A JP2015527373 A JP 2015527373A
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- Prior art keywords
- compound
- hydroxyphenoxy
- diisopropanolamine
- hexyl
- salt
- Prior art date
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- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- C07C217/14—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 a carbon atom of a six-membered aromatic ring
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- C07C217/20—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 a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
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Abstract
Description
しかしながら、容易に調製でき、広範囲にわたる活性剤を多様な投与経路で送達できる、シンプルで、廉価で、安全な送達システムが、今なお必要とされている。
化合物1
送達剤化合物は、遊離塩基またはその塩の形態でもよい。適した塩として、有機および無機塩類、例えば、アンモニウム、酢酸塩、クエン酸、ハライド(好ましくは塩酸塩)、水酸化物、、硫酸塩、硝酸塩、りん酸塩、アルコキシ、ペルクロレイト、テトラフルオロボレート、カルボキシル酸、メシレート、フマル酸、マロン酸、コハク酸、酒石酸、アセテート、グルコン酸塩、マレイン酸などが挙げられるが、これに限定されない。
本発明の使用に適した生物活性剤は、薬剤または治療剤を含む。適した活性剤は、胃腸管内で、酸加水分解や、酵素等により、効果が低下するか、効果を失うか、破壊される活性剤を含む。また、適した活性剤として、経口投与した時に、大きさ、構造または充填量によって、吸収を妨げたり、阻害したりする高分子薬剤も含まれる。
トロンボポイエチン;フィルグラスチム;プロスタグランジン;シクロスポリン;バソプレシン;クロモリンナトリウム(クロモグリク酸ナトリウムまたはクロモグリク酸二ナトリウム);バンコマイシン;デスフェリオキサミン(DFO);アレンドロネート、チルドロネート、エチドロナート、クロドロネート、パミドロネート、オルパドロネート、およびインカドロネートを含むビスホスホネート類;フラグメントを含む副甲状腺ホルモン(PTH);BIBN−4096BSおよびその他のカルシトニン遺伝子関連タンパク質アンタゴニスト類を含む片頭痛剤;グルカゴン様ペプチド1(GLP−1);抗生物質、抗菌剤、抗真菌剤を含む抗微生物剤;ビタミン類;およびこれら化合物の類似体、フラグメント、模倣体、またはポリエチレングリコール(PEG)修飾誘導体;またはこれらの任意の組み合わせの物質、およびその合成、天然、および組換え源を含むがこれに限定されない。抗生物質の非限定的な例として、グラム陽性菌に作用する抗生物質、殺菌性抗生物質、ダプトマイシンやその類似体などの、リポペプチドや環状ペプチド抗生物質を含む。
本発明の化合物は、本発明に記載する1つ以上の送達剤化合物、および1つ以上の生物活性剤を含む。一実施形態においては、投与に先だって、1つ以上の送達剤化合物、または、それら化合物の塩を活性剤と混合して投与組成物を形成し、送達剤として使用してもよい。
化合物3および4を、4−ベンジルオキシフェノールと適量のジアルキルブロミド(それぞれヘキシルまたはオクチル)を出発材料として、化合物2と同様の方法にて合成した。
周知のhERG実験数値を有する化合物を使用して一連の計算モデルを作成した。個別の化合物のhERG活性を予測するために、3つの異なるモデルの結果を組み合わせたコンセンサスモデルを使用した。化合物を分類するIC50閾値は、下記の通りである:
・“****”: <2.0μM(高)
・“***”: 2.0〜5.0μM(中)
・“**”: 5.0〜50.0μM(低)
・“*”: >50.0μM(超低)
本発明の送達剤化合物を使用したラット(250〜300gのラット)へのトロデュスケミンの経口送達を、下記のように評価した。トロデュスケミン3.8mgと、送達剤30mgを含有するミニ錠剤を調製した。各ラットは、投与総量がトロデュスケミン25mg/kg、送達剤200mg/kgとなるようミニ錠剤を2つ投与された。血液サンプルを眼球後出血(retro−orbital bleeding)により連続して採集し、また、それぞれ投与前と、投与後1、3、6、10、24時間後に採血した。血漿中のトロデュスケミン存在量をアッセイした。
Claims (24)
- 下記から選択される化合物、またはその塩:
化合物1
化合物2
化合物3
化合物4
化合物5
化合物6
化合物7
化合物8
- 4−(2−フルオロ−5−メチルフェノキシ)ブチルジエタノールアミン、または薬剤的に許容できるその塩。
- 6−(2−ヒドロキシフェノキシ)ヘキシルジエタノールアミン、または薬剤的に許容できるその塩。
- 6−(4−ヒドロキシフェノキシ)ヘキシルジエタノールアミン、または薬剤的に許容できるその塩。
- 8−(4−ヒドロキシフェノキシ)オクチルジエタノールアミン、または薬剤的に許容できるその塩。
- 4−(2−フルオロ−5−メチルフェノキシ)ブチルジイソプロパノールアミン、または薬剤的に許容できるその塩。
- 6−(2−ヒドロキシフェノキシ)ヘキシルジイソプロパノールアミン、または薬剤的に許容できるその塩。
- 6−(4−ヒドロキシフェノキシ)ヘキシルジイソプロパノールアミン、または薬剤的に許容できるその塩。
- 8−(4−ヒドロキシフェノキシ)オクチルジイソプロパノールアミン、または薬剤的に許容できるその塩。
- (A)生物活性剤;および
(B)請求項1〜17のいずれか1項に記載の化合物、を含む医薬組成物。 - 前記生物活性剤が、少なくとも1つのタンパク質、ポリペプチド、ペプチド、ホルモン、多糖類、ムコ多糖類、炭水化物、または脂質、およびそれらの任意の組み合わせを含む、請求項18に記載の医薬組成物。
- 前記生物活性剤が:
トリプタン、BIBN−4096BS、成長ホルモン、ヒト成長ホルモン、遺伝子組み換えヒト成長ホルモン(rhGH)、ウシ成長ホルモン、ブタ成長ホルモン、成長ホルモン放出ホルモン、成長ホルモン放出因子、インターフェロン、α−インターフェロン、β−インターフェロン、γ−インターフェロン、インターロイキン1、インターロイキン2、インスリン、ブタインスリン、ウシインスリン、ヒトインスリン、ヒト組み換えインスリン、インスリン様成長因子(IGF)、IGF−1、ヘパリン、未分画ヘパリン、ヘパリノイド、デルマタン、コンドロイチン、低分子量ヘパリン、超低分子量ヘパリン、極超低分子量ヘパリン、カルシトニン、サケカルシトニン、ウナギカルシトニン、ヒトカルシトニン、
エリトロポエチン(EPO)、心房ナトリウム利尿因子、抗原、モノクローナル抗体、ソマトスタチン、プロテアーゼ阻害剤、副腎皮質刺激ホルモン、ゴナドトロビン放出ホルモン、オキシトシン、黄体化ホルモン放出ホルモン、卵胞刺激ホルモン、グルコセルブトシターゼ、トロンボポイエチン、フィルグラスチム、プロスタグランジン、シクロスポリン、バソプレシン、クロモリンナトリウム、クロモグリク酸ナトリウム、クロモグリク酸二ナトリウム、バンコマイシン、デスフェリオキサミン(DFO)、副甲状腺ホルモン(PTH)、PTHのフラグメント、抗微生物剤、抗真菌剤、ビタミン類;および
これら化合物の類似体、フラグメント、模倣体、およびポリエチレングリコール(PEG)修飾誘導体;
およびその任意の組み合わせ;
からなる群から選択される、請求項18に記載の医薬組成物。 - 前記生物活性剤が、トリプタン、インスリン、BIBN−4096BS、カルシトニン、副甲状腺ホルモン、エリトロポエチン、成長ホルモン、およびこれらの任意の組み合わせを含む、請求項18に記載の医薬組成物。
- (A)請求項18〜21のいずれか1項に記載の医薬組成物;および
(B)
(a)賦形剤、
(b)希釈剤、
(c)崩壊剤、
(d)潤滑剤、
(e)可塑剤、
(f)着色料、
(g)投与ビヒクル、または
(h)これらの任意の組み合わせ、のうちの少なくとも1つ、
を含む単位投与形態。 - 生物活性剤を、それを必要とする動物に投与する方法であって、請求項18〜21のいずれか1項に記載の医薬組成物を、該動物に経口投与することを含む、方法。
- (A)少なくとも1つの生物活性剤;
(B)請求項1−17のいずれか1項に記載の、少なくとも1つの化合物;および
(C)任意に、投与ビヒクル;
を混合することを含む、組成物を調製する方法。
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CN104703962A (zh) | 2015-06-10 |
BR112015003761B1 (pt) | 2022-02-15 |
WO2014031874A1 (en) | 2014-02-27 |
AU2013305664B2 (en) | 2018-02-01 |
CA2882719C (en) | 2021-01-26 |
BR112015003761A2 (pt) | 2017-07-04 |
EP2888224B1 (en) | 2017-11-15 |
CN104703962B (zh) | 2017-11-07 |
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