JP2008534630A - 疼痛の軽減のためのn型カルシウムチャネルブロッカーを含む組み合わせ治療の方法 - Google Patents
疼痛の軽減のためのn型カルシウムチャネルブロッカーを含む組み合わせ治療の方法 Download PDFInfo
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- JP2008534630A JP2008534630A JP2008504594A JP2008504594A JP2008534630A JP 2008534630 A JP2008534630 A JP 2008534630A JP 2008504594 A JP2008504594 A JP 2008504594A JP 2008504594 A JP2008504594 A JP 2008504594A JP 2008534630 A JP2008534630 A JP 2008534630A
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- compound
- piperazin
- calcium channel
- pain
- phenyl
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
Landscapes
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- Veterinary Medicine (AREA)
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- Medicinal Chemistry (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
本発明は、疼痛の処置において有用な組成物および方法に関する。それは、異なる機序によって働く活性構成要素と組み合わせられるN型カルシウムチャネルブロッカーである活性構成要素を有する組成物を含む。N型カルシウムチャネルブロッカーの好ましいクラスが同定される。本発明はまた、N型カルシウムチャネルブロッカーおよびN型カルシウムチャネルを遮断する以外の機序によって働く少なくとも一つの疼痛緩和治療的化合物または非薬理学的プロトコールによって、疼痛緩和を必要とする被験体を並行して処置する段階を含む、疼痛を処置するための方法に関する。
N型カルシウムチャネルは、主に神経に局在し、これらのチャネルを介するイオン輸送を阻害するチャネルブロッカーと呼ばれる化合物は、疼痛を含む様々な状態に対する処置として説明されている。N型カルシウムチャネルを遮断する特定のペプチジル化合物は、疼痛を軽減することが公知である。例えば、ジコノチド(プリアルト(商標))は、N型カルシウムチャネルを阻害することが示されておりかつ重度の慢性疼痛を処置するために使用されるペプチジル天然産物の合成バージョンである。「Ziconotide: Neuronal Calcium Channel Blocker for Severe Chronic Pain」, G. P. Miljanich, Current Medical Chemistry, vol. 11(23), pp. 3029-3040 (Dec. 2004)を参照されたい。Textbook of Pain, 4th ed., P.D. Wall and R. Melzack, ed., Elsevier Science, pg.1236 (2003);およびwww.fda.gov/cder/foi/label/2004/021060lbl.pdfでオンラインで利用できるプリアルト(商標)におけるFDAラベル情報も参照されたい。ジコノチドは、その使用者によって必要とされるオピオイド疼痛薬の量を低減し得る;しかしながら、それは、生体利用性における難しい問題を抱えており、経口的に、または典型的な筋内注射もしくは静脈内注射によってさえも、投与することができない。そのため、ジノコチドは、脊髄における後角に直接的に緩徐に送達するポンプデバイスによって、髄腔内にのみ投与され、そこで、後角の表層(Rexed層IおよびII)における一次侵害受容性(A-δおよびC)求心性神経上に位置するN型カルシウムチャネルに結合することによって作用すると考えられている。ジコノチドは、脊髄に直接的に送達されるが、それは、しばしば、オピオイドなどのその他の非常に強力な疼痛緩和剤との組み合わせにおいて使用される。さらに、ジコノチドの使用は、その他の公知の薬に反応しない重度の慢性疼痛問題の非常に狭いカテゴリーに対してのみ適当である。
本発明は、N型カルシウムチャネル遮断化合物の疼痛緩和効果が、N型カルシウムチャネルを遮断する以外の機序によって働く化合物および処置の疼痛緩和効果と組み合わせられる場合に強化されるという観察に基づく。したがって、N型カルシウムチャネルブロッカーは、疼痛緩和の強化を提供するためにその他の疼痛緩和治療と組み合わせられ得、組み合わせは、疼痛緩和薬剤の単一のタイプに対する依存性の増加に関連するリスクを最小にする。例えば、オピオイドの過剰な使用は、依存および耐性をもたらし得る;公知の選択的COX-2阻害剤は、有害な心事故のリスクを増加させることが疑われている;COX-1およびCOX-2の両方を阻害するほとんどの化合物は、抗凝固活性を有し、胃腸出血を引き起こす傾向があり、アセトアミノフェンなどのその他の鎮痛剤は、しばしば、肝毒性などの副作用を示す。したがって、これらの因子は、任意の一つの鎮痛剤について安全に使用できる投薬量を頻繁に限定する。
疼痛は、多くの形式で現れ、それを処理するための手法は、罹患した個人の健康および快適性に必須である。疼痛は、多くの形式を取るため、疼痛の処置も、処置を患者の必要性に合わせられるように、多くの形式を取る必要がある。例えば、急性疼痛に対する処置は、迅速に機能する必要があるが、有害作用が速やかに消えるように、急性疼痛を処置する薬物を患者の体から速やかに取り除くことが望ましい場合がある。慢性疼痛は、より長く持続する効果を有する薬物を必要とし得る;これらは、迅速に作用する必要はない場合があるが、慢性疼痛は持続的な処置を要求するため、特定の副作用およびその他の薬との相互作用が、慢性疼痛に対する処置において、より問題である場合がある。一次疼痛処置プロトコールの有効性を圧倒する突出疼痛は、最大量の一次処置ですでに投薬治療された患者に投与され得る即効性処置を必要とし得る。かつ、極度の疼痛は、その他のより良い選択肢が存在しない場合に、実質的な有害作用を有する薬物の使用を正当化し得る;オピオイドは、依存性の発生に関して公知の潜在性を有する疼痛緩和剤の例であるが、それでも重度の疼痛を処置するために必須である。
式中、各々のm1およびm2は、独立に0〜5であり;
m3は、0〜2であり;
R1、R2、およびR3の各々は、独立に非干渉置換基(noninterfering substituent)であり;
Zは、NまたはCHであり;
n1およびn2の各々は、独立に0または1であり;
X1およびX2は、リンカーであり;かつ
Wは、ArまたはCyであり、
Arは、一つまたは二つの置換されたまたは非置換の芳香族環またはヘテロ芳香族環を示し、かつ
Cyは、一つもしくは二つの置換されたもしくは非置換の脂肪族環部分もしくは複素環部分を示す、または一つの置換されたもしくは非置換の脂肪族環部分もしくは複素環部分および一つの置換されたもしくは非置換の芳香族部分もしくはヘテロ芳香族部分からなる。
6,6-ビス-(4-フルオロ-フェニル)-1-[4-(2-フェニルスルファニル-エチル)-ピペラジン-1-イル]-ヘキサン-1-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-[2-(4-フルオロ-フェノキシ)-エチル]-ピペラジン;
1-{4-[2-(ベンゾ[1,3]ジオキソール-5-イルオキシ)-エチル]-ピペラジン-1-イル}-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(2-フェニルスルファニル-エチル)-ピペラジン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-[2-(4-メトキシ-フェノキシ)-エチル]-ピペラジン;
1-{4-[2-(2,4-ジフルオロ-フェノキシ)-エチル]-ピペラジン-1-イル}-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
6,6-ビス-(4-フルオロ-フェニル)-1-[4-(2-フェノキシ-エチル)-ピペラジン-1-イル]-ヘキサン-1-オン;
1-{4-[2-(2,4-ジクロロ-フェノキシ)-エチル]-ピペラジン-1-イル}-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
6,6-ビス-(4-フルオロ-フェニル)-1-{4-[2-(4-メトキシ-フェノキシ)-エチル]-ピペラジン-1-イル}-ヘキサン-1-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(2-フェノキシ-エチル)-ピペラジン;
6,6-ビス-(4-フルオロ-フェニル)-1-{4-[2-(3,4,5-トリメトキシ-フェノキシ)-エチル]-ピペラジン-1-イル}-ヘキサン-1-オン;
1-{4-[2-(ベンゾチアゾール-2-イルスルファニル)-エチル]-ピペラジン-1-イル}-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
[4-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキサノイル]-ピペラジン-1-イル}-エトキシ)-2,3,6-トリメチル-フェニル]-カルバミン酸tert-ブチルエステル;
4-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-エトキシ)-2,3,6-トリメチル-フェニルアミン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-[2-(2,4-ジクロロ-フェノキシ)-エチル]-ピペラジン;
[2-(4-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イルメチル}-2,6-ジ-tert-ブチル-フェノキシ)-エチル]-ジメチル-アミン;
4-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イルメチル}-2,6-ジ-tert-ブチル-フェノール;
1-[4-(3,5-ジ-tert-ブチル-4-メトキシ-ベンゾイル)-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-[4-(3,5-ジ-tert-ブチル-4-メトキシ-ベンジル)-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(3,5-ジ-tert-ブチル-4-メトキシ-ベンジル)-ピペラジン;
{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-(3,5-ジ-tert-ブチル-4-メトキシ-フェニル)-メタノン;
1-{4-[3,5-ジ-tert-ブチル-4-(2-ジメチルアミノ-エトキシ)-ベンゾイル]-ピペラジン-1-イル}-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-ベンゾ[1,3]ジオキソール-5-イルメチル-4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(3,5-ジ-tert-ブチル-ベンジル)-ピペラジン;
{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-(3,5-ジ-tert-ブチル-4-ヒドロキシ-フェニル)-メタノン;
1-[4-(3,5-ジ-tert-ブチル-4-ヒドロキシ-ベンジル)-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-[4-(3,5-ジブロモ-4-ヒドロキシ-ベンゾイル)-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-[4-(3,5-ジ-tert-ブチル-4-ヒドロキシ-ベンゾイル)-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-[4-(3,5-ジ-tert-ブチル-ベンゾイル)-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(4-tert-ブチル-ベンジル)-ピペラジン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(9H-チオキサンテン-9-イル)-ピペラジン;
2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-ベンゾチアゾール;
6,6-ビス-(4-フルオロ-フェニル)-1-(4-ピリミジン-2-イル-ピペラジン-1-イル)-ヘキサン-1-オン;
2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-ピリミジン;
6,6-ビス-(4-フルオロ-フェニル)-1-[4-(9H-チオキサンテン-9-イル)-ピペラジン-1-イル]-ヘキサン-1-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(3,4,5-トリメトキシ-ベンジル)-ピペラジン-2-カルボン酸エチルエステル;
6,6-ビス-(4-フルオロ-フェニル)-1-{4-[2-(3,4,5-トリメトキシ-ベンジルアミノ)-エチル]-ピペラジン-1-イル}-ヘキサン-1-オン;
9,9-ビス-(4-フルオロ-フェニル)-1-[4-(3,4,5-トリメトキシ-ベンジル)-ピペラジン-1-イル]-ノナン-1-オン;
(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-エチル)-フェニル-アミン;
1-[9,9-ビス-(4-フルオロ-フェニル)-ノニル]-4-(3,4,5-トリメトキシ-ベンジル)-ピペラジン;
(4-{4-[ビス-(4-フルオロ-フェニル)-メトキシ]-ブチル}-ピペラジン-1-イル)-(3,4,5-トリメトキシ-フェニル)-メタノン;
6,6-ビス-(4-フルオロ-フェニル)-1-[4-(4-トリフルオロメトキシ-ベンゾイル)-ピペラジン-1-イル]-ヘキサン-2-オン;
1-[4-(4-ブロモ-ベンゾイル)-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
6,6-ビス-(4-フルオロ-フェニル)-5-ヒドロキシ-1-[4-(3,4,5-トリメトキシ-ベンゾイル)-ピペラジン-1-イル]-ヘキサン-1-オン;
1-{4-[ビス-(4-フルオロ-フェニル)-メトキシ]-ブチル}-4-(3,4,5-トリメトキシ-ベンジル)-ピペラジン;
6,6-ビス-(4-フルオロ-フェニル)-6-ヒドロキシ-1-[4-(3,4,5-トリメトキシ-ベンゾイル)-ピペラジン-1-イル]-ヘキサン-1-オン;
4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-1-(3,4,5-トリメトキシ-ベンジル)-ピペラジン-2-カルボン酸;
4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキサノイル]-1-(3,4,5-トリメトキシ-ベンジル)-ピペラジン-2-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキサノイル]-4-(3,5-ジ-tert-ブチル-4-メトキシ-ベンゾイル)-ピペラジン-2-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(3,4,5-トリメトキシ-ベンゾイル)-ピペラジン-2-オン;
4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-1-(3,4,5-トリメトキシ-ベンジル)-ピペラジン-2-オン;
4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキサノイル]-1-(3,5-ジ-tert-ブチル-4-メトキシ-ベンジル)-ピペラジン-2-オン;
4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキサノイル]-1-[2-(4-フルオロ-フェノキシ)-エチル]-ピペラジン-2-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(3,5-ジ-tert-ブチル-4-メトキシ-ベンゾイル)-ピペラジン-2-オン;
4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキサノイル]-1-(3,5-ジ-tert-ブチル-4-メトキシ-ベンゾイル)-ピペラジン-2-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(3,5-ジ-tert-ブチル-4-メトキシ-ベンジル)-ピペラジン-2-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキサノイル]-4-(3,5-ジ-tert-ブチル-4-ヒドロキシ-ベンゾイル)-ピペラジン-2-オン;
6,6-ビス-(4-フルオロ-フェニル)-1-[4-(3,4,5-トリメトキシ-ベンゾイル)-ピペラジン-1-イル]-hex-5-エン-1-オン;
1-{4-[2-(3,4-ジメトキシ-フェノキシ)-エチル]-ピペラジン-1-イル}-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-[2-(3,4-ジメトキシ-フェノキシ)-エチル]-ピペラジン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(3,4,5-トリメトキシ-ベンジル)-ピペラジン-2-カルボン酸;
4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-1-(3,4,5-トリメトキシ-ベンジル)-ピペラジン-2-カルボン酸エチルエステル;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(3,4-ジメトキシ-ベンジル)-ピペラジン;
1-[4-(3,4-ジメトキシ-ベンゾイル)-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-[2-(ベンゾ[1,3]ジオキソール-5-イルオキシ)-エチル]-4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-[2-(3,4,5-トリメトキシ-フェノキシ)-エチル]-ピペラジン;
1-(4-アミノ-2,3,5-トリメチル-フェノキシ)-3-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-プロパン-2-オール;
1-{4-[3-(4-アミノ-2,3,5-トリメチル-フェノキシ)-2-ヒドロキシ-プロピル]-ピペラジン-1-イル}-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-(4-ベンゾチアゾール-2-イル-ピペラジン-1-イル)-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(3,5-ビス-トリフルオロメチル-ベンジル)-ピペラジン;
1-[4-(3,5-ビス-トリフルオロメチル-ベンゾイル)-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-[4-(4-tert-ブチル-ベンゾイル)-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(4-ブロモ-ベンジル)-ピペラジン;
2-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-エチルスルファニル)-ベンゾチアゾール;
6,6-ビス-(4-フルオロ-フェニル)-1-[4-(4-ヒドロキシ-3,5-ジメトキシ-ベンゾイル)-ピペラジン-1-イル]-ヘキサン-1-オン;
4-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イルメチル}-2,6-ジブロモ-フェノール;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-(4-トリフルオロメトキシ-ベンジル)-ピペラジン;
(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-エチル)-(3,4,5-トリメトキシ-ベンジル)-アミン;
1-{4-[2-(4-フルオロ-フェノキシ)-エチル]-ピペラジン-1-イル}-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
6,6-ビス-(4-フルオロ-フェニル)-1-[4-(2-フェニルアミノ-エチル)-ピペラジン-1-イル]-ヘキサン-1-オン;
1-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-4-[2-(2,4-ジフルオロ-フェノキシ)-エチル]-ピペラジン;
N-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-2-オキソ-エチル)-ベンズアミド;
N-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-2-オキソ-エチル)-4-クロロ-ベンズアミド;
N-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-2-オキソ-エチル)-4-メチル-ベンズアミド;
N-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-2-オキソ-エチル)-4-イソプロピル-ベンズアミド;
N-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-2-オキソ-エチル)-4-tert-ブチル-ベンズアミド;
N-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イル}-2-オキソ-エチル)-4-フルオロ-ベンズアミド;
N-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキサノイル]-ピペラジン-1-イル}-2-オキソ-エチル)-ベンズアミド;
N-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキサノイル]-ピペラジン-1-イル}-2-オキソ-エチル)-4-クロロ-ベンズアミド;
N-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキサノイル]-ピペラジン-1-イル}-2-オキソ-エチル)-4-メチル-ベンズアミド;
N-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキサノイル]-ピペラジン-1-イル}-2-オキソ-エチル)-4-イソプロピル-ベンズアミド;
N-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキサノイル]-ピペラジン-1-イル}-2-オキソ-エチル)-4-tert-ブチル-ベンズアミド;
N-(2-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキサノイル]-ピペラジン-1-イル}-2-オキソ-エチル)-4-フルオロ-ベンズアミド;
1-[4-(2-ベンジルアミノ-エチル)-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-{4-[2-(4-クロロ-ベンジルアミノ)-エチル]-ピペラジン-1-イル}-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
6,6-ビス-(4-フルオロ-フェニル)-1-{4-[2-(4-メチル-ベンジルアミノ)-エチル]-ピペラジン-1-イル}-ヘキサン-1-オン;
6,6-ビス-(4-フルオロ-フェニル)-1-{4-[2-(4-イソプロピル-ベンジルアミノ)-エチル]-ピペラジン-1-イル}-ヘキサン-1-オン;
1-{4-[2-(4-tert-ブチル-ベンジルアミノ)-エチル]-ピペラジン-1-イル}-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-{4-[2-(4-フルオロ-ベンジルアミノ)-エチル]-ピペラジン-1-イル}-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
6,6-ビス-(4-フルオロ-フェニル)-1-[4-(1-ヒドロキシ-ピリジン-4-カルボニル)-ピペラジン-1-イル]-ヘキサン-1-オン;
4-{4-[6,6-ビス-(4-フルオロ-フェニル)-ヘキシル]-ピペラジン-1-イルメチル}-2,6-ジメトキシ-フェノール;
9,9-ジフェニル-1-[4-(3,4,5-トリメトキシ-ベンジル)-ピペラジン-1-イル]-ノナン-1-オン;
1-[4-(3,5-ジ-tert-ブチル-4-メトキシ-ベンゾイル)-2-メチル-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-[4-(3,5-ジ-tert-ブチル-4-メトキシ-ベンゾイル)-3-メチル-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;
1-[4-(3,5-ジ-tert-ブチル-ベンゾイル)-2-メチル-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン;および
1-[4-(4-tert-ブチル-ベンゾイル)-2-メチル-ピペラジン-1-イル]-6,6-ビス-(4-フルオロ-フェニル)-ヘキサン-1-オン。
これらの化合物の塩も、対イオンが薬学的に許容される限り、有用である。
1-{4-[4-(4-フルオロ-ベンジル)-フェニル]-ピペラジン-1-イル}-3,3-ジフェニル-プロパン-1-オン;
1-[4-(3,5-ジ-tert-ブチル-4-ヒドロキシ-ベンジル)-ピペラジン-1-イル]-3,3-ジフェニル-プロパン-1-オン;
1-{4-[3-(4-アミノ-2,3,5-トリメチル-フェノキシ)-2-ヒドロキシ-プロピル]-ピペラジン-1-イル}-3,3-ジフェニル-プロパン-1-オン;
1-(4-アダマンタン-1-イルメチル-ピペラジン-1-イル)-3,3-ジフェニル-プロパン-1-オン;
1-(4-ベンゾチアゾール-2-イル-ピペラジン-1-イル)-3,3-ジフェニル-プロパン-1-オン;
3,3-ジフェニル-1-{4-[2-(3,4,5-トリメトキシ-フェノキシ)-エチル]-ピペラジン-1-イル}-プロパン-1-オン;
1-{4-[2-(3,4-ジメトキシ-フェノキシ)-エチル]-ピペラジン-1-イル}-3,3-ジフェニル-プロパン-1-オン;
1-{4-[2-(ベンゾチアゾール-2-イルスルファニル)-エチル]-ピペラジン-1-イル}-3,3-ジフェニル-プロパン-1-オン;
N-(2,6-ジメチル-フェニル)-2-[4-(3,3-ジフェニル-プロピオニル)-ピペラジン-1-イル]-アセトアミド;
2-[4-(3,3-ジフェニル-プロピオニル)-ピペラジン-1-イル]-N-メチル-N-フェニル-アセトアミド;
3,3-ジフェニル-1-[4-(1-フェニル-エチル)-ピペラジン-1-イル]-プロパン-1-オン;
1-[4-(2-ジアリルアミノ-エチル)-ピペラジン-1-イル]-3,3-ジフェニル-プロパン-1-オン;
1-[4-(2-ジプロピルアミノ-エチル)-ピペラジン-1-イル]-3,3-ジフェニル-プロパン-1-オン;
1-(4-sec-ブチル-ピペラジン-1-イル)-3,3-ジフェニル-プロパン-1-オン;
1-[4-(1-エチル-プロピル)-ピペラジン-1-イル]-3,3-ジフェニル-プロパン-1-オン;
1-[4-(1-メチル-ピペリジン-3-イルメチル)-ピペラジン-1-イル]-3,3-ジフェニル-プロパン-1-オン;
1-(4-ヘプチル-ピペラジン-1-イル)-3,3-ジフェニル-プロパン-1-オン;
3,3-ジフェニル-1-(4-ピリジン-4-イルメチル-ピペラジン-1-イル)-プロパン-1-オン;
1-[4-(3,5-ジクロロ-フェニル)-ピペラジン-1-イル]-3,3-ジフェニル-プロパン-1-オン;
1-(4-シクロヘプチル-ピペラジン-1-イル)-3,3-ジフェニル-プロパン-1-オン;
1-[4-(3,4-ジメチル-フェニル)-ピペラジン-1-イル]-3,3-ジフェニル-プロパン-1-オン;
1-(4-ビフェニル-4-イル-ピペラジン-1-イル)-3,3-ジフェニル-プロパン-1-オン;
1-[4-(2,3-ジクロロ-フェニル)-ピペラジン-1-イル]-3,3-ジフェニル-プロパン-1-オン;
1-[4-(1-メチル-ピペリジン-4-イルメチル)-ピペラジン-1-イル]-3,3-ジフェニル-プロパン-1-オン;
N-{2-[4-(3,3-ジフェニル-プロピオニル)-ピペラジン-1-イル]-エチル}-3,4,5-トリメトキシ-ベンズアミド;
1-(4-イソプロピル-ピペラジン-1-イル)-3,3-ジフェニル-プロパン-1-オン;
1-[4-(3-ジメチルアミノ-プロピル)-ピペラジン-1-イル]-3,3-ジフェニル-プロパン-1-オン;
3,3-ジフェニル-1-[4-(4-トリメチルシラニル-フェニル)-ピペラジン-1-イル]-プロパン-1-オン;
3,3-ジフェニル-1-[4-(2-フェニルアミノ-エチル)-ピペラジン-1-イル]-プロパン-1-オン;
1-{4-[2-(2,4-ジフルオロ-フェノキシ)-エチル]-ピペラジン-1-イル}-3,3-ジフェニル-プロパン-1-オン;
3,3-ジフェニル-1-{4-[2-(2,3,5,6-テトラフルオロ-フェノキシ)-エチル]-ピペラジン-1-イル}-プロパン-1-オン;
1-[4-(1-ベンジル-1H-ベンゾイミダゾール-2-イル)-ピペラジン-1-イル]-3,3-ジフェニル-プロパン-1-オン;
3,3-ジフェニル-1-[4-(フェニル-チオフェン-2-イル-メチル)-ピペラジン-1-イル]-プロパン-1-オン;
1-{4-[シクロプロピル-(4-フルオロ-フェニル)-メチル]-ピペラジン-1-イル}-3,3-ジフェニル-プロパン-1-オン;
(4-{2-[4-(3,3-ジフェニル-プロピオニル)-ピペラジン-1-イル]-エトキシ}-2,3,6-トリメチル-フェニル)-カルバミン酸tert-ブチルエステル;
1-{4-[2-(4-アミノ-2,3,5-トリメチル-フェノキシ)-エチル]-ピペラジン-1-イル}-3,3-ジフェニル-プロパン-1-オン;
1-{4-[2-(4-メトキシ-フェノキシ)-エチル]-ピペラジン-1-イル}-3,3-ジフェニル-プロパン-1-オン;
1-{4-[2-(ベンゾ[1,3]ジオキソール-5-イルオキシ)-エチル]-ピペラジン-1-イル}-3,3-ジフェニル-プロパン-1-オン;
1-{4-[2-(2,4-ジクロロ-フェノキシ)-エチル]-ピペラジン-1-イル}-3,3-ジフェニル-プロパン-1-オン;
1-{4-[2-(4-フルオロ-フェノキシ)-エチル]-ピペラジン-1-イル}-3,3-ジフェニル-プロパン-1-オン;および
3,3-ジフェニル-1-[4-(2-フェニルスルファニル-エチル)-ピペラジン-1-イル]-プロパン-1-オン;ならびに
その塩。
SNLラットにおける触覚過敏および温熱性痛覚過敏に対するN型カルシウムチャネルブロッカーおよびモルフィンの相互作用の評価:イソボログラフィー(isobolographic)分析
触覚過敏および温熱性痛覚過敏に対する二つの薬物(1-(4-ベンズヒドリルピペラジン-1-イル)-3,3-ジフェニルプロパン-1-オンなどのN型ブロッカーおよびモルフィン)の相互作用を、脊髄神経結紮(SNL)ラットにおいて測定する。各々のエンドポイントに対する用量応答曲線は、化合物の各々に対して確立されており、A50値(最大効果50%を産生する用量)は公知である。計算A50値の比に基づいて、薬物の固定比を採用する。混合物に関する用量応答曲線を、触覚および温熱性エンドポイントに対して生成し、薬物組み合わせが相乗的であるかまたは単純に加法的であるかどうかを決定するために、イソボログラフィー分析を採用する。オスのスプラーグドーリーラットに、SNLまたは擬似外科手術を受けさせ、外科手術の10日後にテストする。各々の用量応答曲線は、4つのデータポイント(用量)を必要とし、各々の用量に対して、8匹のラットを使用する。動物を、時間経過およびピーク効果の時間を確立するために注射後10分、20分、30分、45分、および60分にテストし、用量応答曲線を、ピーク効果の時間に集められたデータから生成する。N型ブロッカー+モルフィン(固定比)に対する別個の曲線を、触覚過敏および温熱性痛覚過敏について作成する。
慢性疼痛を経験している被験体における疼痛の処置のための組成物を、N型カルシウムチャネルブロッカーをNSAIDと混和することによって調製する。N型カルシウムチャネルブロッカーは、1-(4-ベンズヒドリルピペラジン-1-イル)-3,3-ジフェニルプロパン-1-オンであり、NSAIDは、イブプロフェンである。二つの化合物を混合する;活性化合物の相対量を、投与される各々の投薬量に基づいて決定する。充填剤および結合剤を添加し、混合物を、400 mgのイブプロフェンおよびN型カルシウムチャネルブロッカーの有効用量を送達するサイズの錠剤に形成する。
慢性疼痛を経験している被験体を同定する。実施例2の組成物を、被験体に提供し、適切な疼痛緩和を得るために必要に応じて6時間おきに一つの錠剤を摂取するように被験体を指導する。
6,6-ジフェニル-1-[4-(3-フェニル-2-プロペン-1-イル)-ピペラジン-1-イル]ヘキサン-1-オンであるN型カルシウムチャネルブロッカーを、経口投与用に調剤し、各々の錠剤が化合物の単位投薬量を含むように、錠剤へと形成する。重度の疼痛を経験している被験体を同定する。経皮的送達を介してフェンタニルの有効量を提供するように作られるフェンタニルパッチを、被験体の皮膚に貼る。N型カルシウムチャネルブロッカーを含む一つの錠剤を、最初の12時間の間に3時間おきに被験体に投与する。その後、被験体を、疼痛を軽減するために必要なだけN型カルシウムチャネルブロッカーの錠剤を自己投与するように指導する。フェンタニルパッチは、その製造業者によって提供される推奨スケジュールに従って置き換えられる。
アミトリプチリンの低用量(1日あたり一つの50 mg丸剤)を、糖尿病性神経障害および吐き気を経験している被験体に投与する。N型カルシウムチャネルブロッカー、6,6-ジフェニル-1-[4-(シクロヘキシルメチルアミノ)-ピペラジン-1-イル]ヘキサン-1-オンの有効量を、標準的な制御放出製剤を使用して、坐剤として投与する。
重度の手術後疼痛を経験している被験体を、連続IV点滴として静脈内に投与される、N型カルシウムチャネルブロッカー、6,6-ビス-(4-フルオロフェニル)-1-[4-(3,4,5-トリメトキシフェニルメチル)ピペラジン-1-イル]ヘキサンの有効量で処置する。患者に、必要に応じて自己投与できるモルフィンの患者管理供給を提供し、アセトアミノフェン錠剤を、6時間ごとに500 mgの速度で定期的に投与する。
Claims (32)
- 非ペプチジルN型カルシウムチャネルブロッカーまたはその薬学的に許容される塩である第一の化合物とN型カルシウムチャネル遮断以外の機序を介して疼痛を軽減する第二の化合物との組み合わせを含み、組み合わせが疼痛を軽減するのに効果的である、疼痛の軽減のための組成物。
- N型カルシウムチャネルブロッカーが、四環系もしくは五環系のチャネルブロッカー、またはその薬学的に許容される塩である、請求項1記載の組成物。
- N型カルシウムチャネルブロッカーが、式(1)の化合物またはその薬学的に許容される塩である、請求項1記載の組成物:
式中、各々のm1およびm2は、独立に0〜5であり;
m3は、0〜2であり;
R1、R2、およびR3の各々は、独立に非干渉置換基(noninterfering substituent)であり;
Zは、NまたはCHであり;
n1およびn2の各々は、独立に0または1であり;
X1およびX2は、リンカーであり;かつ
Wは、ArまたはCyであり、
Arは、一つまたは二つの置換されたまたは非置換の芳香族環またはヘテロ芳香族環を示し、かつ
Cyは、一つもしくは二つの置換されたもしくは非置換の脂肪族環部分もしくは複素環部分を示す、または一つの置換されたもしくは非置換の脂肪族環部分もしくは複素環部分および一つの置換されたもしくは非置換の芳香族部分もしくはヘテロ芳香族部分からなる。 - Zが、CHである、請求項3記載の組成物。
- Zが、Nである、請求項3記載の組成物。
- N型カルシウムチャネルブロッカーが、
1-(4-ベンズヒドリルピペラジン-1-イル)-3,3-ジフェニルプロパン-1-オン;
6,6-ジフェニル-1-[4-(3-フェニル-2-プロペン-1-イル)-ピペラジン-1-イル]ヘキサン-1-オン;
6,6-ジフェニル-1-[4-(シクロヘキシルメチルアミノ)-ピペリジン-1-イル]ヘキサン-1-オン;
6,6-ビス-(4-フルオロフェニル)-1-[4-(3,4,5-トリメトキシフェニルメチル)ピペラジン-1-イル]ヘキサン;もしくは
4-ベンズヒドリル-ピペラジン-1-カルボン酸ベンズヒドリル-アミド;または
その薬学的に許容される塩である、
請求項1記載の組成物。 - N型カルシウムチャネルブロッカーが、1-(4-ベンズヒドリルピペラジン-1-イル)-3,3-ジフェニルプロパン-1-オン、またはその薬学的に許容される塩である、請求項1記載の組成物。
- 経口的にまたは非経口的に投与される、請求項1記載の組成物。
- 組成物が、経粘膜的にまたは経皮的に投与される、請求項1記載の組成物。
- 第二の化合物が、NSAIDである、請求項1〜9のいずれか一項記載の組成物。
- 第二の化合物が、選択的COX-2阻害剤である、請求項1〜9のいずれか一項記載の組成物。
- 第二の化合物が、オピオイドである、請求項1〜9のいずれか一項記載の組成物。
- 第二の化合物が、アジュバント鎮痛剤である、請求項1〜9のいずれか一項記載の組成物。
- 被験体において疼痛を改善するための方法であって、そのような改善を必要とする被験体に非ペプチジルN型カルシウムチャネルブロッカーである第一の化合物を投与する段階、および該被験体にN型カルシウムチャネル遮断以外の機序によって疼痛を改善する第二の化合物を投与する段階を含み、該化合物が、組み合わせにおいて該疼痛を改善するのに効果的である量において投与される方法。
- 第一の化合物が、四環系もしくは五環系のチャネルブロッカー、またはその薬学的に許容される塩である、請求項14記載の方法。
- 第一の化合物が、式(1)の化合物またはその薬学的に許容される塩を含む、請求項14記載の方法:
式中、各々のm1およびm2は、独立に0〜5であり;
m3は、0〜2であり;
R1、R2、およびR3の各々は、独立に非干渉置換基であり;
Zは、NまたはCHであり;
n1およびn2の各々は、独立に0または1であり;
X1およびX2は、リンカーであり;かつ
Wは、ArまたはCyであり、
Arは、一つまたは二つの置換されたまたは非置換の芳香族環またはヘテロ芳香族環を示し、かつ
Cyは、一つもしくは二つの置換されたもしくは非置換の脂肪族環部分もしくは複素環部分を示す、または一つの置換されたもしくは非置換の脂肪族環部分もしくは複素環部分および一つの置換されたもしくは非置換の芳香族部分もしくはヘテロ芳香族部分からなる。 - 式(1)におけるZが、CHである、請求項14記載の方法。
- 式(1)におけるZが、Nである、請求項14記載の方法。
- 第一の化合物が、
1-(4-ベンズヒドリルピペラジン-1-イル)-3,3-ジフェニルプロパン-1-オン;
6,6-ジフェニル-1-[4-(3-フェニル-2-プロペン-1-イル)-ピペラジン-1-イル]ヘキサン-1-オン;
6,6-ジフェニル-1-[4-(シクロヘキシルメチルアミノ)-ピペリジン-1-イル]ヘキサン-1-オン;
6,6-ビス-(4-フルオロフェニル)-1-[4-(3,4,5-トリメトキシフェニルメチル)ピペラジン-1-イル]ヘキサン;もしくは
4-ベンズヒドリル-ピペラジン-1-カルボン酸ベンズヒドリル-アミド;または
その薬学的に許容される塩である、
請求項14記載の方法。 - 第一の化合物が、1-(4-ベンズヒドリルピペラジン-1-イル)-3,3-ジフェニルプロパン-1-オン、またはその薬学的に許容される塩である、請求項14記載の方法。
- 第一および第二の化合物が、実質的に同時に投与される、請求項14記載の方法。
- 第一および第二の化合物が、別個に投与される、請求項14記載の方法。
- 第二の化合物が、NSAIDである、請求項14〜22のいずれか一項記載の方法。
- 第二の化合物が、選択的COX-2阻害剤である、請求項14〜22のいずれか一項記載の方法。
- 第二の化合物が、オピオイドである、請求項14〜25のいずれか一項記載の方法。
- 第二の化合物が、アジュバント鎮痛剤である、請求項14〜25のいずれか一項記載の方法。
- 被験体に非ペプチジルN型カルシウムチャネルブロッカーを投与する段階、および同じ被験体に疼痛を軽減する少なくとも一つの非薬理学的治療的プロトコールを並行して投与する段階を含む、被験体において疼痛を軽減するための方法。
- 非ペプチジルN型カルシウムチャネルブロッカーが、四環系または五環系のチャネルブロッカーである、請求項27記載の方法。
- 非ペプチジルN型カルシウムチャネルブロッカーが、式(1)の化合物またはその薬学的に許容される塩を含む、請求項27記載の方法:
式中、各々のm1およびm2は、独立に0〜5であり;
m3は、0〜2であり;
R1、R2、およびR3の各々は、独立に非干渉置換基であり;
Zは、NまたはCHであり;
n1およびn2の各々は、独立に0または1であり;
X1およびX2は、リンカーであり;かつ
Wは、ArまたはCyであり、
Arは、一つまたは二つの置換されたまたは非置換の芳香族環またはヘテロ芳香族環を示し、かつ
Cyは、一つもしくは二つの置換されたもしくは非置換の脂肪族環部分もしくは複素環部分を示す、または一つの置換されたもしくは非置換の脂肪族環部分もしくは複素環部分および一つの置換されたもしくは非置換の芳香族部分もしくはヘテロ芳香族部分からなる。 - N型カルシウムチャネルブロッカーが、以下からなる群より選択される、請求項27記載の方法:
1-(4-ベンズヒドリルピペラジン-1-イル)-3,3-ジフェニルプロパン-1-オン;
6,6-ジフェニル-1-[4-(3-フェニル-2-プロペン-1-イル)-ピペラジン-1-イル]ヘキサン-1-オン;
6,6-ジフェニル-1-[4-(シクロヘキシルメチルアミノ)-ピペリジン-1-イル]ヘキサン-1-オン;
6,6-ビス-(4-フルオロフェニル)-1-[4-(3,4,5-トリメトキシフェニルメチル)ピペラジン-1-イル]ヘキサン;もしくは
4-ベンズヒドリル-ピペラジン-1-カルボン酸ベンズヒドリル-アミド;または
その薬学的に許容される塩。 - N型カルシウムチャネルブロッカーが、1-(4-ベンズヒドリルピペラジン-1-イル)-3,3-ジフェニルプロパン-1-オン、またはその薬学的に許容される塩である、請求項27記載の方法。
- 非薬理学的治療的プロトコールが、経皮的電気神経刺激(TENS)または経皮性電気神経刺激(PENS)である、請求項27記載の方法。
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US66982005P | 2005-04-08 | 2005-04-08 | |
PCT/CA2006/000545 WO2006105670A1 (en) | 2005-04-08 | 2006-04-10 | Combination therapy comprising an n-type calcium channel blocker for the alleviation of pain |
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US (1) | US20080300262A1 (ja) |
EP (1) | EP1871372A4 (ja) |
JP (1) | JP2008534630A (ja) |
CA (1) | CA2603926A1 (ja) |
WO (1) | WO2006105670A1 (ja) |
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PL387984A1 (pl) * | 2009-05-07 | 2010-11-08 | Instytut Medycyny Doświadczalnej I Klinicznej Im. Mirosława Mossakowskiego Pan | Nowe kompozycje substancji leczniczych do leczenia bólów przewlekłych |
CN102595896B (zh) | 2009-11-06 | 2016-02-17 | 爱尔皮奥治疗有限公司 | 提高低氧诱导因子-1α的稳定性的方法 |
US8409560B2 (en) * | 2011-03-08 | 2013-04-02 | Zalicus Pharmaceuticals Ltd. | Solid dispersion formulations and methods of use thereof |
WO2012122279A1 (en) * | 2011-03-08 | 2012-09-13 | Zalicus Pharmaceuticals Ltd. | Solid dispersion formulations and methods of use thereof |
US10045979B2 (en) * | 2014-05-19 | 2018-08-14 | Merial Inc. | Anthelmintic compounds |
GB201516183D0 (en) * | 2015-09-14 | 2015-10-28 | Calchan Ltd | Novel pharmaceutical composition |
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EP1871372A1 (en) | 2008-01-02 |
WO2006105670A8 (en) | 2006-12-14 |
WO2006105670A1 (en) | 2006-10-12 |
EP1871372A4 (en) | 2010-06-02 |
CA2603926A1 (en) | 2006-10-12 |
US20080300262A1 (en) | 2008-12-04 |
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