JP6091593B2 - 慢性閉塞性肺疾患の急性増悪の治療におけるピラゾール誘導体の使用 - Google Patents
慢性閉塞性肺疾患の急性増悪の治療におけるピラゾール誘導体の使用 Download PDFInfo
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- JP6091593B2 JP6091593B2 JP2015500892A JP2015500892A JP6091593B2 JP 6091593 B2 JP6091593 B2 JP 6091593B2 JP 2015500892 A JP2015500892 A JP 2015500892A JP 2015500892 A JP2015500892 A JP 2015500892A JP 6091593 B2 JP6091593 B2 JP 6091593B2
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- cyanobenzoyl
- methylbenzamide
- pyrazol
- cyclopropyl
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- 125000002324 prednisone group Chemical group 0.000 description 1
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- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
Description
本発明は、有機化合物および医薬品(pharmaceuticals)としてのその使用に関し、より具体的には、3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその誘導体の新規な使用、すなわち、慢性閉塞性肺疾患の急性増悪の治療における新規な使用に関する。
国際特許出願WO2005/009973は、サイトカイン阻害剤活性を有する、種々のピラゾール−およびイミダゾール系化合物または医薬的に許容されるその誘導体を開示している。そのような化合物は、とりわけ、ぜんそく、アレルギー、成人呼吸窮迫症候群および慢性閉塞性肺疾患を含めて、p38キナーゼ、特にp38αおよびβキナーゼに関連する状態を治療するのに使用することができることを開示している。
第1の態様では、本発明は、慢性閉塞性肺疾患の急性増悪を治療するための医薬(medicament)の製造における3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドの使用に関する。
別段の定義がない限り、本明細書で使用されるすべての専門用語および科学用語は、本発明(複数可)が属する分野の当業者により一般に理解されるのと同じ意味を有する。
本発明は、3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその誘導体の新規な使用、すなわち、慢性閉塞性肺疾患の急性増悪治療での新規な使用に関する。
急性COPD増悪を有する患者に経口投与した3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドの単一75mg用量の有効性、安全性および忍容性を評価するための調査、無作為化、二重盲検、プラセボ対照、多施設共同研究
急性COPD増悪を有する患者に経口投与される3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミド(化合物A)の単一75mg用量の有効性、安全性および忍容性を実施した。
第一目的:プラセボと比べて、治療の最初の5日間でのFEV1の改善により測定される増悪を呈するCOPD患者における化合物Aの単一の75mg用量の有効性を評価する
第二目的:安全性および忍容性、患者報告結果、ならびに次の増悪までの時間。
90名の患者を無作為に1:1:1の3つの治療群に分けた。
治療A(n=15)
=1日目に化合物Aの単一75mg用量+プレドニゾン プラセボ×10日間
治療B(n=15)
=1日目に化合物A プラセボの単一用量+プレドニゾン プラセボ×10日間
治療C(n=15)
=1日目に化合物A プラセボの単一用量+40mgの経口によるプレドニゾン プラセボ×10日間
すべての治療群
=ドキシサイクリン100mg用量×10日間または局所処方抗生物質ガイドラインと併用の非マクロライド抗生物質。
3、5および14日目の訪問および30および90日間のフォローアップ訪問。研究訪問は6カ月間で終了。
第1暫定分析は、5日目の患者45名を含んだ。
本データ(present data)(第2暫定)は、30日間のフォローアップを伴う総計91名の無作為に選ばれた患者を含む。
・男性/女性 40歳以上〜80歳以下
・GOLDステージ 2〜4
・喫煙歴 少なくとも10たばこの箱年(10 pack years)
・治験責任医師により画定されたCOPD増悪
・動脈血pH 無作為で7.26未満
・臨床的に制御されていない左心不全の病歴または存在
・肺炎の臨床的または放射線学的証拠
・長期酸素 1日当たり15時間超
・臨床的に重要なECG異常の病歴
・腎機能障害の病歴または存在
・無作為化の48時間以内のマクロライド抗生物質の使用
・5日目のベースラインからのFEV1改善
・BORGスコア
・EXACT PRO:
・回復は、発症に続く14日間にわたる最大観察スコア(MOV:3日周期平均を使用する最高EXACTスコア)を基準にして9ポイント以上のEXACTスコアの減少と定義される。
・回復時間
・重度
・最大重度−30日間での最高exactスコア
・総重症度−発症(すなわち1日目)〜回復/30日目(どちらが最初に来るにせよ)の総exactスコアを基準にする曲線下面積。
・増悪の期間(発症から回復/30日目までの日数)
・30日目で回復した患者の頻度
・治療の失敗:
・経口コルチコステロイドを用いて治療した患者が、COPDに関連する症状で病院に入院した、COPDに関連する抗生物質療法に変更された、または主治医の意見で、別の増悪のための治療を必要とした。
ベースラインは、安定な状況であり、4週間毎にリセットし、第4週の最後の7日間がベースライン値をリセットするのに使用される。
事象の発症は、連続2日間の患者の平均ベースラインスコアから12ポイント以上のEXACTスコアの増加(2日間の1日目を1日目(事象の発症)とする)、または連続3日間の患者の平均ベースラインから9ポイント以上の増加(3日間の1日目を事象の1日目(発症)とする)として定義される。
回復は、3日周期平均を使用して7日間持続する事象の14日間の最大観測値から少なくとも9ポイントのEXACTスコアの改善または減少と定義される。
事象期間は、発症、3日周期平均、最大観測値、改善および回復の閾値により定義される。
3日周期平均は、増悪時に起こり得るEXACTスコアの日々の変動を説明するのに使用される(それは発症の1日目に始まり、回復の1日目に終了する)。
・化合物A=患者0名
・プラセボ(標準治療+抗生物質のみ)=患者5名
・プレドニゾン=患者5名
本発明は、以下の態様を包含し得る。
[1]
慢性閉塞性肺疾患の急性増悪の治療に使用するための3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその誘導体。
[2]
慢性閉塞性肺疾患の急性増悪の治療に使用するための3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその誘導体の単一用量。
[3]
慢性閉塞性肺疾患の急性増悪を治療するための医薬の製造における3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドの使用。
[4]
慢性閉塞性肺疾患の急性増悪の治療のための医薬の製造における、単一用量の3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドの使用。
[5]
3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその誘導体の有効量を、それを必要とする被験者に投与する工程を含む、慢性閉塞性肺疾患の急性増悪の治療方法。
[6]
3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその誘導体の単一用量が投与される、上記[5]に記載の方法。
[7]
前記単一用量が50〜100mgの3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその誘導体を含む、上記[6]に記載の方法。
[8]
前記単一用量が60〜90mgの3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその誘導体を含む、上記[6]に記載の方法。
[9]
前記単一用量が75mgの3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその誘導体を含む、上記[6]に記載の方法。
[10]
前記単一用量が75mgの遊離形態の3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドを含む、上記[6]に記載の方法。
[11]
3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその誘導体を含有する経口投与のための医薬組成物。
[12]
50〜100mgの3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその誘導体を含有する、上記[11]に記載の医薬組成物。
[13]
60〜90mgの3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその誘導体を含有する、上記[12]に記載の医薬組成物。
[14]
75mgの3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその誘導体を含有する、上記[13]に記載の医薬組成物。
[15]
75mgの遊離形態の3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドを含有する、上記[14]に記載の医薬組成物。
[16]
錠剤形態である、上記[11]に記載の医薬組成物。
[17]
錠剤形態である、上記[15]に記載の医薬組成物。
Claims (9)
- 慢性閉塞性肺疾患の急性増悪を治療するための医薬組成物であって、3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその塩、水和物または溶媒和物を含む、医薬組成物。
- 慢性閉塞性肺疾患の急性増悪の治療のための医薬組成物であって、単一用量の3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその塩、水和物または溶媒和物を含む、医薬組成物。
- 慢性閉塞性肺疾患の急性増悪を治療するための経口医薬組成物であって、3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその塩、水和物または溶媒和物を含む、経口医薬組成物。
- 50〜100mgの3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその塩、水和物または溶媒和物を含む、請求項3に記載の医薬組成物。
- 60〜90mgの3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその塩、水和物または溶媒和物を含む、請求項4に記載の医薬組成物。
- 75mgの3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドまたは医薬的に許容されるその塩、水和物または溶媒和物を含む、請求項5に記載の医薬組成物。
- 75mgの遊離形態の3−[5−アミノ−4−(3−シアノベンゾイル)−ピラゾール−1−イル]−N−シクロプロピル−4−メチルベンズアミドを含む、請求項6に記載の医薬組成物。
- 錠剤形態である、請求項3に記載の医薬組成物。
- 錠剤形態である、請求項7に記載の医薬組成物。
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RU2600833C1 (ru) * | 2015-09-03 | 2016-10-27 | ФЕДЕРАЛЬНОЕ ГОСУДАРСТВЕННОЕ БЮДЖЕТНОЕ УЧРЕЖДЕНИЕ "РОССИЙСКИЙ НАУЧНЫЙ ЦЕНТР РАДИОЛОГИИ И ХИРУРГИЧЕСКИХ ТЕХНОЛОГИЙ" МИНИСТЕРСТВА ЗДРАВООХРАНЕНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ (ФГБУ "РНЦРХТ" Минздрава России) | Способ лечения хронической обструктивной болезни легких |
RU2600822C1 (ru) * | 2015-09-03 | 2016-10-27 | ФЕДЕРАЛЬНОЕ ГОСУДАРСТВЕННОЕ БЮДЖЕТНОЕ УЧРЕЖДЕНИЕ "РОССИЙСКИЙ НАУЧНЫЙ ЦЕНТР РАДИОЛОГИИ И ХИРУРГИЧЕСКИХ ТЕХНОЛОГИЙ" МИНИСТЕРСТВА ЗДРАВООХРАНЕНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ (ФГБУ "РНЦРХТ" Минздрава России) | Способ лечения хронического обструктивного бронхита |
CA3016488C (en) | 2016-03-08 | 2023-04-11 | Mereo Biopharma 1 Limited | Dosage regimen for the treatment of acute exacerbations of chronic obstructive pulmonary disease |
WO2017153701A1 (en) * | 2016-03-08 | 2017-09-14 | Mereo Biopharma 1 Limited | Dosage regimen for the treatment of acute exacerbations of inflammatory conditions |
US10331542B2 (en) * | 2016-06-23 | 2019-06-25 | International Business Machines Corporation | System and method for detecting and alerting unexpected behavior of software applications |
GB201612238D0 (en) * | 2016-07-14 | 2016-08-31 | Mereo Biopharma 1 Ltd | Method for producing a polymorphic form of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-Yl]-n-cyclopropyl-4-methylbenzamide |
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CA3128468A1 (en) | 2017-10-05 | 2019-04-11 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce dux4 and downstream gene expression for the treatment of fshd |
US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
HUE054266T2 (hu) | 2017-12-11 | 2021-08-30 | Mereo Biopharma 1 Ltd | 3-[5-amino-4-(3-cianobenzoil)-pirazol-1-il]-N-ciklopropil-4-metilbenzamid alkalmazása krónikus obstruktív tüdõbetegség akut megjelenésének megelõzésében |
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