JP2021505630A - 慢性閉塞性肺疾患の急性増悪の予防または減少における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 - Google Patents
慢性閉塞性肺疾患の急性増悪の予防または減少における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 Download PDFInfo
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- JP2021505630A JP2021505630A JP2020531614A JP2020531614A JP2021505630A JP 2021505630 A JP2021505630 A JP 2021505630A JP 2020531614 A JP2020531614 A JP 2020531614A JP 2020531614 A JP2020531614 A JP 2020531614A JP 2021505630 A JP2021505630 A JP 2021505630A
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- cyclopropyl
- methylbenzamide
- cyanobenzoyl
- amino
- pyrazole
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- 239000001488 sodium phosphate Substances 0.000 description 1
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- 239000000600 sorbitol Substances 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
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- 229960004306 sulfadiazine Drugs 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
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- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
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- 238000012360 testing method Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- 229960001262 tramazoline Drugs 0.000 description 1
- QQJLHRRUATVHED-UHFFFAOYSA-N tramazoline Chemical compound N1CCN=C1NC1=CC=CC2=C1CCCC2 QQJLHRRUATVHED-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
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- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
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その医薬的に許容される誘導体の新規の使用、すなわち、慢性閉塞性肺疾患の増悪の予防または減少に関係する。
1)例えば、アルクロメタゾン(alcometasone)、ベクロメタゾン、ベクロメタゾンジプロピオン酸エステル、ベタメタゾン、ブデソニド、クロベタゾール、デフラザコート、ジフルコルトロン、デソキシメタゾン(desoxymethasone)、デキサメタゾン、フルドロコルチゾン、フルニソリド、フルオシノロン、フルオメソロン、フルチカゾン、フルチカゾンプロピオン酸エステル、フルチカゾンフロ酸エステル、モメタゾンフロ酸エステル、ヒドロコルチゾン、トリアムシノロン、ナンドロロンデカン酸エステル、ネオマイシン硫酸塩、リメキソロン、メチルプレドニゾロンおよびプレドニゾロンのようなステロイド薬;
2)例えば、メトロニダゾール、スルファジアジン、トリクロサン、ネオマイシン、アモキシシリン、アムホテリシン、クリンダマイシン、アクラルビシン、ダクチノマイシン、ナイスタチン、ムピロシンおよびクロルヘキシジンのような抗生物質および抗菌剤;
3)例えば、二硝酸イソソルビド、一硝酸イソソルビド、アポモルフィンおよびニコチンのような全身的に活性な薬物;
4)例えば、アゼラスチン、クロルフェニラミン、アステミゾール、セチチジン(cetitizine)、シンナリジン、デスロラタジン、ロラタジン、ヒドロキシジン、ジフェンヒドラミン、フェキソフェナジン、ケトチフェン、プロメタジン、トリメプラジンおよびテルフェナジンのような抗ヒスタミン薬;
5)例えば、ピロキシカム、ベンジダミン、ジクロフェナクナトリウム、ケトプロフェン、イブプロフェン、ヘパリノイド、ネドクロミル、ナトリウムクロモグリケート(sodium cromoglycate)、ファサフンジン(fasafungine)およびヨードキサミド(iodoxamide)のような抗炎症剤;
6)例えば、アトロピン、ベンザトロピン、ビペリデン、シクロペントレート(cyclopentolate)、オキシブチニン(oxybutinin)、オルフェナジン塩酸塩(orphenadine hydrochloride)、プロシクリジン、プロパンテリン、プロピベリン、チオトロピウム、トロピカミド、トロスピウム、イプラトロピウム臭化物、GSK573719およびオキシトロプリウム臭化物(oxitroprium bromide)のような抗ムスカリン/抗コリン薬;
7)サルブタモール、フェノテロール、フォルモテロール、インダカテロール、ビランテロールおよびサルメテロールのような気管支拡張剤;
8)アドレナリン、ノルアドレナリン、デキサンフェタミン、ディピレフィン、ドブタミン、ドペキサミン、フェニレフリン、イソプレナリン、ドパミン、プソイドエフェドリン、トラマゾリンおよびキシロメタゾリンのような交感神経刺激薬;
9)例えば、ブプレノルフィン、デキストロモラミド、ジアモルヒネ、コデインリン酸塩、デキストロプロポキシフェン、ジヒドロコデイン、パパベレタム、ホルコデイン(pholcodeine)、ロペラミド、フェンタニル、メサドン、モルヒネ、オキシコドン、フェナゾシン、ペチジンおよび制吐薬とそれらの組合せのような疼痛管理用のような鎮静剤;
10)クロニジン、コジン(codine)、コプロキサモール(coproxamol)、デキストロプロポキシペン(dextropropoxypene)、エルゴタミン、スマトリプタン、トラマドールおよび非ステロイド性抗炎症薬のような鎮痛薬および片頭痛を処置するための薬物;
11)前述のいずれかの医薬的に許容される塩。
別途定義されない限り、本明細書において使用されるすべての技術用語および科学用語は、本発明が属する分野の当業者によって一般的に理解されているものと同一の意味を有する。
BCT197を、1mg、5mg、7mg、10mgおよび20mg、25mgおよび50mgの経口投与のための硬質ゼラチンカプセル剤として、現在調製する。硬質ゼラチンカプセル剤は、淡紅色の不透明な硬質ゼラチンカプセル剤中に、白色からオフホワイト色の粉末を含有する。カプセル剤に使用する以下の賦形剤を、概括的品質の標準賦形剤とする。乳糖一水和物、デンプングリコール酸ナトリウム、ポビドン、コロイド状二酸化ケイ素、ステアリン酸マグネシウム。
第2相試験(AETHERと称される)は、AECOPDを有する患者の処置についての、標準治療に加えたBCT−197の使用を調査する二重盲験無作為化プラセボ対照臨床試験であった。標準治療には、患者の慢性COPD薬物療法および対症の気管支拡張剤に、ステロイドおよび/または抗生物質を加えることが含まれた。ベースライン評価に続き、282名の適格患者を無作為化し、BCT−197の2つの異なる用量レジメンのうちの一方またはプラセボ(5日間にわたり3回の用量)のいずれかを投与した。
・≧40の男性/女性
・COPDについての通常の処置を受けている(2015 GOLDガイドラインによるカテゴリーCおよびD)
・処置のために入院を要する、進行中のCOPDの活性な増悪の存在
・先行する12カ月間における、少なくとも1つの中等度または重度のCOPDの増悪
・少なくとも10パックイヤーの喫煙歴
・予測される正常値の65%未満のFEV1
であった。
・現在喘息と診断されている
・以前の4週間における、全身性コルチコステロイドまたは抗生物質を用いる処置
・集中治療室処置を要する
・臨床的に有意なECG異常の臨床的に有意な心血管状態
・肺炎、肺塞栓または気胸の併発
であった。
第2相試験(AETHERと称される)は、AECOPDを有する患者の処置について、標準治療に加えたBCT−197の使用を調査する二重盲験無作為化プラセボ対照臨床試験であった。標準治療には、患者の慢性COPD薬物療法および対症の気管支拡張剤に、ステロイドおよび/または抗生物質を加えることが含まれた。ベースライン評価に続き、282名の適格患者を無作為化し、BCT−197の2つの異なる用量レジメンのうちの一方またはプラセボ(5日間にわたり3回の用量)のいずれかを投与した。主要エンドポイントは、試験の各群における、ベースラインから7日目までの1秒量(FEV1)の変化の比較であった。
・≧40の男性/女性
・COPDについての通常の処置を受けている(2015 GOLDガイドラインによるカテゴリーCおよびD)
・処置のために入院を要する、進行中のCOPDの活性な増悪の存在
・先行する12カ月間における、少なくとも1つの中等度または重度のCOPDの増悪
・少なくとも10パックイヤーの喫煙歴
・予測される正常値の65%未満のFEV1
であった。
・現在喘息と診断されている
・以前の4週間における、全身性コルチコステロイドまたは抗生物質を用いる処置
・集中治療室処置を要する
・臨床的に有意なECG異常の臨床的に有意な心血管状態
・肺炎、肺塞栓または気胸の併発
であった。
Claims (18)
- COPDを患うヒト患者の処置のための医薬組成物であって、前記患者に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1回または複数の有効用量を、各用量間を少なくとも1日として、7日以内の期間にわたり投与すること、および先行する投与の開始から少なくとも1カ月の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処置の休止後に、前記患者に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その医薬的に許容される誘導体の前記1回または複数の有効用量の前記投与を繰り返すことを含む、医薬組成物。
- COPDを患うヒト患者の処置のための医薬組成物であって、前記患者に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3回の用量を、各用量間を少なくとも1日として、7日以内の期間にわたり投与すること、および先行する投与の開始から少なくとも1カ月の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処置の休止後に、前記患者にその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前記3回の用量の前記投与を繰り返すことを含む、医薬組成物。
- ヒト患者におけるCOPDの急性増悪の予防または急性増悪率の減少のための方法であって、前記ヒト患者に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3回の別個の治療的有効用量を、各用量間を少なくとも1日として、7日以内の期間にわたり投与すること、および先行する投与の開始から少なくとも1カ月の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処置の休止後に、前記患者に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前記3回の用量の前記投与を繰り返すことを含む、方法。
- ヒト患者におけるCOPDの急性増悪の予防または急性増悪率の減少のための方法であって、(a)前記ヒト患者に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3回の別個の治療的有効用量を、各用量間を少なくとも1日として、7日以内の期間にわたり投与すること;(b)(先行する投与の開始から測定して)少なくとも1カ月の期間、前記患者に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前記投与を中止すること;および(c)前記ヒト患者に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3回の別個の治療的有効用量を、各用量間を少なくとも1日として、7日以内の期間にわたり投与することを含む、方法。
- COPDの急性増悪を患うまたはCOPDの急性増悪を発症するリスクがあるヒト患者の処置のための医薬組成物であって、前記患者に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1回または複数の有効用量を、各用量間を少なくとも1日として、7日以内の期間にわたり投与すること、および先行する投与の開始から少なくとも1カ月の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処置の休止後に、前記患者に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その医薬的に許容される誘導体の前記1回または複数の有効用量の前記投与を繰り返すことを含む、医薬組成物。
- 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繰り返し投与前の、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処置の休止が、前記先行する投与の開始から、好ましくは少なくとも2カ月、好ましくは約3カ月である、請求項1から5のいずれかに記載の組成物または方法。
- 前記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繰り返し投与前の、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処置の休止が、前記先行する投与の開始後、好ましくは7カ月未満、より好ましくは6カ月未満、より好ましくは5カ月未満、より好ましくは4カ月未満である、請求項1から6のいずれかに記載の組成物または方法。
- COPDの急性増悪を患うヒト患者におけるCOPDの急性増悪の再発予防のための医薬組成物であって、前記患者に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3回の用量を、各用量間を少なくとも1日として、7日以内の期間にわたり投与することを含む、医薬組成物。
- 前記患者が、前記投与における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最終用量後少なくとも30日間、または少なくとも60日間、または少なくとも90日間、または少なくとも120日間、または少なくとも150日間、または少なくとも180日間、COPDの急性増悪の再発を患っていない、請求項8に記載の組成物。
- 前記先行する投与の開始から少なくとも1カ月の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処置の休止後に、前記患者に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前記3回の用量の前記投与を繰り返すことをさらに含む、請求項8または9に記載の組成物。
- COPDの急性増悪を患うヒト患者におけるCOPDの急性増悪の処置不成功の予防のための医薬組成物であって、前記患者に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3回の用量を、各用量間を少なくとも1日として、7日以内の期間にわたり投与することを含む、医薬組成物。
- 前記患者が、前記投与における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最終用量後1日間以内、好ましくは2日間以内、より好ましくは5日間以内、より好ましくは7日間以内、最も好ましくは14日間以内に、処置不成功に苦しんでいない、請求項11に記載の組成物。
- 先行する投与の開始から少なくとも1カ月の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処置の休止後に、前記患者に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前記3回の用量の前記投与を繰り返すことをさらに含む、請求項11または12に記載の組成物。
- 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その医薬的に許容される誘導体を含む3回の別個の用量の医薬組成物を投与することを含み、投与は、1日目、4日目および7日目になされる、請求項1から13のいずれかに記載の組成物または方法。
- 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その医薬的に許容される誘導体を含む3回の別個の用量の医薬組成物を、用量の投与毎に少なくとも1日おきに、5日間の期間にわたり投与することを含む、請求項1から13のいずれかに記載の組成物または方法。
- 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その医薬的に許容される誘導体を含む3回の別個の用量の医薬組成物を投与することを含み、投与は、1日目、3日目および5日目になされる、請求項1から13のいずれかに記載の組成物または方法。
- 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3回の用量が投与され、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前記3回の別個の治療的有効用量が、前記3回の別個の投与の間にわたり減少する、請求項1から16のいずれかに記載の組成物または方法。
- 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3回の用量が投与され、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最初の用量が、その後の用量のいずれかよりも少なくとも20%大きく、その後の用量よりも好ましくは少なくとも30%大きく、より好ましくは40%大きく、最も好ましくは50%から100%大きい、請求項1から17のいずれかに記載の組成物または方法。
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GB1720624.4 | 2017-12-11 | ||
GBGB1720624.4A GB201720624D0 (en) | 2017-12-11 | 2017-12-11 | Use of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-n-cyclopropyl-4-methylbenzamide in the prevention or reduction of acute exacerbations |
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GBGB1802353.1A GB201802353D0 (en) | 2018-02-13 | 2018-02-13 | Treatment of chronic obstructive pulmonary disease |
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PCT/GB2018/053591 WO2019116022A1 (en) | 2017-12-11 | 2018-12-11 | Use of 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-n-cyclopropyl-4-methylbenzamide in the prevention or reduction of acute exacerbations of chronic obstructive pulmonary disease |
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