JP6621534B2 - 慢性咳の処置のためのオルブピタント - Google Patents
慢性咳の処置のためのオルブピタント Download PDFInfo
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- JP6621534B2 JP6621534B2 JP2018532045A JP2018532045A JP6621534B2 JP 6621534 B2 JP6621534 B2 JP 6621534B2 JP 2018532045 A JP2018532045 A JP 2018532045A JP 2018532045 A JP2018532045 A JP 2018532045A JP 6621534 B2 JP6621534 B2 JP 6621534B2
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Classifications
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
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- A—HUMAN NECESSITIES
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
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- A—HUMAN NECESSITIES
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- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
CAS索引名
1−ピペリジンカルボキサミド、N−[(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エチル]−2−(4−フルオロ−2−メチルフェニル)−4−[(8aS)−ヘキサヒドロ−6−オキソピロロ[1,2−a]ピラジン−2(1H)−イル]−N−メチル−、(2R,4S)
および
IUPAC名:
(2R,4S)−N−{(1R)−1−[3,5−ビス(トリフルオロメチル)フェニル]エチル}−2−(4−フルオロ−2−メチルフェニル)―N−メチル−4−[(8aS)−6−オキソヘキサヒドロピロロ[1,2−a]ピラジン−2(1H)−イル]−1−ピペリジンカルボキサミドとしても知られ得る。
明細書および特許請求の範囲で使用する、量、百分率、または比率を表す全ての数字および他の数値は、いかなる場合も用語「約」により修正されていることを理解されたい。
−特発性間質性肺炎(IPP)、例えば非特異性間質性肺炎、剥離性間質性肺炎、急性間質性肺炎、特発性器質化肺炎、リンパ性間質性肺炎、気腫合併肺線維症(CPFE)など;
−過敏症を原因とする環境職業病、例えば:石綿症、珪肺、および、粉炭、ベリリウム、硬質金属粉塵への暴露を原因とする塵肺、ならびに外在アレルギー性肺胞炎、例えば愛鳥家肺、放射線線維症、または、肺炎マイコプラズマなどのバクテリアおよびカビへの暴露を原因とするもの;
−自己免疫疾患と関連する多臓器疾患、例えば:全身性強皮症などの膠原病、サルコイドーシス、関節リウマチ、ウェゲナー肉芽腫症;多発筋炎、皮膚筋炎、抗ARS抗体症候群などの、ある筋肉疾患、または、例えばアミオダロン、メトトレキセートおよびブレオマイシンとの薬物反応の結果としてのもの;
−稀有な肺疾患、例えば:肺胞蛋白症、肺組織球症、肺好酸球増加症、および特発性肺ヘモジデローシス、ヘルマンスキー・パドラック症候群、結節性硬化症(リンパ脈管筋腫症);
−遺伝性疾患または遺伝病、例えば:家族性肺線維症(FPF)、また家族性間質性肺炎(FIP);
−肺移植後の閉塞性細気管支炎症候群が含まれる。
難治性慢性咳のための研究デザイン
男性患者および女性患者における多数回投薬の有効性を、3か月超にわたる慢性期処置難治性咳の診断で判断するために、オルブピタントマレイン酸塩形態1をオープンラベルパイロット試験で評価した。研究は、単一群(1日に1回、30mgのオルブピタントマレイン酸塩形態1)の、4週間のフォローアップ付き4週間研究だった。5回のクリニック訪問;スクリーニング訪問、ベースライン訪問、1週目訪問、4週目訪問(処置期間終了)、および8週目のフォローアップ訪問を予定した。
・対象に携帯型咳モニター(ACM)を装着して、スクリーニング時、1週目、4週目、および8週目に、24時間にわたり客観的な咳頻度を記録した。
・咳特異的QOL質問票(CQLQ):対象に、スクリーニング時、1週目、4週目、および8週目に、この質問票に記入するように依頼した。
・咳の頻度および重症度スケールについての包括的変化評価:対象に、1週目、4週目、および8週目にこのスケールに記入するように依頼した。
・咳重症度VAS:対象に、咳重症度VASスコアの日録用日誌を支給した。
本パイロット研究では、咳QOLおよび包括的変化評価アセスメントだけでなく、咳の頻度および重症度の客観的尺度および主観的尺度の両方で、統計的に著しい改善が見られた。
図1および2に示すように、負の二項分布回帰モデルより導かれるように、ベースラインと比較した4週目における日中の客観的な咳頻度の変化という第1エンドポイントについて、著しい減少(−18.9咳/時(−26%)は、ベースラインからの変化を意味する)が見られた(p<0.001)。
日中の客観的咳頻度:図1および2で提供するように、1週目(−27.0咳/時(−38%)は、ベースラインからの変化を意味する)と、8週目(−20.4咳/時(−28%)は、ベースラインからの変化を意味する)において、日中の客観的な咳頻度に著しい減少があったが(それぞれ、p=0.001およびp=0.02)、4週目と比較した8週目には、日中の客観的な咳頻度に著しい変化はなかった(p=0.86)。
オルブピタントマレイン酸塩形態1を、IPF関連咳のある患者において、ランダム化二重盲検プラセボ比較試験で評価し;息切れを評価する。
・対象に携帯型咳モニター(ACM)を装着して、スクリーニング時(ベースライン値)および2週目に、24時間にわたり客観的な咳頻度を記録する。
・咳特異的QOL質問票:対象に、スクリーニング時、ベースライン時、2週目、および4週目に、この質問票に記入するように依頼する。
・咳の頻度および重症度スケールについての包括的変化評価:対象に、2週目および4週目にこのスケールに記入するように依頼する。
・咳重症度VAS:対象に、咳重症度VASスコアの日録用日誌を支給する。
・息切れスケール。サン・ディエゴ大学の呼吸困難質問票およびBorg CR10スケール。対象に、スクリーニング時、ベースライン時、2週目、および4週目に、この質問票に記入するように依頼する。
オルブピタントマレイン酸塩形態1を、肺腫瘍が原因で慢性咳のある患者において、ランダム化二重盲検プラセボ比較試験で評価する。
in vitroアッセイ
式(I)の化合物またはその医薬的に許容される塩の、抗IPF剤としての使用について、以下に記載するように、1つまたは複数のin vitroアッセイにおいて評価することが可能である。適切なヒト細胞株を、正常なドナーとIPFドナーに由来するヒト初代肺細胞と一緒に、これらのアッセイで利用することができる。
式(I)の化合物またはその医薬的に許容される塩の、「アラーミン」およびTGF−βなどの増殖因子を放出することにより応答する肺上皮細胞がサブスタンスPにより活性化されるのを阻害する効果について、アッセイする。ヒートショックプロテイン60(HSP−60)、high−mobility group box−1 protein(HMGB1)およびインターロイキン(IL)−1αを含むこれらのアラーミンは、損傷上皮細胞により放出される炎症性分子の「危険信号」であり、これらは、免疫細胞および他の細胞タイプを活性化することにより自然免疫応答の一因となり、増殖因子を含み得る線維芽細胞活性化メディエーターを放出させ得る。上皮細胞により放出されるアラーミンおよび増殖因子は、また、線維芽細胞に対し直接的な刺激効果を有し得る。刺激された線維芽細胞は、筋線維芽細胞に分化すると共に遊走および増殖することにより、かつ、線維化マトリックスタンパク質を過剰発現し、線維化促進サイトカインおよび結合組織増殖因子(CTGF)などの増殖因子のさらなる発現を誘発することにより応答し、結果として、細胞外マトリックスの堆積および進行性線維症を生じさせる。
式(I)の化合物またはその医薬的に許容される塩の、炎症性メディエーターおよび線維化促進メディエーターを放出することにより応答するヒト肺マクロファージがサブスタンスPにより活性化されるのを阻害する効果について、アッセイする。
式(I)の化合物またはその医薬的に許容される塩の、トリプターゼ、キマーゼ、TGF−β、IL−13、CCL2、CCL5、IL−4、PDGF、およびFGFなどの多くの線維化促進メディエーターを放出することにより応答するヒト肺マスト細胞がサブスタンスPにより活性化されるのを阻害する効果について、アッセイする。
式(I)の化合物またはその医薬的に許容される塩の、IPFにおける自然細胞免疫反応および適応細胞免疫反応に必要であって、サブスタンスPにより促進されるT細胞の活性化、極性化、および生存を阻害する効果について、アッセイする。
式(I)の化合物またはその医薬的に許容される塩の、ヒト肺線維芽細胞の増殖、遊走、および筋線維芽細胞への分化がサブスタンスPにより活性化されるのを阻害する効果について、アッセイする。
式(I)の化合物またはその医薬的に許容される塩の、サブスタンPにより誘発される細胞外マトリックス(ECM)の堆積を阻害する効果について、アッセイする。
式(I)の化合物または医薬的に許容される塩の、サブスタンスPによって促進される内皮細胞による血管新生を阻害する効果について、アッセイする。
ヒト肺:上皮細胞、線維芽細胞、筋線維芽細胞、マクロファージ、マスト、および内皮細胞のうち、2つ以上の異なる組み合わせの共培養を使用する。例えば、ヒト肺上皮細胞とヒト肺線維芽細胞;またはヒト肺マスト細胞とヒト肺線維芽細胞;またはヒト肺マクロファージとヒト肺線維芽細胞などである。これらのヒト肺細胞の2つ以上の組み合わせを、足場を使用して3次元モデルに構築する。このような共培養系に対するサブスタンスPの効果、例えば、肺上皮細胞の活性化、マクロファージおよびマスト細胞などの免疫細胞による炎症反応、線維芽細胞の増殖、遊走、および筋線維芽細胞への分化、ECM堆積、ならびに血管新生の促進などを、上記のアッセイフォーマットを使用して調査する。式(I)の化合物またはその医薬的に許容される塩に、これらのサブスタンスPによって促進される有害な活性を抑える機能があるかを判断する。
単剤治療としての、または、患者に少なくとも3か月間安定して投与される標準治療のIPF処置、例えば、ピフェニドンもしくはニンテンダニブへの追加としての式(I)の化合物またはその医薬的に許容される塩の有効性を、IPFと診断され、スクリーニング時に、努力肺活量(FVC)率が≧50%かつ≦100%の値と予測された患者において、52週間のプラセボ比較二重盲検ランダム化研究で評価する。
・無増悪生存(PFS)
・胸部高分解能コンピュータ断層診断装置による肺内線維症スコア;
・FVCにより測定される肺機能
・FVCの年間変化率
・一酸化炭素に関する肺の拡散能
・健康に関連するQOLスコア
・6分間歩行テスト
・ランダム化からIPFの急性増悪の最初の発症までの時間
オルブピタントマレイン酸塩形態1は、必ずというわけではないが、通常は、患者への投与の前に医薬組成物に製剤化される。一態様では、本発明は、オルブピタントマレイン酸塩形態1を含む医薬組成物を対象とする。
Claims (14)
- 2−(R)−(4−フルオロ−2−メチル−フェニル)−4−(S)−((8aS)−6−オキソ−ヘキサヒドロ−ピロロ[1,2−a]−ピラジン−2−イル)−ピペリジン−1−カルボン酸[1−(R)−(3,5−ビス−トリフルオロメチル−フェニル)−エチル]−メチルアミド(オルブピタント)またはその医薬的に許容される塩を含む、慢性咳の処置用医薬組成物。
- ニンテダニブもしくはピルフェニドンから選択される、またはP2X3プリン受容体アンタゴニスト、ムスカリン受容体アンタゴニスト、もしくはベータ−2アドレナリン受容体アゴニストから選択される、1つまたは複数の治療薬と組み合わせた、2−(R)−(4−フルオロ−2−メチル−フェニル)−4−(S)−((8aS)−6−オキソ−ヘキサヒドロ−ピロロ[1,2−a]−ピラジン−2−イル)−ピペリジン−1−カルボン酸[1−(R)−(3,5−ビス−トリフルオロメチル−フェニル)−エチル]−メチルアミド(オルブピタント)またはその医薬的に許容される塩を含む、慢性咳の処置用医薬組成物。
- 前記慢性咳は、難治性慢性咳である、請求項1または2に記載の処置用医薬組成物。
- 前記慢性咳は、サルコイドーシス、肺気腫、もしくは突発性肺線維症(IPF)を原因とするかまたはそれに関連する、請求項1〜3の何れか一項に記載の処置用医薬組成物。
- 前記慢性咳は、喘息、慢性気管支炎、慢性後鼻漏、好酸球性気管支炎、もしくは慢性閉塞性肺疾患(COPD)を原因とするかまたはそれに関連する、請求項1〜3の何れか一項に記載の処置用医薬組成物。
- 前記慢性咳は、気管支拡張症、結核、もしくは嚢胞性線維症などの慢性感染症を原因とするかまたはそれに関連する、請求項1〜3の何れか一項に記載の処置用医薬組成物。
- 前記慢性咳は、気管支原性がん、細気管支肺胞上皮がん、良性上気道腫瘍、もしくは縦隔腫瘍などの肺腫瘍を原因とするかまたはそれに関連する、請求項1〜3の何れか一項に記載の処置用医薬組成物。
- 前記慢性咳は、左室不全、肺梗塞、もしくは大動脈瘤などの心血管疾患を原因とするかまたはそれに関連する、請求項1〜3の何れか一項に記載の処置用医薬組成物。
- 前記慢性咳は、逆流性食道炎、反復性誤嚥、気管支内縫合、後鼻漏症候群、もしくは副鼻腔炎を原因とするかまたはそれに関連する、請求項1〜3の何れか一項に記載の処置用医薬組成物。
- 前記オルブピタントの医薬的に許容される塩はマレイン酸塩である、請求項1〜9の何れかに記載の処置用医薬組成物。
- 前記オルブピタントマレイン酸塩は、オルブピタントマレイン酸塩形態1である、請求項10に記載の処置用医薬組成物。
- P2X3プリン受容体アンタゴニストは、5−(2,4−ジアミノ−ピリミジン−5−イルオキシ)−4−イソプロピル−2−メトキシ−ベンゼンスルホンアミド(AF−219)またはAF−130である、請求項2〜11の何れか一項に記載の処置用医薬組成物。
- 前記ベータ−2アドレナリン受容体アゴニストはサルブタモールである、請求項2〜11の何れか一項に記載の処置用医薬組成物。
- 前記ムスカリン受容体アンタゴニストはイプラトロピウム臭化物である、請求項2〜11の何れか一項に記載の処置用医薬組成物。
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- 2016-12-27 DK DK16819325.8T patent/DK3377064T3/da active
- 2016-12-27 JP JP2018532045A patent/JP6621534B2/ja active Active
- 2016-12-27 RU RU2018122121A patent/RU2746601C2/ru active
- 2016-12-27 CN CN201680078401.6A patent/CN108430475B/zh active Active
- 2016-12-27 BR BR112018013903-3A patent/BR112018013903B1/pt active IP Right Grant
- 2016-12-27 KR KR1020187022777A patent/KR102136017B1/ko active IP Right Grant
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- 2016-12-27 LT LTEP16819325.8T patent/LT3377064T/lt unknown
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2017
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CN113274392A (zh) | 2021-08-20 |
RU2018122121A (ru) | 2020-02-11 |
CN108430475B (zh) | 2021-03-16 |
PL3377064T3 (pl) | 2020-02-28 |
RS59313B1 (sr) | 2019-10-31 |
BR112018013903B1 (pt) | 2023-11-07 |
PT3377064T (pt) | 2019-07-23 |
RU2746601C2 (ru) | 2021-04-16 |
CY1122170T1 (el) | 2020-11-25 |
BR112018013903A2 (pt) | 2018-12-18 |
DK3377064T3 (da) | 2019-09-23 |
SI3377064T1 (sl) | 2019-11-29 |
US20170326140A1 (en) | 2017-11-16 |
EP3377064A1 (en) | 2018-09-26 |
CA3009283C (en) | 2023-10-03 |
RU2018122121A3 (ja) | 2020-06-26 |
KR20180100651A (ko) | 2018-09-11 |
US20170196860A1 (en) | 2017-07-13 |
WO2017118584A1 (en) | 2017-07-13 |
US9750739B2 (en) | 2017-09-05 |
AU2016384267A1 (en) | 2018-07-05 |
CA3009283A1 (en) | 2017-07-13 |
CN108430475A (zh) | 2018-08-21 |
LT3377064T (lt) | 2019-09-10 |
ES2738678T3 (es) | 2020-01-24 |
EP3377064B1 (en) | 2019-06-26 |
MX371178B (es) | 2020-01-21 |
HUE045764T2 (hu) | 2020-01-28 |
KR102136017B1 (ko) | 2020-07-20 |
HRP20191725T1 (hr) | 2019-12-27 |
AU2016384267B2 (en) | 2022-02-03 |
JP2019501162A (ja) | 2019-01-17 |
MX2018008439A (es) | 2018-08-14 |
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