JP2023539979A - 動物の病原体感染に対する予防及び/又は治療におけるhpk1キナーゼ阻害剤の応用 - Google Patents
動物の病原体感染に対する予防及び/又は治療におけるhpk1キナーゼ阻害剤の応用 Download PDFInfo
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Abstract
Description
Aは、C又はNから選択され、
Arは、芳香族5員複素環基、芳香族6員複素環基又はフェニル基から選択され、該芳香族5員複素環基は、フリル基、チエニル基、ピロリル基、ピラゾリル基、イミダゾリル基、オキサゾリル基、チアゾリル基又はセレノチアゾリル基から選択されてもよく、芳香族6員複素環基は、ピリジル基、ピリダジニル基、ピリミジニル基又はピラジニル基から選択されてもよく、任意に、上記芳香族5員複素環基、芳香族6員複素環基又はフェニル基上のHは、-SO2、-SO2N(C0-10アルキル基)(C0-10アルキル基)、-N(C0-10アルキル基)SO2(C0-10アルキル基)、-CON(C0-10アルキル基)(C0-10アルキル基)、-N(C0-10アルキル基)CO(C0-10アルキル基)、-N(C0-10アルキル基)COO(C0-10アルキル基)、-OCON(C0-10アルキル基)(C0-10アルキル基)、ハロゲン、-CN、-OCH2F、-OCHF2、-OCF3、C1-10直鎖/分岐鎖アルキル基、-N(C0-10アルキル基)(C0-10アルキル基)、-OC0-10アルキル基、C3-10シクロアルキル基、-Oヘテロシクロアルキル基、-Nヘテロシクロアルキル基、-N複素環芳香族基、-O複素環芳香族基又は-S複素環芳香族基で置換されてもよく、アルキル基部分は、-SO2、-SO2N(C0-10アルキル基)(C0-10アルキル基)、-N(C0-10アルキル基)SO2(C0-10アルキル基)、-CON(C0-10アルキル基)(C0-10アルキル基)、-N(C0-10アルキル基)CO(C0-10アルキル基)、-N(C0-10アルキル基)COO(C0-10アルキル基)、-OCON(C0-10アルキル基)(C0-10アルキル基)、ハロゲン、-CN、-OCH2F、-OCHF2、-OCF3、-N(C0-10アルキル基)(C0-10アルキル基)、-OC0-10アルキル基、-N複素環芳香族基、-O複素環芳香族基又は-S複素環芳香族基のうちの1つ以上で任意に置換されてもよく、
R1は、-H、ハロゲン、-NO2、-CN、C1-5直鎖/分岐鎖アルキル基、C3-10シクロアルキル基、-N(C0-10アルキル基)(C0-10アルキル基)、-CF3、-OCF3、-OCHF2、-OCH2F又は-OC0-10アルキル基から選択され、
R2及びR3は、独立して、-H、ハロゲン及びC1-10直鎖/分岐鎖アルキル基から選択され、
R4及びR5は、独立して、-H、重水素、ハロゲン、C1-10直鎖/分岐鎖アルキル基及び重水素化C1-10直鎖/分岐鎖アルキル基から選択され、
Qは、O又はSから選択され、
x及びzは、独立して、0~6の整数(具体的には、0、1、2、3、4、5、6)から選択され、
yは、0又は1であり、
B1、B2、B3、B4及びB5は、独立して、CR6又はNから選択され、各R6は、独立して、-H、ハロゲン、-CN、-OC0-10アルキル基、C1-10直鎖/分岐鎖アルキル基、O又はN含有のヘテロアルキル基、-N(C0-10アルキル基)(C0-10アルキル基)、C3-10シクロアルキル基、-C≡C-R7、-Oヘテロシクロアルキル基、-Nヘテロシクロアルキル基、-COO(C0-10アルキル基)(C0-10アルキル基)、-CO(C0-10アルキル基)(C0-10アルキル基)、-CON(C0-10アルキル基)(C0-10アルキル基)及び-N(C0-10アルキル基)CO(C0-10アルキル基)(C0-10アルキル基)から選択され、或いは、2つのR6とそれらの間の炭素原子とは、C3-8シクロアルキル基又は-O-及び-S-含有のC3-8ヘテロシクロアルキル基、-N複素環芳香族基、-O複素環芳香族基又は-S複素環芳香族基、フェニル基を形成し、C原子上のHは、-SO2、-SO2N(C0-10アルキル基)(C0-10アルキル基)、-N(C0-10アルキル基)SO2(C0-10アルキル基)、-CON(C0-10アルキル基)(C0-10アルキル基)、-N(C0-10アルキル基)CO(C0-10アルキル基)、-N(C0-10アルキル基)COO(C0-10アルキル基)、-OCON(C0-10アルキル基)(C0-10アルキル基)、ハロゲン、-CN、-OCH2F、-OCHF2、-OCF3、C1-10直鎖/分岐鎖アルキル基、-N(C0-10アルキル基)(C0-10アルキル基)、-OC0-10アルキル基、C3-10シクロアルキル基、-Oヘテロシクロアルキル基、-Nヘテロシクロアルキル基、-N複素環芳香族基、-O複素環芳香族基又は-S複素環芳香族基で置換されてもよく、
R7は、H、C1-5直鎖/分岐鎖アルキル基、C3-10シクロアルキル基及び
R11は、-H、-Oヘテロシクロアルキル基、-Nヘテロシクロアルキル基、C1-10直鎖/分岐鎖アルキル基、C3-10シクロアルキル基、-OC0-10アルキル基、-N(C0-10アルキル基)(C0-10アルキル基)、-SO2(C0-10アルキル基)、-O(C0-10アルキル基)、-O-フェニル基、-S(C0-10アルキル基)、-N複素環芳香族基、-O複素環芳香族基又は-S複素環芳香族基から選択され、C原子又はヘテロ原子上のHは、C1-3直鎖アルキル基、-N(C0-10アルキル基)(C0-10アルキル基)及び-CF3で置換されてもよい。
8月齢のイギリス短毛ネコ(楽楽)、雌性、未去勢、体重2.5kg。2020年1月に、該ネコは、体温の上昇、意気消沈、食欲減退、腹囲増大などの症状が出現した。1週間後に入院し、1月18日にネコ伝染性腹膜炎(FIP)陽性と診断され、GS-441524で3日治療した後、フロセミド、速諾、プレドニゾロン、イトラコナゾール(経口、q 24h、10mg/kg)を1ヶ月使用し続け、腹水が消失した後に休薬した。4月初に病状反復、食量減退、倦怠が出現し、X光で胸水を検出し、PCRでネココロナウイルス陽性(CT値25.11)と検出した。4月8日に登録し、第1-14日(D1~14):本発明の薬物を2.0mg/kg、SC q 24hで投与した。同時に適切な支援治療を行い、補助治療薬物として莫瑞加(肝臓保護剤)、豊茲頼(リジン)、康健靈(ラクトフェリン類)を使用した。
本発明の上記薬物活性化合物は、純粋な粉末に、0.9%の生理食塩水(50mlの無エンドトキシン水、0.45gのNaCl)を添加して均一に混合し、濾過膜で溶液が透明になるまで濾過した構造を有する。プラスチックパッケージバイアル瓶で希釈した薬物を貯蔵し、4℃の冷蔵庫に保存し、注射する前に室温まで調整し、使い捨て注射器で使用する。注射範囲は、肩甲骨後部の2cmから腰椎中部まで背部を跨ぎ、隣接する胸部と脇腹との距離の半分となる。
毎日午前に薬物を注射した後、午後15:00に体温を一回測定し、食欲、精神状態及び呼吸状態を評価し、排尿及び排便状況を記録し、結果を表1に示す。
1mlの血清サンプルを凍結保存し、多因子検出に用い、結果を表2に示す。
図1に示す。
以上の結果から分かるように、該症例は、湿性FIP(胸部)が検出され、臨床症状として胸水、倦怠、食欲減退が出現し、典型的なネコ伝染性腹膜炎症状を呈した。
Claims (15)
- 動物の病原体感染による疾患若しくは病症又は病原体感染に関連する疾患若しくは病症を予防及び/又は治療する薬物の製造におけるHPK1キナーゼ阻害剤の応用。
- 前記HPK1キナーゼ阻害剤は、小分子阻害剤であり、
好ましくは、前記小分子HPK1キナーゼ阻害剤は、以下の一般式Iで表される化合物、又はその薬学的に許容可能な塩、立体異性体、エステル、プロドラッグ、溶媒和物若しくは重水素化化合物であり、
Aは、C又はNから選択され、
Arは、芳香族5員複素環基、芳香族6員複素環基又はフェニル基から選択され、
R1は、-H、ハロゲン、-NO2、-CN、C1-5直鎖/分岐鎖アルキル基、C3-10シクロアルキル基、-N(C0-10アルキル基)(C0-10アルキル基)、-CF3、-OCF3、-OCHF2、-OCH2F又は-OC0-10アルキル基から選択され、
R2及びR3は、独立して、-H、ハロゲン及びC1-10直鎖/分岐鎖アルキル基から選択され、
R4及びR5は、独立して、-H、重水素、ハロゲン、C1-10直鎖/分岐鎖アルキル基及び重水素化C1-10直鎖/分岐鎖アルキル基から選択され、
Qは、O又はSから選択され、
x及びzは、独立して、0~6の整数から選択され、
yは、0又は1であり、
B1、B2、B3、B4及びB5は、独立して、CR6又はNから選択され、各R6は、独立して、-H、ハロゲン、-CN、-OC0-10アルキル基、C1-10直鎖/分岐鎖アルキル基、O又はN含有のヘテロアルキル基、-N(C0-10アルキル基)(C0-10アルキル基)、C3-10シクロアルキル基、-C≡C-R7、-Oヘテロシクロアルキル基、-Nヘテロシクロアルキル基、-COO(C0-10アルキル基)(C0-10アルキル基)、-CO(C0-10アルキル基)(C0-10アルキル基)、-CON(C0-10アルキル基)(C0-10アルキル基)及び-N(C0-10アルキル基)CO(C0-10アルキル基)(C0-10アルキル基)から選択され、或いは、2つのR6と、それらの間の炭素原子とは、C3-8シクロアルキル基又は-O-及び-S-含有のC3-8ヘテロシクロアルキル基、-N複素環芳香族基、-O複素環芳香族基又は-S複素環芳香族基、フェニル基を形成し、
R7は、H、C1-5直鎖/分岐鎖アルキル基、C3-10シクロアルキル基及び
- 前記芳香族5員複素環基は、フリル基、チエニル基、ピロリル基、ピラゾリル基、イミダゾリル基、オキサゾリル基、チアゾリル基及びセレノチアゾリル基から選択され、及び/又は、前記芳香族6員複素環基は、ピリジル基、ピリダジニル基、ピリミジニル基及びピラジニル基から選択される、ことを特徴とする請求項2に記載の応用。
- 前記Arは、
R10、R12及びR13は、独立して、-H、C1-10直鎖/分岐鎖アルキル基、-N(C0-10アルキル基)(C0-10アルキル基)、-OC0-10アルキル基及びC3-10シクロアルキル基から選択され、
R11は、-H、-Oヘテロシクロアルキル基、-Nヘテロシクロアルキル基、C1-10直鎖/分岐鎖アルキル基、C3-10シクロアルキル基、-OC0-10アルキル基、-N(C0-10アルキル基)(C0-10アルキル基)、-SO2(C0-10アルキル基)、-O(C0-10アルキル基)、-O-フェニル基、-S(C0-10アルキル基)、-N複素環芳香族基、-O複素環芳香族基又は-S複素環芳香族基から選択される、ことを特徴とする請求項2に記載の応用。 - 前記R11は、
- 前記B1、B2、B3、B4及びB5のうちの少なくとも1つは、Nであるか、又は
前記B1、B2、B3、B4及びB5は、いずれもCR6であり、前記一般式Iにおいて、
- 前記R63は、-H、ハロゲン、-OC0-10アルキル基、C1-10直鎖/分岐鎖アルキル基、-N(C0-10アルキル基)(C0-10アルキル基)又はC3-10シクロアルキル基から選択され、
好ましくは、前記R63は、-H、ハロゲン、-OC0-10アルキル基及びC1-10直鎖/分岐鎖アルキル基から選択され、
より好ましくは、前記R63は、-H、-F又は-OCH3から選択される、ことを特徴とする請求項6に記載の応用。 - 前記R62は、-H、ハロゲン、-OC0-10アルキル基、-CN、C3-10シクロアルキル基及び-C≡C-R7から選択され、
好ましくは、前記R62は、-H、-F、-Cl、-OCH3、-CN、
より好ましくは、前記R62は、C≡C-R7である、ことを特徴とする請求項6に記載の応用。 - 前記R61、R64及びR65は、独立して、-H、ハロゲン、-CN、-OC0-10アルキル基、C1-10直鎖/分岐鎖アルキル基、-N(C0-10アルキル基)(C0-10アルキル基)、C3-10シクロアルキル基、-C≡C-R7、-Oヘテロシクロアルキル基又は-Nヘテロシクロアルキル基及びO又はN含有のC1-5直鎖/分岐鎖アルキル基から選択され、或いは、R64及びR65と、R64及びR65に結合された炭素原子とは、C3-8シクロアルキル基又は-O-及び-S-含有のC3-8ヘテロシクロアルキル基を形成し、
好ましくは、前記R61、R64及びR65は、独立して、-H、ハロゲン、C1-3直鎖/分岐鎖アルキル基、-OC0-3アルキル基、N含有のC1-3直鎖/分岐鎖アルキル基から選択され、或いは、R64及びR65と、R64及びR65に結合された炭素原子とは、C3-8シクロアルキル基又は-O-含有のC3-8ヘテロシクロアルキル基を形成し、
より好ましくは、前記R61、R64及びR65は、独立して、-H、-F、-Cl、-CH3、-CH2NH2、-CN及び-OCH3から選択され、或いは、R64及びR65と、R64及びR65に結合された炭素原子とは、-O-含有の5員シクロアルキル基を形成する、ことを特徴とする請求項6に記載の応用。 - 前記R8及びR9は、独立して、-H、-CF3、-CHF2、-CH2F、-CH3、-CH2CH3、-CH=CH2、
- 前記化合物は、
- 前記病原体は、ウイルスであり、
好ましくは、前記ウイルスは、ヘルペスウイルス科、イリドウイルス科、バキュロウイルス科、ラブドウイルス科、レオウイルス科、ビルナウイルス科、ポックスウイルス科、アスファウイルス科、アデノウイルス科、パルボウイルス科、サーコウイルス科、レトロウイルス科、オルトミクソウイルス科、パラミスウイルス科、コロナウイルス科、アルテリウイルス科、ピコルナウイルス科、カリシウイルス科、フラビウイルス科、プリオン、フィロウイルス科、ポリオーマウイルス科及びパピローマウイルス科、ニマウイルス科、レトロウイルス科、ヘパドナウイルス科、パポーバウイルス科、ボルナウイルス科、ブンヤウイルス科、アレナウイルス科、ロニウイルス科、ヘペウイルス科、アストロウイルス科、トガウイルス科、ジシストロウイルス科及びノダウイルス科から選択され、
好ましくは、前記ウイルスは、コロナウイルスである、ことを特徴とする請求項1~11のいずれか1項に記載の応用。 - 前記ウイルスは、鶏伝染性気管支炎ウイルス、ブタ伝染性胃腸炎ウイルス、ブタ流行性下痢ウイルス、ブタ赤血球凝集性脳脊髄炎ウイルス、マウス肝炎ウイルス、七面鳥コロナウイルス、ウシコロナウイルス、イヌコロナウイルス、ネコ伝染性腹膜炎ウイルス、ラットコロナウイルス、ラット唾液腺涙腺炎ウイルス、ミンク流行性下痢コロナウイルス、羊痘ウイルス、山羊痘ウイルス、ランピースキン病ウイルス、鶏痘ウイルス、ネコ類ポックスウイルス、オルフウイルス、兎粘液腫ウイルス、アフリカブタ熱ウイルス、仮性狂犬病ウイルス、ブタサイトメガロウイルス、鶏伝染性喉頭気管炎ウイルス、アヒルウイルス性腸炎ウイルス、ネコウイルス性鼻気管炎ウイルス、イヌヘルペスウイルス、ウシ伝染性鼻気管炎ウイルス、ウマ伝染性鼻腔肺炎ウイルス、マレック病ウイルス、悪性カタル性熱ウイルス、ブタアデノウイルス、イヌウイルス性肝炎ウイルス、ネコアデノウイルス、ブタパルボウイルス、ネコ汎白血球減少症ウイルス、ガズリングペストウイルス、イヌパルボウイルス、ノバリケンパルボウイルス、ブタサーコウイルス、鶏伝染性貧血ウイルス、トリ白血病ウイルス、ネコ白血病ウイルス、ウシ白血病ウイルス、ネコ免疫不全ウイルス、メディビスナ病ウイルス、山羊ウイルス性関節炎-脳炎ウイルス、ウマ伝染性貧血ウイルス、ウシ免疫不全ウイルス、ネコ合胞体形成ウイルス、トリウイルス性関節炎ウイルス、ブルータングウイルス、イバラキ病ウイルス、チュウザン病ウイルス、アフリカウマ病ウイルス、ロタウイルス、伝染性ファブリキウス嚢病ウイルス、イヌウイルス性パピローマウイルス、ネコウイルス性パピローマウイルス、ニパウイルス、ヘンドラウイルス、ブタブルーアイ病ウイルス、イヌパラインフルエンザウイルス、禽類パラミソウィルス、鶏ニューカッスル病ウイルス、イヌジステンパーウイルス、小反芻獣疫ウイルス、牛疫ウイルス、トリニューモウイルス、アブラウイルス、ネコパラミクソウイルス、狂犬病ウイルス、水疱性口内炎ウイルス、ウシ流行熱/三日熱/一過性熱ウイルス、ボルナウィルス、インフルエンザウイルス、リフトバレー熱ウイルス、アカバネ病ウイルス、ハンタウィルス、ネコ腸コロナウイルス、ブタ赤血球凝集性脳脊髄炎ウイルス、ブタ生殖器呼吸器症候群ウイルス、ウマウイルス性動脈炎ウイルス、口蹄疫ウイルス、ブタ水疱病ウイルス、ブタ腸ウイルス、アヒルウイルス性肝炎ウイルス、トリ脳脊髄炎ウイルス、脳心筋炎ウイルス、ブタヘルペスウイルス、ネコカリシウイルス、ウサギウイルス性出血性疾患ウイルス、イヌE型ウイルス性肝炎ウイルス、ゲタウイルス、日本脳炎B型/日本脳炎ウイルス、ニ媒介性脳炎ウイルス、アヒルテンブスウイルス、ブタ熱ウイルス、ウシウイルス性下痢-粘膜病ウイルス及びボーダー病ウイルスから選択され、
好ましくは、前記ウイルスは、コロナウイルスであり、鶏伝染性気管支炎ウイルス、ブタ伝染性胃腸炎ウイルス、ブタ流行性下痢ウイルス、ブタ赤血球凝集性脳脊髄炎ウイルス、マウス肝炎ウイルス、七面鳥コロナウイルス、ウシコロナウイルス、イヌコロナウイルス、ネコ伝染性腹膜炎ウイルス、ラットコロナウイルス、ラット唾液腺涙腺炎ウイルス及びミンク流行性下痢コロナウイルスから選択され、
より好ましくは、前記ウイルスは、ネコ伝染性腹膜炎ウイルスである、ことを特徴とする請求項12に記載の応用。 - 前記動物は、飼育動物であり、
好ましくは、前記動物は、商業用動物、ペット又は実験用動物である、ことを特徴とする請求項12に記載の応用。 - 前記疾患又は病症は、鶏伝染性気管支炎、ブタ伝染性胃腸炎、ブタ流行性下痢、イヌコロナウイルス病、ブタ赤血球凝集性脳脊髄炎、マウス肝炎ウイルスによる肝炎、脳炎及び腸炎、七面鳥コロナ病、新生仔ウシ下痢、ウシ血痢、ネコ伝染性腹膜炎、ラット唾液腺涙腺炎、ミンク流行性下痢、羊痘、山羊痘、ランピースキン病、鶏痘、ネコ類ポックス、伝染性膿痂疹、兎粘液腫、アフリカブタ熱、仮性狂犬病、ブタサイトメガロウイルス感染、鶏伝染性喉頭気管炎、アヒルウイルス性腸炎、ネコウイルス性鼻気管炎、イヌヘルペスウイルス感染、ウシ伝染性鼻気管炎、ウマ伝染性鼻腔肺炎、マレック病、悪性カタル性熱、ブタアデノウイルス感染、イヌウイルス性肝炎、ネコアデノウイルス病、ブタパルボウイルス病、ネコ汎白血球減少症(ネコジステンバー、ネコ伝染性腸炎)、ガズリングペスト、イヌパルボウイルス病、ノバリケンパルボウイルス病、ブタサーコウイルス病、鶏伝染性貧血、トリ白血病、ネコ白血病、ウシ白血病、ネコ免疫不全、メディビスナ病、山羊ウイルス性関節炎-脳炎、ウマ伝染性貧血、ウシ免疫不全ウイルス感染、ネコ合胞体形成ウイルス(泡沫状ウイルス)感染、トリウイルス性関節炎、ブルータング、イバラキ病、チュウザン病、アフリカウマ病、ロタウイルス病、伝染性ファブリキウス嚢病、イヌウイルス性パピローマ、ネコウイルス性パピローマ、ニパ病、ヘンドラ病、ブタブルーアイ病、イヌパラインフルエンザウイルス感染、禽類パラミソウィルス感染、鶏ニューカッスル病、イヌジステンパー、小反芻獣疫、牛疫、トリニューモウイルス感染、アブラウイルス感染、ネコパラミクソウイルス病、狂犬病、水疱性口内炎、ウシ流行熱/三日熱/一過性熱、ボルナ、インフルエンザ、リフトバレー熱、アカバネ病、ハンタウィルス病、ネコ腸コロナウイルス感染、ブタ赤血球凝集性脳脊髄炎、ブタ生殖器呼吸器症候群、ウマウイルス性動脈炎、口蹄疫、ブタ水疱病、ブタ腸ウイルス感染、アヒルウイルス性肝炎、トリ脳脊髄炎、脳心筋炎、ブタヘルペス、ネコカリシウイルス病、ウサギウイルス性出血性疾患、イヌE型ウイルス性肝炎、ゲタウイルス病、日本脳炎B型/日本脳炎、ニ媒介性脳炎、アヒルテンブスウイルス感染、ブタ熱、ウシウイルス性下痢-粘膜病及びボーダー病を含み、
好ましくは、前記疾患は、ネコ伝染性腹膜炎である、ことを特徴とする請求項12に記載の応用。
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- 2021-05-27 US US18/009,954 patent/US20230241050A1/en active Pending
- 2021-05-27 CA CA3182850A patent/CA3182850A1/en active Pending
- 2021-05-27 MX MX2022016344A patent/MX2022016344A/es unknown
- 2021-05-27 WO PCT/CN2021/096276 patent/WO2021254118A1/zh unknown
-
2022
- 2022-12-19 ZA ZA2022/13687A patent/ZA202213687B/en unknown
- 2022-12-20 CO CONC2022/0018508A patent/CO2022018508A2/es unknown
Also Published As
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WO2021254118A1 (zh) | 2021-12-23 |
AU2021290594A1 (en) | 2023-02-02 |
CN113797202A (zh) | 2021-12-17 |
BR112022025714A2 (pt) | 2023-01-03 |
CA3182850A1 (en) | 2021-12-23 |
EP4154881A4 (en) | 2023-11-22 |
EP4154881A1 (en) | 2023-03-29 |
ZA202213687B (en) | 2023-11-29 |
US20230241050A1 (en) | 2023-08-03 |
CO2022018508A2 (es) | 2022-12-30 |
CN113797202B (zh) | 2024-06-28 |
MX2022016344A (es) | 2023-01-24 |
KR20230026387A (ko) | 2023-02-24 |
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