JP6205425B2 - 新規のrock阻害剤 - Google Patents
新規のrock阻害剤 Download PDFInfo
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- JP6205425B2 JP6205425B2 JP2015540120A JP2015540120A JP6205425B2 JP 6205425 B2 JP6205425 B2 JP 6205425B2 JP 2015540120 A JP2015540120 A JP 2015540120A JP 2015540120 A JP2015540120 A JP 2015540120A JP 6205425 B2 JP6205425 B2 JP 6205425B2
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Description
網膜症、視神経症、緑内障、及び黄斑変性症、増殖性硝子体網膜症、増殖性糖尿病性網膜症、網膜色素変性症等の網膜変性疾患、及び炎症性眼疾患、緑内障濾過手術ミス、ドライアイ、アレルギー性結膜炎、後嚢混濁、角膜創治癒異常及び眼痛を含むが、これらに限定されない眼疾患又は眼障害;
肺線維症、肺気腫、慢性気管支炎、喘息、線維症、肺炎、嚢胞性(cystic)線維症、慢性閉塞性肺疾患(COPD)、気管支炎、及び鼻炎、及び呼吸窮迫症候群を含むが、これらに限定されない気道疾患;
副鼻腔問題、聴覚問題、歯痛、扁桃炎、潰瘍、及び鼻炎を含むが、これらに限定されない耳鼻咽喉疾患;
過角化症、錯角化症、顆粒層肥厚、表皮肥厚症、異常角化症、海綿状態、及び潰瘍形成を含むが、これらに限定されない皮膚疾患;
炎症性腸疾患(IBD)、大腸炎、胃腸炎、腸閉塞、回腸炎、虫垂炎、及びクローン病を含むが、これらに限定されない腸疾患;
肺高血圧及び肺血管収縮を含むが、これらに限定されない心血管及び他の血管の疾患;
接触性皮膚炎、アトピー性皮膚炎、乾癬、関節リウマチ、若年性関節リウマチ、強直性脊椎炎、乾癬性関節炎、炎症性腸疾患、クローン病、及び潰瘍性大腸炎を含むが、これらに限定されない炎症性疾患;
神経障害痛を含むが、これに限定されない神経障害。本化合物はしたがって、様々な神経障害における神経変性の予防及び神経発生の刺激に好適である;
乳房、結腸、腸、皮膚、頭頸部、神経、子宮、腎臓、肺、卵巣、膵臓、前立腺、又は甲状腺のがん、キャッスルマン病、肉腫、悪性腫瘍、及び黒色腫等(これらに限定されない)の増殖性疾患;
腎線維症又は腎機能障害を含むが、これらに限定されない腎疾患;
性機能障害(これは、血管作動性の応答の欠陥によって引き起こされる男性及び女性の両方の性機能障害を含むことが意図される)。本発明のソフトROCK阻害剤は、様々な原因から生じる性機能障害を治療するためにも使用することができる。例えば、1つの実施の形態では、ソフトROCK阻害剤は、性腺機能低下症(より具体的には、性腺機能低下症はアンドロゲンホルモンレベルの低下に関連する)に関連する性機能障害を治療するために使用することができる。別の実施の形態では、ソフトROCK阻害剤は、膀胱疾患、高血圧、糖尿病、又は骨盤手術を含むが、これらに限定されない様々な原因に関連する性機能障害を治療するために使用することができる。加えて、ソフトROCK阻害剤は、高血圧、鬱病、又は不安神経症の治療に使用される薬物等の或る特定の薬物を用いた治療に関連する性機能障害を治療するために使用することができる;
骨粗鬆症及び変形性関節炎を含むが、これらに限定されない骨疾患。
加えて、本発明の化合物は、良性前立腺過形成、移植片拒絶反応、痙攣、慢性閉塞性膀胱疾患、及びアレルギー等の疾患及び障害の予防及び/又は治療において使用することができる。
Ar2はアリール又はヘテロアリールを表し、
Cyは、
1つの炭素原子が窒素原子により任意に置き換えられているC3〜15シクロアルキルであり、
Xは、直接結合、-NH-又は-N(C1〜6アルキル)-であり、
R1は、水素、ハロゲン、C1〜6アルキル、及びC1〜6アルコキシルを含む群から選択され、
R2は、水素及びC1〜3アルキルを含む群から選択され、
R3は、水素、ハロゲン、C1〜6アルキル、及びC1〜6アルコキシルを含む群から選択され、
R4は、C1〜20アルキル、C1〜20アルケニル、C1〜20アルキニル、C3〜15シクロアルキル、アリール、ヘテロシクリル、及びヘテロアリールを含む群から選択される任意に置換された基であり、
R5は、水素、C1〜6アルキル及びNH2から選択され、
R6は、水素、ハロ及びC1〜6アルキルから選択され、
kは、0〜3の整数であり、
lは、0〜3の整数であり、
mは0〜3の整数である)。
4-イル、2,1,3-ベンゾチアジアゾール-5-イル、2,1,3-ベンゾチアジアゾール-6-イル及び2,1,3-ベンゾチアジアゾール-7-イルを含む。「チエノピリジニル」という用語は、本明細書で使用される場合、チエノ[2,3-b]ピリジニル、チエノ[2,3-c]ピリジニル、チエノ[3,2-c]ピリジニル及びチエノ[3,2-b]ピリジニルを含む。「プリニル」という用語は、本明細書で使用される場合、プリン-2-イル、プリン-6-イル、プリン-7-イル及びプリン-8-イルを含む。「イミダゾ[1,2-a]ピリジニル」という用語は、本明細書で使用される場合、イミダゾ[1,2-a]ピリジン-2-イル、イミダゾ[1,2-a]ピリジン-3-イル、イミダゾ[1,2-a]ピリジン-4-イル、イミダゾ[1,2-a]ピリジン-5-イル、イミダゾ[1,2-a]ピリジン-6-イル及びイミダゾ[1,2-a]ピリジン-7-イルを含む。「1,3-ベンゾジオキソリル」という用語は、本明細書で使用される場合、1,3-ベンゾジオキソール-4-イル、1,3-ベンゾジオキソール-5-イル、1,3-ベンゾジオキソール-6-イル及び1,3-ベンゾジオキソール-7-イルを含む。「キノリニル」という用語は、本明細書で使用される場合、キノリン-2-イル、キノリン-3-イル、キノリン-4-イル、キノリン-5-イル、キノリン-6-イル、キノリン-7-イル及びキノリン-8-イルを含む。「イソキノリニル」という用語は、本明細書で使用される場合、イソキノリン-1-イル、イソキノリン-3-イル、イソキノリン-4-イル、イソキノリン-5-イル、イソキノリン-6-イル、イソキノリン-7-イル及びイソキノリン-8-イルを含む。「シンノリニル」という用語は、本明細書で使用される場合、シンノリン-3-イル、シンノリン-4-イル、シンノリン-5-イル、シンノリン-6-イル、シンノリン-7-イル及びシンノリン-8-イルを含む。「キナゾリニル」という用語は、本明細書で使用される場合、キナゾリン-2-イル、キナゾリン(quinazolin)-4-イル、キナゾリン-5-イル、キナゾリン-6-イル、キナゾリン-7-イル及びキナゾリン-8-イルを含む。「キノキサリニル」という用語は、本明細書で使用される場合、キノキサリン-2-イル、キノキサリン-5-イル及びキノキサリン-6-イルを含む。「7-アザインドリル」という用語は、本明細書で使用される場合、1H-ピロロ[2,3-b]ピリジニルを表し、7-アザインドール-1-イル、7-アザインドール-2-イル、7-アザインドール-3-イル、7-アザインドール-4-イル、7-アザインドール-5-イル、7-アザインドール-6-イルを含む。「6-アザインドリル」という用語は、本明細書で使用される場合、1H-ピロロ[2,3-c]ピリジニルを表し、6-アザインドール-1-イル、6-アザインドール-2-イル、6-アザインドール-3-イル、6-アザインドール-4-イル、6-アザインドール-5-イル、6-アザインドール-7-イルを含む。「5-アザインドリル」という用語は、本明細書で使用される場合、1H-ピロロ[3,2-c]ピリジニルを表し、5-アザインドール-1-イル、5-アザインドール-2-イル、5-アザインドール-3-イル、5-アザインドール-4-イル、5-アザインドール-6-イル、5-アザインドール-7-イルを含む。「4-アザインドリル」という用語は、本明細書で使用される場合、1H-ピロロ[3,2-b]ピリジニルを表し、4-アザインドール-1-イル、4-アザインドール-2-イル、4-アザインドール-3-イル、4-アザインドール-5-イル、4-アザインドール-6-イル、4-アザインドール-7-イルを含む。
Ar2はアリール又はヘテロアリールを表し、
Cyは、1つの炭素原子が窒素原子により任意に置き換えられているC3〜15シクロアルキルであり、
Xは、直接結合、-NH-又は-NC1〜6アルキル-であり、
R1は、水素、ハロゲン、C1〜6アルキル、及びC1〜6アルコキシルを含む群から選択され、
R2は、水素及びC1〜3アルキルを含む群から選択され、
R3は、水素、ハロゲン、C1〜6アルキル、及びC1〜6アルコキシルを含む群から選択され、
R4は、C1〜20アルキル、C1〜20アルケニル、C1〜20アルキニル、C3〜15シクロアルキル、アリール、ヘテロシクリル、及びヘテロアリールを含む群から選択される任意に置換された基であり、
R5は、水素、C1〜6アルキル及びNH2から選択され、
R6は、水素、ハロ又はC1〜6アルキルから選択され、具体的には水素、ハロ又はメチルから選択され、
kは、0〜3の整数であり、
lは、0〜3の整数であり、
mは0〜3の整数であり、
ただし、Cyが窒素原子を含有する場合、Xが直接結合であり、Cyが窒素原子を含有しない場合、Xが-N(C1〜6アルキル)-又は-NH-である)。
Ar1が、
Ar1が、
Ar2がアリール、具体的にはフェニルである;
Cyが、任意に1つの炭素原子が窒素原子によって置き換えられているC3〜15シクロアルキルである;
Cyが、1つの炭素原子が窒素原子によって置き換えられているC3〜15シクロアルキルである;
Xが直接結合である場合、Cyがその環(複数の場合もあり)内の窒素原子を介して、
Cyが窒素原子を含有する場合、Xは直接結合であり、Cyが窒素原子を含有しない場合、Xは--N(C1〜6アルキル)--又は-NH-である;
-Cy-X-が、
R1が水素、ハロゲン、メチル及びメトキシル、具体的には水素、フルオロ、クロロ、メチル及びメトキシルからなる群から選択される;
R1が水素、ハロゲン及びC1〜6アルキル、具体的には水素、フルオロ、クロロ及びメチルからなる群から選択される;
R2が水素である;
R3が水素又はC1〜6アルコキシル、具体的には水素又はC1〜2アルコキシル、より具体的には水素又はエトキシルである;
R3が水素又はハロゲン、具体的には水素、クロロ又はフルオロ、より具体的には水素である;
R4が、C1〜20アルキル、C3〜15シクロアルキル及びヘテロシクリルからなる群から選択される任意に置換された基である、具体的にはR4が任意に置換されたC1〜20アルキルである;
R4が、C1〜20アルキル、C3〜15シクロアルキル、アリール、ヘテロアリール及びヘテロシクリルからなる群から選択される任意に置換された基である、具体的にはR4が、C1〜20アルキル、C3〜15シクロアルキル、アリール及びヘテロシクリルからなる群から選択される任意に置換された基である;
R4の定義内の任意の置換基が、C1〜6アルコキシ及びヘテロシクリル、具体的にはメトキシル及びオキソラニルから選択される;
R4の定義内の任意の置換基が、ハロ、ヒドロキシル、ニトロ、アミノ、シアノ、アリール、シクロアルキル、ヘテロシクリル、アルキル、アルケニル、アルキニル、アルキルアミノ、ジアルキルアミノ及びアルコキシ、具体的にはC1〜6アルコキシ、C1〜6アルキル、C1〜6アルケニル、C1〜6アルキニル、ジアルキルアミノ及びヘテロシクリル、より具体的にはメチル、メトキシル、エチニル、ジメチルアミノ及びオキソラニルから選択される;
R5が水素、メチル及びNH2からなる群から選択される、具体的にはR5が水素である;
R6が水素、フルオロ又はメチル、具体的には水素である;
kが0又は1、具体的には0である;
lが0又は1、具体的には0である;
mが0又は1である。
本発明は、ROCKが関与する少なくとも1つの疾患又は障害を予防及び/又は治療する方法であって、それを必要とする対象に治療的有効量の本発明の化合物又は組成物を投与することを含む、方法を更に提供する。
A.1. 化合物の純度
他に指定のない限り、化合物の純度は下記のように確認した:
液体クロマトグラフィー/質量分析(LC/MS、HPLC/MS又はUPLC/MS)、C18カラム。
1H NMR
特定の鏡像異性体(又はジアステレオ異性体)を、キラル分割(例えば、光学的に活性な酸又は塩基により形成された塩を使用して、式Iの化合物又はその任意のサブグループの光学的に活性な異性体の分離を容易にし得るジアステレオ異性体塩を形成することができる)、不斉(asymmetric)合成、又は分取キラルクロマトグラフィー(Chiral Technologies Europe(Illkirch, France)製のChiralcel OD-H(トリス-3,5-ジメチルフェニルカルバメート、46×250 mm又は100×250 mm、5 μm)、Chiralcel OJ(トリス-メチルベンゾエート、46×250 mm又は100×250 mm、5 μm)、Chiralpak AD(トリス-3,5-ジメチルフェニルカルバメート、46×250 mm、10 μm)、及びChiralpak AS(トリス-(S)-1-フェニルエチルカルバメート、46×250 mm、10 μm)等の種々のカラムを用いる)等(これらに限定されない)の種々の方法によって得ることができることは当業者に既知である。都合のよい場合には、既知の立体配置を有する市販の材料から出発して立体異性体を得ることができる(かかる化合物は例えばアミノ酸を含む)。
B.1. 中間体
本発明の化合物は、当業者に既知の方法によって、下記に示す合成手順及び実験手順に記載されるとおりに調製することができる。
中間体4の合成に用いた実験プロトコルを、最低限の変更を伴って中間体7〜13の合成に用いた。中間体7〜13は中間体1〜3を適切な市販の試薬と反応させることにより得ることができる。
IUPAC name:名
化合物名:
N-(1-(3-ニトロベンジル)ピペリジン-3-イル)イソキノリン-5-アミン
N-(1-(3-ニトロ-4-メチルベンジル)ピロリジン-3-イル)イソキノリン-5-アミン
N-(1-(3-ニトロ-4-フルオロベンジル)ピロリジン-3-イル)イソキノリン-5-アミン
N-(1-(3-ニトロ-4-クロロベンジル)ピロリジン-3-イル)イソキノリン-5-アミン
N-(1-(3-ニトロ-4-メトキシベンジル)ピロリジン-3-イル)イソキノリン-5-アミン
5-(N-(3-ニトロベンジル)ピペリジン-3-イルアミノ)-インダゾール-1-カルボン酸tert-ブチルエステル
5-(N-(3-ニトロ-4-メチルベンジル)ピペリジン-3-イルアミノ)-インダゾール-1-カルボン酸tert-ブチルエステル
中間体14の合成に用いた実験プロトコルを、中間体5〜13に存在するニトロ基の還元に合わせて最低限の変更を伴って用いた。それにより、中間体17〜23が得られた。
中間体17:N-(1-(3-アミノベンジル)ピペリジン-3-イル)イソキノリン-5-アミン
中間体18:N-(1-(3-アミノ-4-メチルベンジル)ピロリジン-3-イル)イソキノリン-5-アミン
中間体19:N-(1-(3-アミノ-4-フルオロベンジル)ピロリジン-3-イル)イソキノリン-5-アミン
中間体20:N-(1-(3-アミノ-4-クロロベンジル)ピロリジン-3-イル)イソキノリン-5-アミン
中間体21:N-(1-(3-アミノ-4-メトキシベンジル)ピロリジン-3-イル)イソキノリン-5-アミン
中間体22:1-N-(イソキノリン-5-イル)-4-N-(3-アミノベンジル)シクロヘキサン-1,4-ジアミン
中間体23:N-{1-(3-アミノベンジル)ピペリジン-4-イル}イソキノリン-5-アミン
B.2.1. メチルエステル:
化合物1:メチル3-((3-((3-(イソキノリン-5-イルアミノ)ピロリジン-1-イル)メチル)フェニル)カルバモイル)ベンゾエート
B.2.2.1:カルボン酸中間体:
中間体24:3-((3-((3-(イソキノリン-5-イルアミノ)ピロリジン-1-イル)メチル)フェニル)カルバモイル)安息香酸
プロトコルA(イソキノリン誘導体):DCM(1mL)中のカルボン酸中間体(100 mg、1.0当量)及びR-OH(10当量)の懸濁液に、0℃にて、2,4,6-トリプロピル-1,3,5,2,4,6-トリオキサトリホスフィナン2,4,6-トリオキシド(EtOAc中50%、3当量)及びN,N-ジメチルピリジン-4-アミン(4当量)を添加した。反応混合物を室温で2時間撹拌し、EtOAcで希釈して、飽和NaHCO3及びブラインで洗浄し、Na2SO4で乾燥させ、真空で濃縮した。残渣を水/ACN(100/0→0/100)で溶出する逆相フラッシュクロマトグラフィーによって精製して、期待される化合物を得た。
下記の本発明の化合物を上記の基本手順(B 2.2.1及びB 2.2.2)に従って合成した。
C.1. ROCKの阻害活性のスクリーニング
C.1.1. キナーゼ阻害(ROCK I及びROCK II)
ROCKに対するオンターゲット活性を、以下の試薬を用いた生化学アッセイにおいて測定した:塩基反応バッファー;20 mM Hepes(pH7.5)、10mM MgCl2、1 mM EGTA、0.02% Brij35、0.02 mg/ml BSA、0.1 mM Na3VO4、2 mM DTT、1 % DMSO。必須補因子を各キナーゼ反応に個々に添加した。反応手順は初めに、新たに調製した反応バッファー中でのペプチド基質の調製を含む。次いで、必須補因子を基質溶液に添加した。次いで、ROCK(最終濃度1 nM)を基質溶液に加えた。穏やかに混合した後、試験化合物のDMSO溶液を酵素に添加した。次いで、基質ミックス33P-ATP(最終比活性0.01 μCI/μl)を反応混合物に加えて、反応を開始した。キナーゼ反応混合物を室温で120分間インキュベートした。次いで、反応混合物をP81イオン交換紙(Whatman #3698-915)にスポットした。フィルターを0.1%リン酸で十分に洗浄した。次いで、放射測定(radiometric count)を行い、IC50値を続いて決定した。
ラット平滑筋細胞株A7r5を使用する。ROCKの内因性発現は、T18/S19での調節ミオシン軽鎖の構成的リン酸化をもたらす。A7r5細胞を、マルチウェル(multiwell)細胞培養プレート中の10 %FCSを添加したDMEMにプレーティングした。一晩の血清飢餓の後、細胞を無血清培地中で化合物とともにインキュベートした。
C.2.1. ヒト(動物)の血漿/全血における安定性アッセイ
化合物を、ヒト又は動物(ラット、マウス又はウサギ)のヒト血漿又は全血中1 μMの濃度でインキュベートする。サンプルを一定の時点で取り、化合物の残留物をタンパク質沈殿後のLC-MS/MSによって決定する。半減期は分単位で表される。
化合物をウサギ房水(AH)中1 μMの濃度でインキュベートする。サンプルを一定の時点で取り、化合物の残留物をタンパク質沈殿後のLC-MS/MSによって決定する。
半減期は分単位で表される。
構造的に類似した従来技術で既知のROCK阻害剤、例えば国際公開第2008/077057号、国際公開第2010/065782号、国際公開第2009/158587号、米国特許出願公開第2009/0325960号、米国特許出願公開第2009/0325959号、Iwakubo et al. (Bioorg. Med. Chem., 2007, 15, 350-364 & Bioorg.Med. Chem., 2007, 15, 1022-1033)及び国際公開第2001/56988号に記載のもの等と比較すると、本発明の化合物は、体循環に入った時点で予測可能な機能的に不活性な化合物へと非常に急速に変換されるが、標的器官で良好な安定性を保持するという点で異なる。上述の文献は、本発明の化合物と構造的に類似したROCK阻害剤を開示しているが、これらの文献のいずれにおいても、ソフトROCK阻害剤の設計、発見又は潜在的利点は論考されていない。特に、血漿、全血、又は考え得る標的器官における開示のROCK阻害剤の安定性に関する情報は提示されていない。
Claims (15)
- 式Iの化合物又はその立体異性体、互変異性体、ラセミ体、塩、水和物、若しくは溶媒和物:
Ar2はアリール又はヘテロアリールを表し、
Cyは、1つの炭素原子が窒素原子により任意に置き換えられているC3〜15シクロアルキルであり、
Xは、直接結合、-NH-又は-N(C1〜6アルキル)-であり、
R1は、水素、ハロゲン、C1〜6アルキル、及びC1〜6アルコキシルを含む群から選択され、
R2は、水素及びC1〜3アルキルを含む群から選択され、
R3は、水素、ハロゲン、C1〜6アルキル、及びC1〜6アルコキシルを含む群から選択され、
R4は、C1〜20アルキル、C1〜20アルケニル、C1〜20アルキニル、C3〜15シクロアルキル、アリール、ヘテロシクリル、及びヘテロアリールを含む群から選択される任意に置換された基であり、
R5は、水素、C1〜6アルキル及びNH2から選択され、
R6は、水素、ハロ又はC1〜6アルキルから選択され、
kは、0〜3の整数であり、
lは、0〜3の整数であり、
mは0〜3の整数である)。 - Ar1が、
Ar2がアリール又はヘテロアリールを表し、
Cyが、1つの炭素原子が窒素原子により任意に置き換えられているC3〜15シクロアルキルであり、
Xが、直接結合、-NH-又は-N(C1〜6アルキル)-であり、
R1が、水素、ハロゲン、C1〜6アルキル、及びC1〜6アルコキシルを含む群から選択され、
R2が、水素及びC1〜3アルキルを含む群から選択され、
R3が、水素、ハロゲン、C1〜6アルキル、及びC1〜6アルコキシルを含む群から選択され、
R4が、C1〜20アルキル、C1〜20アルケニル、C1〜20アルキニル、C3〜15シクロアルキル、アリール、ヘテロシクリル、及びヘテロアリールを含む群から選択される任意に置換された基であり、
R5が、水素、C1〜6アルキル及びNH2から選択され、
R6が、水素、ハロ及びC1〜6アルキルから選択され、
kが、0〜3の整数であり、
lが、0〜3の整数であり、
mが0〜3の整数であり、
ただし、Cyが窒素原子を含有する場合、Xが直接結合であり、Cyが窒素原子を含有しない場合、Xが-N(C1〜6アルキル)-又は-NH-である、
請求項1に記載の化合物。 - Ar2が、アリール、あるいはフェニルである、請求項1〜3のいずれか一項に記載の化合物。
- R1が、水素、ハロゲン、メチル、及びメトキシル、或は水素、フルオロ、クロロ、メチル、及びメトキシルからなる群から選択される、請求項1〜4のいずれか一項に記載の化合物。
- R2が水素であり、
R3が水素又はC1〜6アルコキシル、あるいは水素又はエトキシル、あるいは水素である、請求項1〜5のいずれか一項に記載の化合物。 - R4が、C1〜20アルキル、C3〜15シクロアルキル、及びヘテロシクリルからなる群から選択される任意に置換された基であり、あるいはR4が任意に置換されたC1〜20アルキルであり、
任意の置換基がハロ、ヒドロキシル、ニトロ、アミノ、シアノ、アリール、シクロアルキル、ヘテロシクリル、及びアルコキシ、あるいはC1〜6アルコキシ及びヘテロシクリル、あるいはメトキシル及びオキソラニルから選択される、
請求項1〜6のいずれか一項に記載の化合物。 - R5が、水素、メチル、及びNH2からなる群から選択され、あるいはR5が水素であり、
R6が、水素、フルオロ、又はメチル、あるいは水素である、
請求項1〜7のいずれか一項に記載の化合物。 - k、l、及びmが各々、独立して0及び1から選択される、請求項1〜8のいずれか一項に記載の化合物。
- ヒト又は動物用の医薬として使用される、請求項1〜9のいずれか一項に記載の化合物。
- ヒト又は動物用の医薬として使用される請求項1〜9のいずれか一項に記載の化合物を含む組成物。
- 平滑筋細胞機能、炎症、線維化、過剰な細胞増殖、過剰な血管形成、過敏性、バリア機能障害、神経変性、及びリモデリングに関わる疾患等のROCKが関与する少なくとも1つの疾患又は障害の予防及び/又は治療に使用される、請求項1〜10のいずれか一項に記載の化合物又は請求項11に記載の組成物。
- 眼疾患、気道疾患、耳鼻咽喉疾患、腸疾患、皮膚疾患、心血管及び他の血管の疾患、炎症性疾患、神経障害、増殖性疾患、腎疾患、性機能障害、骨疾患、良性前立腺過形成、移植片拒絶反応、痙攣、慢性閉塞性膀胱疾患、及びアレルギーからなる群から選択される少なくとも1つの疾患又は障害の予防及び/又は治療に使用される、請求項1〜10のいずれか一項に記載の化合物又は請求項11に記載の組成物。
- 網膜症、視神経症、緑内障、炎症性眼疾患、並びに黄斑変性症及び網膜色素変性症の網膜変性疾患からなる群から選択される眼疾患、あるいは緑内障の予防及び/又は治療に使用される、請求項1〜10のいずれか一項に記載の化合物又は請求項11に記載の組成物。
- 眼疾患、気道疾患、耳鼻咽喉疾患、腸疾患、皮膚疾患、心血管及び他の血管の疾患、炎症性疾患、神経障害及びCNS障害、増殖性疾患、腎疾患、性機能障害、骨疾患、良性前立腺過形成、移植片拒絶反応、痙攣、慢性閉塞性膀胱疾患、及びアレルギーを含む群から選択される少なくとも1つの疾患又は障害の予防剤及び/又は治療剤であって、それを必要とする対象に治療的有効量の請求項1〜10のいずれか一項に記載の化合物又は請求項11に記載の組成物を投与することを含む、剤。
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US9394286B2 (en) | 2016-07-19 |
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