JP5512894B2 - 2−置換−8−アルキル−7−オキソ−7,8−ジヒドロピリド[2,3d]ピリミジン−6−カルボニトリル及びその使用 - Google Patents
2−置換−8−アルキル−7−オキソ−7,8−ジヒドロピリド[2,3d]ピリミジン−6−カルボニトリル及びその使用 Download PDFInfo
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Description
2010年8月5日付け米国仮出願第61/370946号の出願日の恩恵をここに主張する。上記出願の全開示は、参照によってここに取り入れられる。
本発明は、化合物、それらの製造方法、それらを含む組成物及び癌を含む(がそれに限定されない)細胞増殖性疾患(疾病も同義)の治療方法に関する。
癌のような細胞増殖性疾患は、先進国における最も一般的な死因の中の1つである。癌のように治療が存在する疾患については、進歩し続けているにも拘わらず、現存の処置には望ましくない副作用及び効き目の限界がある。癌を含む細胞増殖性疾患についての新規の有効な医薬を見出すことは、医薬の研究の継続する焦点となっている。
ある種の化合物及び組成物は癌及び他の細胞増殖性疾患の治療用に有用であることがわかった。本発明の生物学的に活性な化合物は、2−置換−8−アルキル−7−オキソ−7,8−ジヒドロピリド[2,3−d]ピリミジン−6−カルボニトリルである。
R1は(C1−C6)アルキル又は(C3−C8)シクロアルキルであり;
R2は4−(4−メチルピペラジン−1−イル)アニリニル、4−モルホリノアニリニル又は
R3はそれぞれの出現において独立して(C1−C6)アルコキシであり;そして
R4はH又は(C1−C6)アルコキシである。
ある実施形態において、R1は(C3−C8)シクロアルキルである。
特定的な実施形態において、R1はシクロペンチル又はシクロヘキシルである。
ある実施形態において、R2は
特定的な実施形態において、R1はシクロペンチルである。
ある実施形態において、R3はそれぞれの出現においてメトキシである。
ある実施形態において、R4は水素である。
ある実施形態において、R4はメトキシである。
ある実施形態において、R2は4−モルホリノアニリニルである。
ある実施形態において、R1はシクロペンチルである。
より成る群から選択されるアミンで処理することを含む。この方法はさらに、式Iに従う化合物を得ることを含む。
本発明の化合物及び組成物は、癌細胞の増殖を選択的に阻害し、様々なタイプの腫瘍細胞を殺すと信じられる。本発明の化合物は、様々な蛋白質キナーゼを阻害する。同様の化合物がキナーゼ活性を阻害することが報告されている(米国特許第6498163号明細書)が、本発明の化合物は驚くべきことに異なるキナーゼ阻害の側面(プロファイル)を有し、より一層広範な蛋白質キナーゼを阻害する。
・心臓の癌、例えば肉腫、例えば血管肉腫、線維肉腫、横紋筋肉腫及び脂肪肉腫;粘液腫;横紋筋腫;線維腫;脂肪腫及び奇形腫;
・肺癌、例えば気管支原性肺癌、例えば扁平上皮細胞、未分化小細胞、未分化大細胞、及び腺癌;肺胞上皮及び細気管支癌、気管支腺腫、肉腫、リンパ腫、軟骨性過誤腫、中皮腫;
・消化管(胃腸)癌、例えば食道の癌、例えば扁平上皮細胞癌、腺癌、平滑筋肉腫及びリンパ腫;胃の癌、例えば癌腫、リンパ腫及び平滑筋肉腫:膵臓の癌、例えば腺管癌、インスリノーマ、グルカゴノーマ、ガストリノーマ、カルチノイド腫瘍及びビポーマ;小腸の癌、例えば腺癌、リンパ腫、カルチノイド腫瘍、カポジ肉腫、平滑筋腫、血管腫、脂肪腫、神経線維腫及び線維腫;大腸の癌、例えば腺癌、管状腺腫、絨毛腺腫、過誤腫、平滑筋腫;
・尿生殖路癌、例えば腎臓の癌、例えば腺癌、ウィルムス腫瘍(腎芽腫)、リンパ腫、白血病;膀胱と尿道の癌、例えば扁平上皮細胞癌、移行上皮癌及び腺癌;前立腺の癌、例えば腺癌及び肉腫;精巣の癌、例えば、セミノーマ、奇形腫、胎生期癌、奇形癌、絨毛癌、肉腫、間質細胞癌、線維腫、線維腺腫、腺腫様腫瘍並びに脂肪腫;
・肝臓癌、例えば肝癌、例えば肝細胞癌;胆管癌;肝芽腫;血管肉腫;肝細胞腺腫及び血管腫;
・骨の癌、例えば骨原性肉腫(骨肉腫)、線維肉腫、悪性線維性組織球腫、軟骨肉腫、ユーイング肉腫、悪性リンパ腫(細網肉腫)、多発性骨髄腫、悪性巨細胞腫瘍脊索腫、骨軟骨腫(骨軟骨外骨腫症)、良性軟骨腫、軟骨芽細胞腫、軟骨粘液線維腫、類骨骨腫及び巨大細胞腫瘍;
・神経系の癌、例えば頭蓋骨の癌、例えば骨腫、血管腫、肉芽腫、黄色腫及び変形性骨炎;髄膜の癌、例えば髄膜腫、髄膜血管腫症及び神経膠腫症;脳の癌、例えば星状細胞腫、髄芽腫、神経膠腫及び上衣腫、胚細胞腫(松果体腫)、多形性膠芽腫、乏突起膠腫、神経鞘腫、網膜芽細胞腫及び先天性腫瘍;並びに脊髄の癌、例えば神経線維腫、髄膜腫、神経膠腫及び肉腫;
・ 婦人科系の癌、例えば子宮癌、例えば子宮内膜癌;子宮頸管の癌、例えば、子宮頚癌及び腫瘍前の子宮頚部形成異常;卵巣の癌、例えば卵巣癌、漿液性嚢胞腺癌、粘液性嚢胞腺癌、非分類癌腫、コーン型包膜細胞腫、セルトリ−ライディッヒ細胞腫瘍、未分化胚細胞腫及び悪性奇形腫;外陰部の癌、例えば扁平上皮細胞癌、上皮内癌、腺癌、線維肉腫及び黒色腫;膣の癌、例えば明細胞癌、扁平上皮細胞癌、ブドウ状肉腫及び胎児性横紋筋肉腫;並びに卵管の癌、例えば癌腫;
・血液系の癌、例えば、血液の癌、例えば、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ芽球性白血病、慢性リンパ性白血病、骨髄増殖性疾患、多発性骨髄腫及び骨髄異形成症候群、ホジキンリンパ腫、非ホジキンリンパ腫(悪性リンパ腫)並びにワルデンシュトレームマクログロブリン血症;
・皮膚癌、例えば悪性黒色腫、基底細胞癌、扁平上皮細胞癌、カポジ肉腫、ほくろ異形成母斑、脂肪腫、血管腫、皮膚線維腫、ケロイド、乾癬;並びに
・副腎の癌、例えば神経芽細胞腫。
1H NMR (300 MHz, CDCl3), δ8.60 (s, 1H), 8.25 (br s, 1H), 4.49-4.54 (m, 1H), 4.30 (q, 2H), 2.52 (s, 3H), 2.00-2.10 (m, 2H), 1.50-1.79 (m, 6H), 1.35 (t, 3H)。
1H NMR (300 MHz, CDCl3), δ9.65 (s, 1H), 8.60 (br s, 1H), 8.25 (s, 1H), 4.49-4.54 (m, 1H), 2.52 (s, 3H), 2.01-2.12 (m, 2H), 1.50-1.82 (m, 6H)。
1H NMR (300 MHz, CDCl3), 8.55 (s, 1H), 7.79 (s, 1H), 7.40-7.45 (m, 2H), 6.91-6.99 (m, 2H), 3.23-3.27 (m, 4H), 2.63-2.66 (m, 4H), 2.43 (s, 3H), 2.21-2.30 (m, 2H), 1.85 (br s, 4H), 1.62 (br s, 2H). m.p: 290-292℃.
Claims (29)
- R2が4−(4−メチルピペラジン−1−イル)アニリニルである、請求項1に記載の化合物。
- R1が(C3−C8)シクロアルキルである、請求項2に記載の化合物。
- R1がシクロペンチル又はシクロヘキシルである、請求項3に記載の化合物。
- R1がシクロペンチルである、請求項5に記載の化合物。
- 各R3がメトキシである、請求項6に記載の化合物。
- R4が水素である、請求項7に記載の化合物。
- R4がメトキシである、請求項7に記載の化合物。
- R2が4−モルホリノアニリニルである、請求項1に記載の化合物。
- R1がシクロペンチルである、請求項10に記載の化合物。
- 前記化合物が8−シクロペンチル−2−((4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−7−オキソ−7,8−ジヒドロピリド[2,3−d]ピリミジン−6−カルボニトリル;8−シクロヘキシル−2−((4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−7−オキソ−7,8−ジヒドロピリド[2,3−d]ピリミジン−6−カルボニトリル;8−シクロペンチル−2−((3,5−ジメトキシフェニル)アミノ)−7−オキソ−7,8−ジヒドロピリド[2,3−d]ピリミジン−6−カルボニトリル;8−シクロペンチル−7−オキソ−2−((3,4,5−トリメトキシフェニル)アミノ)−7,8−ジヒドロピリド[2,3−d]ピリミジン−6−カルボニトリル;及び8−シクロペンチル−2−((4−モルホリノフェニル)アミノ)−7−オキソ−7,8−ジヒドロピリド[2,3−d]ピリミジン−6−カルボニトリルより成る群から選択される、請求項1に記載の化合物。
- 前記化合物が8−シクロペンチル−2−((4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−7−オキソ−7,8−ジヒドロピリド[2,3−d]ピリミジン−6−カルボニトリル又はその塩である、請求項12に記載の化合物。
- 製薬上許容できるキャリヤーと、請求項1に記載の化合物又はその製薬上許容できる塩とを含む製薬組成物。
- 前記の化合物が8−シクロペンチル−2−((4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−7−オキソ−7,8−ジヒドロピリド[2,3−d]ピリミジン−6−カルボニトリル;8−シクロヘキシル−2−((4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−7−オキソ−7,8−ジヒドロピリド[2,3−d]ピリミジン−6−カルボニトリル;8−シクロペンチル−2−((3,5−ジメトキシフェニル)アミノ)−7−オキソ−7,8−ジヒドロピリド[2,3−d]ピリミジン−6−カルボニトリル;8−シクロペンチル−7−オキソ−2−((3,4,5−トリメトキシフェニル)アミノ)−7,8−ジヒドロピリド[2,3−d]ピリミジン−6−カルボニトリル;8−シクロペンチル−2−((4−モルホリノフェニル)アミノ)−7−オキソ−7,8−ジヒドロピリド[2,3−d]ピリミジン−6−カルボニトリル;及びそれらの製薬上許容できる塩より成る群から選択される、請求項14に記載の製薬組成物。
- 請求項1に記載の少なくとも1種の化合物又はその製薬上許容できる塩を含む、細胞増殖性疾患を処置するための医薬。
- 前記細胞増殖性疾患が新生児の血管腫症、二次性進行型 多発性硬化症、アテローム性動脈硬化症、慢性進行性脊髄変性疾患、神経線維腫症、神経節神経腫症、ケロイド形成、骨ページェット病、乳房線維嚢胞病、子宮筋腫、ペイロニー病、デュピュイトラン病、再狭窄、良性増殖性乳房疾患、良性前立腺肥大症、X連鎖リンパ細胞増殖性疾患、移植後のリンパ細胞増殖性疾患、黄斑変性症、網膜症、増殖性硝子体網膜症及び非癌性のリンパ細胞増殖性疾患より成る群から選択される、請求項16に記載の医薬。
- 前記細胞増殖性疾患が癌である、請求項16に記載の医薬。
- 前記癌が卵巣癌;子宮頸癌;乳癌;前立腺癌;精巣癌, 肺癌, 腎臓癌;結腸直腸癌;皮膚癌;脳腫瘍;並びに急性骨髄性白血病、慢性骨髄性白血病、急性リンパ白血病及び慢性リンパ白血病を含む白血病より成る群から選択される、請求項18に記載の医薬。
- 請求項1に記載の少なくとも1種の化合物又はその製薬上許容できる塩を含む、癌細胞のアポトーシスを誘発するための医薬。
- 前記癌細胞が腫瘍細胞である、請求項20に記載の医薬。
- 前記腫瘍細胞が卵巣、子宮頸、子宮、膣、乳房、前立腺、精巣、肺、腎臓、結腸直腸、胃、副腎、口、食道、肝臓、胆嚢、骨、リンパ管、眼、皮膚及び脳の腫瘍細胞より成る群から選択される、請求項21に記載の医薬。
- 請求項1に記載の化合物又はその製薬上許容できる塩を含む、キナーゼ活性を阻害するための医薬。
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