JP5148597B2 - 医薬化合物 - Google Patents
医薬化合物 Download PDFInfo
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- JP5148597B2 JP5148597B2 JP2009507189A JP2009507189A JP5148597B2 JP 5148597 B2 JP5148597 B2 JP 5148597B2 JP 2009507189 A JP2009507189 A JP 2009507189A JP 2009507189 A JP2009507189 A JP 2009507189A JP 5148597 B2 JP5148597 B2 JP 5148597B2
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Description
本発明は、ピリミジン誘導体及びそのホスファチジルイノシトール3−キナーゼ(PI13K)の阻害剤としての使用に関する。
(a)式(II)
のボロン酸またはそのエステルで処理し;得られる式(III)
(b)式(II)
のボロン酸またはそのエステルで処理する工程を含むプロセスで調製してもよい。
のボロン酸またはそのエステルで処理することによって式(III)の化合物を製造する工程を含んでもよい。
のボロン酸またはそのエステルで処理する工程を含む、前記の本発明の化合物の製造プロセスを提供する。
A)経口的に、例えば、錠剤、被覆錠剤、糖衣錠、トローチ、ロゼンジ、水性または油性懸濁物、溶液、分散性粉末または顆粒、エマルジョン、硬または軟カプセル、あるいはシロップまたはエリキシルとして投与してもよい。経口用途を目的とした組成物は、医薬組成物を製造するために当分野において公知の方法に従って調製してもよく、このような組成物は、医薬として上品で口当たりのよい製剤を提供するために、甘味剤、風味剤、着色剤及び防腐剤からなる群より選択される1種またはそれ以上の薬剤を含有してもよい。
B)非経口的に、皮下に、または静脈内に、または筋肉内に、または胸骨内に、あるいは輸液法によって、滅菌注射剤水性または油性懸濁物の形態。この懸濁物は、公知の技術に従って上記に述べた適当な分散剤または湿潤剤及び懸濁剤を使用して処方し得る。この滅菌注射製剤は、毒性のない非経口的に許容可能な希釈剤または溶媒中の、例えば、1,3−ブタンジオールの溶液としての滅菌注射剤溶液または懸濁物であり得る。
C)ネブライザー用のエアロゾルまたは溶液の形態で吸入によって投与し得る;
D)直腸内に、前記薬剤を、常温で固体であるが直腸温度で液体であり、従って直腸で溶融して薬剤を放出する適当な無刺激賦形剤と混合することによって調製される坐薬の形態で直腸に投与し得る。このような物質は、カカオバター及びポリエチレングリコールである;
E)局所に、クリーム、軟膏、ゼリー、洗顔薬、溶液または懸濁液の形態で投与し得る。
F)膣に、有効成分の他に、当該技術において適切であることが知られているような担体を含有するペッサリー、タンポン、クリーム、ゲル、ペースト、フォームまたはスプレー製剤の形態で投与し得る。
1H NMR(400MHz,d6−DMSO)6.90(1H,d,J=5.2Hz),8.10(1H,d,J=5.2Hz),11.60−11.10(2H,br s)。
1H NMR(400MHz、CDCl3)7.56(1H,d,J=5.5Hz),8.13(1H,d,J=5.5Hz)。
1H NMR(400MHz,d6−DMSO)3.74(4H,t,J=4.9Hz),3.90(4H,t,J=4.9Hz),7.40(1H,d,J=5.6Hz),8.30(1H,d,J=5.6Hz)。
1H NMR(400MHz,d6−DMSO)3.76(4H,t,J=4.9),3.95(4H,t,J=4.9),8.28(1H,s),10.20(1H,s)。
A:1H NMR(400MHz、CDCl3)2.80(3H,s),7.41(1H,t,J=7.8Hz),7.50(1H,d,J=7.8Hz),8.15(1H,s),8.40(1H,d,J=7.8Hz)
B:1H NMR(400MHz、CDCl3)7.25(1H,t,J=7.3Hz),7.33(1H,d,J=7.3Hz),7.46(1H,d,J=7.3Hz),8.11(1H,s),10.20(1H,br s)、
1H NMR(400MHz,d6−DMSO)1.41(12H,s),7.40(1H,dd,J=8.4Hz,6.9Hz),7.59(1H,d,J=8.4Hz),7.67(1H,d,J=6.9Hz),10.00(1H,brs),8.45(1H,s),及び
インダゾール:7.40(1H,t),7.18(1H,t,J=7.9Hz),7.50(1H,d,J=9.1Hz),7.77(1H,d,J=7.9Hz),8.09(1H,s)。1.25に不純物。
2−クロロ−6−(4−メタンスルホニル−ピペラジン−1−イルメチル)−4−モルホリン−4−イル−チエノ[3,2−d]ピリミジン(2.00g)、4−(4,4,5,5−テトラメチル−[1,3,2]ジオキソボロラン−2−イル)−1H−インダゾール(2.26g)、トルエン(24mL)、エタノール(12mL)、水(6mL)、炭酸ナトリウム(1.72g)及びPdCl2(PPh3)2(325mg)の混合物を、マイクロ波中で、130℃で90分間加熱した。
MSデータ:(ESI+):MH+514
NMRデータ:(CDC13):2.67−2.71(4H,m),2.81(3H,s),3.29−3.33(4H,m),3.89(2H,s),3.89−3.93(4H,m),4.08−4.12(4H,m),7.41(1H,s),7.51(1H,t,J=7.2),7.60(1H,d,J=8.3),8.28(1H,d,J=7.5),9.02(1H,s),10.10(1H,br)
ジクロロメタン(50ml)及びメタノール(20ml)中の2−(1H−インダゾール−4−イル)−6−(4−メタンスルホニル−ピペラジン−1−イルメチル)−4−モルホリン−4−イル−チエノ[3,2−d]ピリミジン(2.00g、3.89ミリモル)に、メタンスルホン酸(2当量、505ul)を加えた。反応混合物を室温で3時間攪拌した。その間に、白色沈殿物が徐々に砕けた。揮発性物質を真空中で除去し、残留物をジエチルエーテルと共に磨砕し、溶媒をデカントし、固形物を真空乾燥して表題化合物(2.70g)を得た。
NMR(400MHz,DMSO)。以下のシグナルを含む。
2.32(s,6H),3.00(s,3H),3.84−3.86(4H,m).4.09−4.1l(4H,m),8.8)(1H,s)。
上記のようにして調製した本発明の化合物を、以下の一連の生物アッセイに供した。
(i)PI3K生化学的スクリーニング
PI3Kの化合物阻害を、精製した組換え酵素及びATPを1uMの濃度で使用して放射分析アッセイで調べた。化合物を100%DMSOに連続的に希釈した。キナーゼ反応を室温で1時間インキュベートし、反応を、PBSを加えることにより停止させた。IC50値を、用量応答シグモイド曲線フィット(可変勾配)を使用して順次測定した。本化合物は、PI3Kに対して0.1μMよりも小さいIC50を有した。
細胞を、最適密度で96ウエルプレートに接種し、試験化合物の存在下で4日間インキュベートした。Alamar Blue(商標)をアッセイ培地に順次加え、細胞を6時間インキュベートし、その後に励起544nm、発光590nmで読み取った。EC50値は、用量応答シグモイド曲線フィットを使用して算出した。試験化合物は、一連の利用した細胞株において50uMのEC50を有した。
Caco−2細胞を、Millpore Multiscreenプレートに細胞1×105個/cm2で接種し、20日間培養した。その後に、化合物透過性の評価を行った。化合物を細胞単層の先端面(A)に塗布し、基底(B)区画への化合物の透過を測定した。これは、逆方向(B−A)で行い、能動輸送を調べた。各化合物の透過係数値(Papp)、すなわち膜を横切る化合物の透過の割合の尺度を算出した。確立されたヒト吸収を有する対照化合物との比較に基づいて、化合物を低(Papp</=1.0×106cm/s)吸収ポテンシャルまたは高(Papp>/=1.0×106cm/s)吸収ポテンシャルに分類した。
凍結保存ヒト肝細胞の懸濁物を使用した。インキュベーションは、1mMまたは3μMの化合物濃度で、生存細胞0.5×106個/mLの細胞密度で行った。インキュベーションでの最終DMSO濃度は0.25%であった。また、対照インキュベーションは、非酵素分解を明らかにするために細胞の不在下で行った。二重反復試料(50μL)を、インキュベーション混合物から、0分、5分、10分、20分、40分及び60分(対照試料は60分のみ)で取り出し、MeOH含有内部標準(100μL)に加え、反応を停止させた。トルブタミド、7−ヒドロキシクマリン、及びテストステロンを、対照化合物として使用した。試料を遠心分離し、LC−MSMSで分析するためにそれぞれの時点で上清をプールした。時間に対するlnピーク面積比(親化合物のピーク面積/内部標準のピーク面積)のプロットから、固有クリアランス(CLint)を次の通りに算出した。CLint(μl/分/百万個の細胞)=V×k(式中、kは、時間に対したプロットしたln濃度の勾配から得られる消失速度定数であり;Vはインキュベーション容量から誘導される容量ターム(term)であり、uL 106細胞−1として表される)。
本発明の化合物を、5つのCYP450標的(1A2、2C9、2C19、2D6、3A4)に対して10通りの濃度で、二重反復で選別した。100uMの最高濃度が使用される。標準阻害剤(フラフィリン、スルファフェナゾール、トラニルシプロミン、キニジン、ケトコナゾール)を、対照として使用した。プレートは、BMG Lab Technologies PolarStarを使用して蛍光モードで読み取った。化合物は、CYP450の全てのイソ型に対して弱い活性(IC50>/=5uM)を示した。
単一のドナーから新しく単離したヒト肝細胞を48時間培養し、その後に試験化合物を3通りの濃度で加え、72時間インキュベートした。CYP3A4及びCYP1A2のプローブ基質を、インキュベーションが終わる1時間30分前に加えた。72時間で、細胞及び培地を取り出し、各プローブ基質の代謝の程度をLC−MS/MSで定量した。実験は、1つの濃度で三重反復でインキュベートした個々のP450の誘導物質を使用することによって制御した。本発明の化合物は、シトクロムP450酵素の誘導に対してほとんど影響を及ぼさなかった。
試験化合物の溶液(5um、0.5%の最終DMSO濃度)を、緩衝液及び10%血漿(緩衝液中v/v)中で調製した。96ウエルHT透析プレートを、各ウエルを半透性セルロース膜で2つに分けるように組み立てた。緩衝液を、膜の片側に加え、血漿溶液を他方の側に加えた;次いで、インキュベーションを、三重反復で、37℃で2時間にわたって行った。細胞をその後に空にし、化合物のそれぞれのバッチの溶液を2つの群(血漿無含有群及び血漿含有群)に合わせ、次いで血漿無含有溶液(6点)及び血漿含有溶液(7点)について2組の較正標準を使用することによってLC−MSMSで分析した。化合物について非結合画分値を算出した。高タンパク質結合化合物(>/=90%結合)は、Fu</=0.1を有した。本発明の化合物は、Fu値>/=0.1を有した。
本発明の化合物を、確立された流出方法(flux methodology)を使用してhERGカリウムチャネルを安定的に発現するHEK−294細胞からルビジウムの拡散を調節する能力について評価した。細胞を、RbClを含有する培地で調製し、96ウエルプレートに移植し、一夜増殖させて単層を形成した。拡散実験を、培地を吸引し、各ウエルを3×100μLの予備インキュベーション用緩衝液(低[K+]含有)を用いて室温で洗浄することによって開始した。最終吸引の後に、各ウエルに50μLのワーキングストック(working stock)(2倍)化合物を加え、室温で10分間インキュベートした。次いで、各ウエルに、50μLの刺激用緩衝液(高[K+]含有)を加えて、最終試験化合物濃度を得た。次いで、細胞のプレートを室温でさらに10分間インキュベートした。次いで、各ウエルから80μLの上清を、96ウエルプレートの相当するウエルに移し、原子発光分析法により分析した。化合物を、最大濃度100μMから10pt二重反復IC50曲線(n=2)として選別した。
それぞれ重量0.15gの重量を有し且つ25mgの本発明の化合物を含有する錠剤を、次の通りに製造した。
錠剤10,000個の組成
活性化合物(250g)
ラクトース(800g)
トウモロコシデンプン(415g)
タルク粉末(30g)
ステアリン酸マグネシウム(5g)
活性化合物、ラクトース及び半量のトウモロコシデンプンを混合した。次いで、得られた混合物を、0.5mmの網目サイズの篩に強制的に通した。トウモロコシデンプン(10g)を温水(90mL)に懸濁した。得られたペーストを使用して、粉末を造粒した。得られた顆粒を、乾燥し、1.4mmの網目サイズの篩上で小さな断片に粉砕した。残った量のデンプン、タルク及びマグネシウムを加え、注意深く混合し、錠剤に加工した。
製剤A
活性化合物 200mg
0.1M塩酸溶液または
0.1M水酸化ナトリウム溶液適量 pH4.0から7.0まで
滅菌水適量 10mLまで
本発明の化合物を、大部分の水(35℃、40℃)に溶解し、pHを必要ならば塩酸または水酸化ナトリウムを用いて4.0〜7.0の間に調節した。次いで、このバッチを水で容量を調整し、滅菌微細孔フィルタに通して滅菌10mLアンバーガラスバイアル(タイプ1)に濾過し、滅菌栓で密封し、シールで覆った(overseal)。
活性化合物 125mg
滅菌、発熱物質無含有pH7リン酸緩衝液適量 25mLまで
活性化合物 200mg
ベンジルアルコール 0.10g
グリコフロール75 1.45g
注射用の水適量 3.00mLまで
活性化合物をグリコフロールに溶解した。次いで、ベンジルアルコールを加え、溶解し、水を3mLになるまで加えた。次いで、混合物を滅菌微細孔フィルタに通して滅菌3mLアンバーガラスバイアル(タイプ1)に密封した。
活性化合物 250mg
ソルビトール溶液 1.50g
グリセリン 2.00g
安息香酸ナトリウム 0.005g
香料 0.0125mL
純水適量 5.00mLまで
本発明の化合物を、グリセリン及び大部分の純水の混合物に溶解した。次いで、得られた溶液に、安息香酸ナトリウムの水溶液を加え、次いでソルビトール溶液を加え、最後に香料を加えた。容量を、純水で調整し、十分に混合した。
本発明は以下の態様を含む。
[1] 式(I)
[2] 医薬的に許容可能な塩が、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸、メタンスルホン酸、ベンゼンスルホン酸、ギ酸、酢酸、トリフルオロ酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエン酸、エタンスルホン酸、アスパラギン酸及びグルタミン酸との塩類から選択される、上記[1]に記載の化合物。
[3] 医薬的に許容可能な塩がモノ塩またはビス塩である、上記[1]または[2]に記載の化合物。
[4] メタンスルホン酸、ベンゼンスルホン酸、塩酸、リン酸、及び硫酸とのモノ塩またはビス塩である、上記[1]から[3]のいずれか一項に記載の化合物。
[5] 2−(1H−インダゾール−4−イル)−6−(4−メタンスルホニル−ピペラジン−1−イルメチル)−4−モルホリン−4−イル−チエノ[3,2−d]ピリミジンビスメシル酸塩である、上記[1]に記載の化合物。
[6] 上記[1]に記載の化合物の製造プロセスであって、式(III)
[7] さらに、式(II)
のボロン酸またはそのエステルで処理することによって式(III)の化合物を製造することを含む、上記[6]に記載のプロセス。
[8] 式(VI)
のボロン酸またはそのエステルで処理する工程を含む、上記[1]に記載の化合物の製造プロセス。
[9] さらに、式(II)
[10] 上記[1]に記載の医薬的に許容可能な塩の製造プロセスであって、式(I)
[11] 酸が、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸、メタンスルホン酸、ベンゼンスルホン酸、ギ酸、酢酸、トリフルオロ酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエン酸、エタンスルホン酸、アスパラギン酸、及びグルタミン酸から選択される、上記[10]に記載のプロセス。
[12] 酸が、メタンスルホン酸、ベンゼンスルホン酸、塩酸、リン酸、及び硫酸から選択される、上記[10]または[11]に記載のプロセス。
[13] 医薬的に許容可能な担体または希釈剤と、有効成分として、上記[1]から[5]のいずれか一項に記載の化合物とを含む、医薬組成物。
[14] 経口投与用に処方される、上記[13]に記載の組成物。
[15] 治療によってヒトまたは動物の体の治療方法で使用される、上記[1]に記載の化合物。
[16] 異常な細胞の増殖、機能、もしくは挙動から生じる疾患または障害を治療するための薬物の製造における、上記[1]に記載の化合物の使用。
[17] 異常な細胞の増殖、機能、または挙動が、PI3キナーゼに関連する、上記[16]に記載の使用。
[18] 疾患または障害が、癌、免疫疾患、心臓血管疾患、ウイルス感染症、炎症、代謝/内分泌疾患、及び神経疾患から選択される、上記[16]または[17]に記載の使用。
[19] 癌が、結腸、乳房、脳、肝臓、卵巣、胃、肺、及び頭頸部の固形腫瘍から選択される、上記[18]に記載の使用。
[20] 癌が、グリア芽細胞腫、黒色腫、前立腺癌、子宮内膜癌、卵巣癌、乳癌、肺癌、頭頸部癌、肝細胞癌、及び甲状腺癌から選択される、上記[18]に記載の使用。
[21] 癌が、乳癌、卵巣癌、子宮頸癌、前立腺癌、精巣癌、泌尿生殖器癌、食道癌、喉頭癌、グリア芽細胞腫、神経芽細胞腫、胃癌、皮膚癌、角化棘細胞腫、肺癌、類表皮癌、大細胞癌、非小細胞肺癌(NSCLC)、小細胞癌、肺腺癌、骨肉腫、結腸癌、腺腫、膵臓癌、腺癌、甲状腺癌、濾胞状癌、未分化癌、乳頭状癌、精上皮腫、黒色腫、肉腫、膀胱癌、肝臓癌及び胆道癌、腎臓癌、骨髄性疾患、リンパ系疾患、毛様細胞白血病、口腔及び咽頭癌、口唇癌、舌癌、口唇癌、咽頭癌、小腸癌、結腸直腸癌、大腸癌、直腸癌、脳腫瘍及び中枢神経系の癌、ホジキンリンパ腫並びに白血病から選択される、上記[18]に記載の使用。
[22] 異常な細胞の増殖、機能または挙動から生じる疾患または障害を治療する方法であって、それを必要とする患者に上記[1]に記載の化合物を投与する工程を含む、方法。
[23] 異常な細胞の増殖、機能、または挙動が、PI3キナーゼに関連する、上記[22]に記載の方法。
[24] 疾患または障害が、癌、免疫疾患、心臓血管疾患、ウイルス感染症、炎症、代謝/内分泌疾患、及び神経疾患からなる群より選択される、上記[22]または[23]に記載の方法。
[25] 疾患または障害が、癌、免疫疾患、心臓血管疾患、ウイルス感染症、炎症、代謝/内分泌疾患、及び神経疾患から選択される、上記[24]に記載の方法。
[26] 癌が、グリア芽細胞腫、黒色腫、前立腺癌、子宮内膜癌、卵巣癌、乳癌、肺癌、頭頸部癌、肝細胞癌、及び甲状腺癌から選択される、上記[24]に記載の方法。
[27] 癌が、乳癌、卵巣癌、子宮頸癌、前立腺癌、精巣癌、泌尿生殖器癌、食道癌、喉頭癌、グリア芽細胞腫、神経芽細胞腫、胃癌、皮膚癌、角化棘細胞腫、肺癌、類表皮癌、大細胞癌、非小細胞肺癌(NSCLC)、小細胞癌、肺腺癌、骨肉腫、結腸癌、腺腫、膵臓癌、腺癌、甲状腺癌、濾胞状癌、未分化癌、乳頭状癌、精上皮腫、黒色腫、肉腫、膀胱癌、肝臓癌及び胆道癌、腎臓癌、骨髄性疾患、リンパ系疾患、毛様細胞白血病、口腔及び咽頭癌、口唇癌、舌癌、口唇癌、咽頭癌、小腸癌、結腸直腸癌、大腸癌、直腸癌、脳腫瘍及び中枢神経系の癌、ホジキンリンパ腫並びに白血病から選択される、上記[24]に記載の方法。
[28] 上記[1]に記載の化合物と医薬的に許容可能な担体とを組み合わせる工程を含む医薬組成物の製造プロセス。
[29] (a)上記[1]に記載の化合物を含む第1の医薬組成物;及び
(b)使用するための説明書
を含む、P13K介在疾患を治療するためのキット。
[30] さらに、(c)抗過剰増殖活性を有する第2の化合物を含む第2の医薬組成物を含む、上記[29]に記載のキット。
[31] さらに、前記の第1の医薬組成物と第2の医薬組成物を、投与を必要とする患者に、同時、順次、または別々に投与するための説明書を含む、上記[30]に記載のキット。
[32] 前記の第1の医薬組成物と第2の医薬組成物が別々の容器に収容される、上記[30]に記載のキット。
[33] 前記の第1の医薬組成物と第2の医薬組成物が同じ容器に収容される、上記[30]に記載のキット。
[34] (a)上記[1]に記載の化合物;及び
(b)抗過剰増殖活性を有する第2の化合物
を含み、癌の予防または治療処置において、別々、同時、または順次投与するための製品。
Claims (34)
- 医薬的に許容可能な塩が、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸、メタンスルホン酸、ベンゼンスルホン酸、ギ酸、酢酸、トリフルオロ酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエン酸、エタンスルホン酸、アスパラギン酸及びグルタミン酸との塩類から選択される、請求項1に記載の化合物。
- 医薬的に許容可能な塩がモノ塩またはビス塩である、請求項1または2に記載の化合物。
- メタンスルホン酸、ベンゼンスルホン酸、塩酸、リン酸、及び硫酸とのモノ塩またはビス塩である、請求項1から3のいずれか一項に記載の化合物。
- 2−(1H−インダゾール−4−イル)−6−(4−メタンスルホニル−ピペラジン−1−イルメチル)−4−モルホリン−4−イル−チエノ[3,2−d]ピリミジンビスメシル酸塩である、請求項1に記載の化合物。
- 酸が、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸、メタンスルホン酸、ベンゼンスルホン酸、ギ酸、酢酸、トリフルオロ酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエン酸、エタンスルホン酸、アスパラギン酸、及びグルタミン酸から選択される、請求項10に記載のプロセス。
- 酸が、メタンスルホン酸、ベンゼンスルホン酸、塩酸、リン酸、及び硫酸から選択される、請求項10または11に記載のプロセス。
- 医薬的に許容可能な担体または希釈剤と、有効成分として、請求項1から5のいずれか一項に記載の化合物とを含む、医薬組成物。
- 経口投与用に処方される、請求項13に記載の組成物。
- 治療によってヒトまたは動物の体の治療方法で使用される、請求項1に記載の化合物。
- 異常な細胞の増殖、機能、もしくは挙動から生じる疾患または障害を治療するための薬物の製造における、請求項1に記載の化合物の使用。
- 異常な細胞の増殖、機能、または挙動が、PI3キナーゼに関連する、請求項16に記載の使用。
- 疾患または障害が、癌、免疫疾患、心臓血管疾患、ウイルス感染症、炎症、代謝/内分泌疾患、及び神経疾患から選択される、請求項16または17に記載の使用。
- 癌が、結腸、乳房、脳、肝臓、卵巣、胃、肺、及び頭頸部の固形腫瘍から選択される、請求項18に記載の使用。
- 癌が、グリア芽細胞腫、黒色腫、前立腺癌、子宮内膜癌、卵巣癌、乳癌、肺癌、頭頸部癌、肝細胞癌、及び甲状腺癌から選択される、請求項18に記載の使用。
- 癌が、乳癌、卵巣癌、子宮頸癌、前立腺癌、精巣癌、泌尿生殖器癌、食道癌、喉頭癌、グリア芽細胞腫、神経芽細胞腫、胃癌、皮膚癌、角化棘細胞腫、肺癌、類表皮癌、大細胞癌、非小細胞肺癌(NSCLC)、小細胞癌、肺腺癌、骨肉腫、結腸癌、腺腫、膵臓癌、腺癌、甲状腺癌、濾胞状癌、未分化癌、乳頭状癌、精上皮腫、黒色腫、肉腫、膀胱癌、肝臓癌及び胆道癌、腎臓癌、骨髄性疾患、リンパ系疾患、毛様細胞白血病、口腔及び咽頭癌、口唇癌、舌癌、口唇癌、咽頭癌、小腸癌、結腸直腸癌、大腸癌、直腸癌、脳腫瘍及び中枢神経系の癌、ホジキンリンパ腫並びに白血病から選択される、請求項18に記載の使用。
- 異常な細胞の増殖、機能または挙動から生じる疾患または障害を治療するための、請求項13または14に記載の医薬組成物。
- 異常な細胞の増殖、機能、または挙動が、PI3キナーゼに関連する、請求項22に記載の医薬組成物。
- 疾患または障害が、癌、免疫疾患、心臓血管疾患、ウイルス感染症、炎症、代謝/内分泌疾患、及び神経疾患からなる群より選択される、請求項22または23に記載の医薬組成物。
- 疾患または障害が、癌、免疫疾患、心臓血管疾患、ウイルス感染症、炎症、代謝/内分泌疾患、及び神経疾患から選択される、請求項24に記載の医薬組成物。
- 癌が、グリア芽細胞腫、黒色腫、前立腺癌、子宮内膜癌、卵巣癌、乳癌、肺癌、頭頸部癌、肝細胞癌、及び甲状腺癌から選択される、請求項24に記載の医薬組成物。
- 癌が、乳癌、卵巣癌、子宮頸癌、前立腺癌、精巣癌、泌尿生殖器癌、食道癌、喉頭癌、グリア芽細胞腫、神経芽細胞腫、胃癌、皮膚癌、角化棘細胞腫、肺癌、類表皮癌、大細胞癌、非小細胞肺癌(NSCLC)、小細胞癌、肺腺癌、骨肉腫、結腸癌、腺腫、膵臓癌、腺癌、甲状腺癌、濾胞状癌、未分化癌、乳頭状癌、精上皮腫、黒色腫、肉腫、膀胱癌、肝臓癌及び胆道癌、腎臓癌、骨髄性疾患、リンパ系疾患、毛様細胞白血病、口腔及び咽頭癌、口唇癌、舌癌、口唇癌、咽頭癌、小腸癌、結腸直腸癌、大腸癌、直腸癌、脳腫瘍及び中枢神経系の癌、ホジキンリンパ腫並びに白血病から選択される、請求項24に記載の医薬組成物。
- 請求項1に記載の化合物と医薬的に許容可能な担体とを組み合わせる工程を含む医薬組成物の製造プロセス。
- (a)請求項1に記載の化合物を含む第1の医薬組成物;及び
(b)使用するための説明書
を含む、P13K介在疾患を治療するためのキット。 - さらに、(c)抗過剰増殖活性を有する第2の化合物を含む第2の医薬組成物を含む、請求項29に記載のキット。
- さらに、前記の第1の医薬組成物と第2の医薬組成物を、投与を必要とする患者に、同時、順次、または別々に投与するための説明書を含む、請求項30に記載のキット。
- 前記の第1の医薬組成物と第2の医薬組成物が別々の容器に収容される、請求項30に記載のキット。
- 前記の第1の医薬組成物と第2の医薬組成物が同じ容器に収容される、請求項30に記載のキット。
- (a)請求項1に記載の化合物;及び
(b)抗過剰増殖活性を有する第2の化合物
を含み、癌の予防または治療処置において、別々、同時、または順次投与するための製品。
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