JP2022105170A - 7-ベンジル-4-(2-メチルベンジル)-2,4,6,7,8,9-ヘキサヒドロイミダゾ[1,2-a]ピリド[3,4-e]ピリミジン-5(1h)-オン、その塩及びその使用方法 - Google Patents
7-ベンジル-4-(2-メチルベンジル)-2,4,6,7,8,9-ヘキサヒドロイミダゾ[1,2-a]ピリド[3,4-e]ピリミジン-5(1h)-オン、その塩及びその使用方法 Download PDFInfo
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Abstract
Description
本願は、2014年7月25日出願の一部継続米国特許出願第14/341,392号及び2014年7月25日出願の国際特許出願PCT/US2014/048241、これらの各々は2014年3月13日出願の一部継続米国特許出願第14/208,657号であり、順に、2013年3月13日出願の米国仮特許出願第61/779,828号及び2013年11月15日出願の米仮特許出願第61/904,718号の利益を主張するものであり、これらの全部はその全体が参照により本明細書に組み込まれる。本願はまた、2014年3月13日出願の一部継続米国特許出願第14/208,657号であり、2013年11月15日出願の米国仮特許出願第61/904,718号の利益を主張するものである。
(i)化合物(1):
(ii)対象への第1の治療物質の投与後、所定の待機時間が経過するまで待つことと、
(iii)対象に第2の治療物質を投与することと、を含み、
第1の治療物質と第2の治療物質の可能性のある組み合わされた毒性効果のリスクが増加することなく又はそのリスクが減少して、第1の治療物質の遅延治療効果を達成するために、所定の待機時間が選択される方法を提供する。
(i)化合物(1):
(ii)薬物動態学的プロファイルを用いて、対象における化合物(1)又はその薬学的に許容される塩あるいはその代謝物のレベルを監視することと、
(iii)対象における第1の治療物質のレベル次第で第2の治療物質を投与することと、
を含む方法を提供する。
(i)化合物(1):
(iii)治療を受けている対象において約3時間~約8時間の例示的な化合物(1)の予想される半減期次第で第2の治療物質を投与することと、を含む治療方法を提供する。いくつかの実施形態では、例示的な化合物(1)の予想される半減期は、治療を受けている対象において約3時間~約24時間である。
(i)化合物(1):
(iii)解消したか又は解消しつつある第1の治療物質による有害事象次第で第2の治療物質を投与することと、を含む治療方法を提供する。いくつかの実施形態では、第1の治療物質の有害事象は、治療を受けている対象における第1の治療物質又はその代謝物の血中レベルに関連している。
一態様では、本発明は、化合物(1):
ソキサントロン、LU 223651、ルートテカン、LY-S6AKT1、LY-2780301、マホスファミド、マリマスタット、メクロロエタミン、MEK阻害剤、MEK-162、メチルテストステロン、メチルプレドニゾロン、MEDI-573、MEN-10755、MDX-H210、MDX-447、MDX-1379、MGV、ミドスタウリン、ミノドロン酸、マイトマイシン、ミボブリン、MK-2206、MK-0646(ダロツズマブ)、MLN518、モテキサフィンガドリニウム、MS-209、MS-275、MX6、ネリドロネート、ネラチニブ、ネクサバール、ネオバスタット、ニロチニブ、ニメスリド、ニトログリセリン、ノラトレキセド、ノレリン、N-アセチルシステイン、06-ベンジルグアニン、オブリメルセン、オメプラゾール、オンコファージ、オンコVEXGM-CSF、オルミプラチン(ormiplatin)、オルタタキセル、OX44抗体、OSI-027、OSI-906(リンシチニブ)、4-IBB抗体、オキサトラゾール、エストロゲン、パニツムマブ、パツピロン(patupilone)、ペグフィルグラスチム、PCK-3145、ペグフィルグラスチム、PBI-1402、PBI-05204、PDO325901、PD-1抗体、PEG-パクリタキセル、アルブミン安定化パクリタキセル、PEP-005、PF-05197281、PF-05212384、PF-04691502、PHT-427、P-04、PKC412、P54、PI-88、ペリチニブ、ペメトレキセド、ペントリクス(PEnTrix)、ペリホシン、ペリリルアルコール、ペルツズマブ、PI3K阻害剤、PI3K/mTORの阻害剤、PG-TXL、PG2、PLX-4032/RO-5185426(ベムラフェニブ)、PLX-3603/RO-5212054、PT-100、PWT-33597、PX-866、ピコプラチン、ピバロイルオキシメチルブチレート(ピバロイルオキシメチルブチレート(pivaloyloxymethylbutyrate))、ピクサントロン、フェノキソジオールO、PKI166、プレビトレキセド、プリカマイシン、ポリプレン酸、ポルフィロマイシン、プレドニゾン、プレドニゾロン、キナメド、キヌプリスチン、R115777、RAF-265、ラモセトロン、ランピルナーゼ、RDEA-119/BAY 869766、RDEA436、レベッカマイシン類似体、受容体チロシンキナーゼ(RTK)阻害剤、レビミッド、RG-7167、RG-7304、RG-7421、RG-7321、RG 7440、リゾキシン、rhu-MAb、リンファベート、リセドロネート、リツキシマブ、ロバツムマブ、ロフェコキシブ、RO-31-7453、RO-5126766、RO-5068760、RPR 109881A、ルビダゾン、ルビテカン、R-フルルビプロフェン、RX-0201、S-9788、サバルビシン、SAHA、サルグラモスチム、サトラプラチン、SB 408075、Se-015/Ve-015、SU5416、SU6668、SDX-101、セムスチン、セオカルシトール、SM-11355、SN-38、SN-4071、SR-27897、SR-31747、SR-13668、SRL-172、ソラフェニブ、スピロプラチン、スクアラミン、スベラニロヒドロキサミン酸(suberanilohydroxamic acid)、ステント、T 900607、T 138067、TAK-733、TAS-103、タセジナリン、タラポルフィン、タルセバ、タリキダル(tariquitar)、タシスラム(tasisulam)、タキソテール、タクサオプレキシン、タザロテン、テガフール、テモゾラミド、テスミリフェン、テストステロン、プロピオン酸テストステロン、テスミリフェン、テトラプラチン、テトロドトキシン、テザシタビン、サリドマイド、テラルクス(theralux)、テラルビシン、チマルファシン、チメクタシン、チアゾフリン、チピファルニブ、チラパザミン、トクラデシン、トムデックス、トレモフィン、トラベクテジン、トランスMID-107、トランスレチン酸、トラスツズマブ、トレメリムマブ、トレチノイン、トリアセチルウリジン、トリアピン、トリシリビン、トリメトレキサート、TLK-286TXD 258、タイケルブ/タイバーブ、ウロシジン、バルルビシン、バタラニブ、ビンクリスチン、ビンフルニン、ビルリジン、WX-UK1、WX-554、ベクティビックス、ゼローダ、XELOX、XL-147、XL-228、XL-281、XL-518/R-7420/GDC-0973、XL-765、YM-511、YM-598、ZD-4190、ZD-6474、ZD-4054、ZD-0473、ZD-6126、ZD-9331、ZD1839、ZSTK-474、ゾレドロネート、ゾスキダル、及びそれらの組み合わせからなる群から選択される1つ以上の治療物質を含む。
一実施形態では、本発明による医薬組成物は、約100mg~約2000mgの範囲の用量で化合物(1)又はその薬学的に許容される塩を含み、その重量は、特定の実施形態では、その遊離塩基形態の化合物(1)に基づいてよい。一実施形態では、本発明による医薬組成物は、約40mg~約2000mgの範囲の用量で化合物(1)又はその薬学的に許容される塩を含み、その重量は、特定の実施形態では、その遊離塩基形態の化合物(1)に基づいてよい。一実施形態では、本発明による医薬組成物は、約50mg~約2000mgの範囲の用量で化合物(1)又はその薬学的に許容される塩を含み、その重量は、特定の実施形態では、その遊離塩基形態の化合物(1)に基づいてよい。一実施形態では、本発明による医薬組成物は、約60mg~約2000mgの範囲の用量で化合物(1)又はその薬学的に許容される塩を含み、その重量は、特定の実施形態では、その遊離塩基形態の化合物(1)に基づいてよい。一実施形態では、本発明による医薬組成物は、約50mg~約200mg、約50mg~約300mg、約50mg~約400mg、約50mg~約500mg、約50mg~約600mg、約50mg~約700mg、約50mg~約800mg、約50mg~約900mg、約50mg~約1000mg、約50mg~約1100mg、約50mg~約1200mg、約50mg~約1300mg、約50mg~約1400mg、約50mg~約1500mg、約50mg~約1600mg、約50mg~約1700mg、約50mgから1800mg、及び約50mg~1900mg、40mg~2000mgからなる群から選択される用量レベルで化合物(1)又はその薬学的に許容される塩を含む。一実施形態では、本発明による医薬組成物は、約40mg~約200mg、約40mg~約300mg、約40mg~約400mg、約40mg~約500mg、約40mg~約600mg、約40mg~約700mg、約40mg~約800mg、約40mg~約900mg、約40mg~約1000mg、約40mg~約1100mg、約40mg~約1200mg、約40mg~約1300mg、約40mg~約1400mg、約40mg~約1500mg、約40mg~約1600mg、約40mg~約1700mg、約40mg~約1800mg、約40mg~約1900mg、40mg~2000mgからなる群から選択される用量レベルで化合物(1)又はその薬学的に許容される塩を含む。一実施形態では、本発明による医薬組成物は、約60mg~約200mg、約60mg~約300mg、約60mg~約400mg、約60mg~約500mg、約60mg~約600mg、約60mg~約700mg、約60mg~約800mg、約60mg~約900mg、約60mg~約1000mg、約60mg~約1100mg、約60mg~約1200mg、約60mg~約1300mg、約60mg~約1400mg、約60mg~約1500mg、約60mg~約1600mg、約60mg~約1700mg、約60mg~約1800mg、及び約60mg~約1900mg、60mg~2000mgからなる群から選択される用量レベルで化合物(1)又はその薬学的に許容される塩を含む。一実施形態では、本発明による医薬組成物は、約100mg~約200mg、約100mg~約300mg、約100mg~約400mg、約100mg~約500mg、約100mg~約600mg、約100mg~約700mg、約100mg~約800mg、約100mg~約900mg、約100mg~約1000mg、約100mg~約1100mg、約100mg~約1200mg、約100mg~約1300mg、約100mg~約1400mg、約100mg~約1500mg、約100mg~約1600mg、約100mg~約1700mg、約100mg~約1800mg、及び約100mg~約1900mg、50mg~2000mg並びに40mg~200mgからなる群から選択される用量レベルで化合物(1)又はその薬学的に許容される塩を含む。一実施形態では、本発明による医薬組成物は、その遊離塩基形態の化合物(1)に基づいて約200mg~約300mg、約200mg~約400mg、約200mg~約500mg、約200mg~約600mg、約200mg~約700mg、約200mg~約800mg、約200mg~約900mg、約200mg~約1000mg、約200mg~約1100mg、約200mg~約1200mg、約200mg~約1300mg、約200mg~約1400mg、約200mg~約1500mg、約200mg~約1600mg、約200mg~約1700mg、約200mg~約1800mg、及び約200mg~約1900mgからなる群から選択される用量レベルで化合物(1)又はその薬学的に許容される塩を含む。一実施形態では、本発明による医薬組成物は、その遊離塩基形態の化合物(1)に基づいて約400mg~約500mg、約400mg~約600mg、約400mg~約700mg、約400mg~約800mg、約400mg~約900mg、約400mg~約1000mg、約400mg~約1100mg、約400mg~約1200mg、約400mg~約1300mg、約400mg~約1400mg、約400mg~約1500mg、約400mg~約1600mg、約400mg~約1700mg、約400mg~約1800mg、及び約400mg~約1900mgからなる群から選択される用量レベルで化合物(1)又はその薬学的に許容される塩を含む。一実施形態では、本発明による医薬組成物は、約50mg~約60mg、約50mg~約70mg、約50mg~約80mg、約50mg~約90mg、約50~約100mg、約60mg~約70mg、約60mg~約80mg、約60mg~約90mg、約60mg~約100mg、約70mg~約80mg、約70mg~約90mg、約70~約100mg、約80mg~約90mg、約80mg~約100mg、及び約90mg~約100mgからなる群から選択される用量レベルで化合物(1)又はその薬学的に許容される塩を含む。
約825mg/m2~約1500mg/m2、約830mg/m2~約1500mg/m2、約835mg/m2~約1500mg/m2、約840mg/m2~約1500mg/m2、約845mg/m2~約1500mg/m2、約850mg/m2~約1500mg/m2、約855mg/m2~約1500mg/m2、約860mg/m2~約1500mg/m2、約865mg/m2~約1500mg/m2、約870mg/m2~約1500mg/m2、約875mg/m2~約1500mg/m2、約880mg/m2~約1500mg/m2、約885mg/m2~約1500mg/m2、約890mg/m2~約1500mg/m2、約895mg/m2~約1500mg/m2、約900mg/m2~約1500mg/m2、約905mg/m2~約1500mg/m2、約910mg/m2~約1500mg/m2、約915mg/m2~約1500mg/m2、約920mg/m2~約1500mg/m2、約925mg/m2~約1500mg/m2、約930mg/m2~約1500mg/m2、約935mg/m2~約1500mg/m2、約940mg/m2~約1500mg/m2、約945mg/m2~約1500mg/m2、約950mg/m2~約1500mg/m2、約955mg/m2~約1500mg/m2、約960mg/m2~約1500mg/m2、約965mg/m2~約1500mg/m2、約970mg/m2~約1500mg/m2、約975mg/m2~約1500mg/m2、約980mg/m2~約1500mg/m2、約985mg/m2~約1500mg/m2、約990mg/m2~約1500mg/m2、約995mg/m2~約1500mg/m2、約1000mg/m2~約1500mg/m2、約1005mg/m2~約1500mg/m2、約1010mg/m2~約1500mg/m2、約1015mg/m2~約1500mg/m2、約1020mg/m2~約1500mg/m2、約1025mg/m2~約1500mg/m2、約1030mg/m2~約1500mg/m2、約1035mg/m2~約1500mg/m2、約1040mg/m2~約1500mg/m2、約1045mg/m2~約1500mg/m2、約1050mg/m2~約1500mg/m2、約1055mg/m2~約1500mg/m2、約1060mg/m2~約1500mg/m2、約1065mg/m2~約1500mg/m2、約1070mg/m2~約1500mg/m2、約1075mg/m2~約1500mg/m2、約1080mg/m2~約1500mg/m2、約1085mg/m2~約1500mg/m2、約1090mg/m2~約1500mg/m2、約1095mg/m2~約1500mg/m2、約1100mg/m2~約1500mg/m2、約1105mg/m2~約1500mg/m2、約1110mg/m2~約1500mg/m2、約1115mg/m2~約1500mg/m2、約1120mg/m2~約1500mg/m2、約1125mg/m2~約1500mg/m2、約1130mg/m2~約1500mg/m2、約1135mg/m2~約1500mg/m2、約1140mg/m2~約1500mg/m2、約1145mg/m2~約1500mg/m2、約1150mg/m2~約1500mg/m2、約1155mg/m2~約1500mg/m2、約1160mg/m2~約1500mg/m2、約1165mg/m2~約1500mg/m2、約1170mg/m2~約1500mg/m2、約1175mg/m2~約1500mg/m2、約1180mg/m2~約1500mg/m2、約1185mg/m2~約1500mg/m2、約1190mg/m2~約1500mg/m2、約1195mg/m2~約1500mg/m2、約1200mg/m2~約1500mg/m2、約1205mg/m2~約1500mg/m2、約1210mg/m2~約1500mg/m2、約1215mg/m2~約1500mg/m2、約1220mg/m2~約1500mg/m2、約1225mg/m2~約1500mg/m2、約1230mg/m2~約1500mg/m2、約1235mg/m2~約1500mg/m2、約1240mg/m2~約1500mg/m2、約1245mg/m2~約1500mg/m2、約1250mg/m2~約1500mg/m2、約1255mg/m2~約1500mg/m2、約1260mg/m2~約1500mg/m2、約1265mg/m2~約1500mg/m2、約1270mg/m2~約1500mg/m2、約1275mg/m2~約1500mg/m2、約1280mg/m2~約1500mg/m2、約1285mg/m2~約1500mg/m2、約1290mg/m2~約1500mg/m2、約1295mg/m2~約1500mg/m2、約1300mg/m2~約1500mg/m2、約1305mg/m2~約1500mg/m2、約1310mg/m2~約1500mg/m2、約1315mg/m2~約1500mg/m2、約1320mg/m2~約1500mg/m2、約1325mg/m2~約1500mg/m2、約1330mg/m2~約1500mg/m2、約1335mg/m2~約1500mg/m2、約1340mg/m2~約1500mg/m2、約1345mg/m2~約1500mg/m2、約1350mg/m2~約1500mg/m2、約1355mg/m2~約1500mg/m2、約1360mg/m2~約1500mg/m2、約1365mg/m2~約1500mg/m2、約1370mg/m2~約1500mg/m2、約1375mg/m2~約1500mg/m2、約1380mg/m2~約1500mg/m2、約1385mg/m2~約1500mg/m2、約1390mg/m2~約1500mg/m2、約1395mg/m2~約1500mg/m2、約1400mg/m2~約1500mg/m2、約1405mg/m2~約1500mg/m2、約1410mg/m2~約1500mg/m2、約1415mg/m2~約1500mg/m2、約1420mg/m2~約1500mg/m2、約1425mg/m2~約1500mg/m2、約1430mg/m2~約1500mg/m2、約1435mg/m2~約1500mg/m2、約1440mg/m2~約1500mg/m2、約1445mg/m2~約1500mg/m2、約1450mg/m2~約1500mg/m2、約1455mg/m2~約1500mg/m2、約1460mg/m2~約1500mg/m2、約1465mg/m2~約1500mg/m2、約1470mg/m2~約1500mg/m2、約1475mg/m2~約1500mg/m2、約1480mg/m2~約1500mg/m2、約1485mg/m2~約1500mg/m2、約1490mg/m2~約1500mg/m2、及び約1495mg/m2~約1500mg/m2からなる群から選択される用量レベルで化合物(1)又はその薬学的に許容される塩を含む。
本発明の方法を用いて使用するのに適する医薬組成物は、患者に投与できる任意の剤形に製剤化できる。一実施形態では、医薬組成物は、経口投与単位又は非経口投与単位の形態である。一実施形態では、医薬組成物は、経口投与単位の形態である。いくつかの実施形態では、経口投与単位は、投与される治療物質の毒性を低減するために、所定の期間にわたって対象に投与されるいくつかのより小さな用量に分割される。いくつかの実施形態では、経口投薬単位は、複数の粒子、顆粒、ペレット、ミニ錠又は錠剤を含み得る制御放出製剤を含む錠剤又はカプセルによって投与される。一実施形態では、医薬組成物は、非経口投与単位の形態である。一実施形態では、医薬組成物は非経口投与単位の形態であり、非経口投与単位は、静脈内(IV)、皮下(SC)、及び筋肉内(M)、直腸(PR)並びに経皮投与単位からなる群から選択される。一実施形態では、医薬組成物は、滅菌液剤、懸濁剤、坐剤、錠剤及びカプセル剤からなる群から選択される剤形である。一実施形態では、組成物は、錠剤、カプレット剤、カプセル剤、トローチ剤、シロップ剤、液剤、懸濁剤及びエリキシル剤からなる群から選択される経口剤形である。一実施形態では、組成物は、錠剤、ハードシェルカプセル剤、軟ゼラチンカプセル剤、ビーズ、顆粒、凝集物、粉末、ゲル、固体及び半固体からなる群から選択される経口剤形である。
本発明の組成物及び方法は、癌(例えば、大腸癌、脳癌、及び神経膠芽腫)を含む多くの疾患(病状)の治療に有用性を有する。一実施形態では、本発明の組成物及び方法は、眼の黒色腫、線維形成円形細胞腫瘍、軟骨肉腫、軟膜疾患、びまん性大細胞型B細胞リンパ腫、急性リンパ性白血病、急性骨髄性白血病、副腎皮質癌、エイズ関連癌、エイズ関連リンパ腫、肛門癌又は直腸癌、虫垂癌、星細胞腫、及び非定型奇形腫様/ラブドイド腫瘍などの疾患を治療するために使用される。一実施形態では、本発明の組成物及び方法は、基底細胞癌、基底細胞母斑症候群、ゴーリン-母斑症候群、胆管癌、膀胱癌、骨癌、骨肉腫及び悪性線維性組織球腫、脳腫瘍、乳癌、気管支腫瘍、バーキットリンパ腫、及び脊髄腫瘍などの疾患を治療するために使用される。一実施形態では、本発明の組成物及び方法は、カルチノイド腫瘍、未知の原発性の中枢神経系非定型奇形腫様/ラブドイド腫瘍、軟膜疾患、中枢神経系胚芽腫、中枢神経系リンパ腫、子宮頸癌、脊索腫、慢性リンパ性白血病、慢性骨髄性白血病、慢性骨髄増殖性障害、結腸癌、結腸直腸癌、頭蓋咽頭腫、及び皮膚T細胞リンパ腫(セザリー症候群及び菌状息肉腫(MF)を含むが、これらに限定されない)などの疾患を治療するために使用される。一実施形態では、本発明の組成物及び方法は、中枢神経系胚芽腫、子宮内膜癌、上衣芽細胞腫、上衣腫、食道癌、ユーイング肉腫腫瘍ファミリー、頭蓋外胚細胞腫瘍、性腺外胚細胞腫瘍、肝外胆管癌、及び眼の癌などの疾患を治療するために使用される。一実施形態では、本発明の組成物及び方法は、胆嚢癌、胃癌、消化管カルチノイド腫瘍、消化管間質腫瘍(GIST)、胚細胞腫瘍、妊娠性絨毛腫瘍、及び神経膠腫などの疾患を治療するために使用される。一実施形態では、本発明の組成物及び方法は、ヘアリー細胞白血病、頭頸部癌、肝細胞(肝臓)癌、組織球症、ホジキンリンパ腫、及び下咽頭癌からなる群から選択される癌を治療するために使用される。一実施形態では、本発明の組成物及び方法は、カポジ肉腫、及び腎臓(腎細胞)癌などの疾患を治療するために使用される。一実施形態では、本発明の組成物及び方法は、ランゲルハンス細胞組織球症、喉頭癌、口唇及び口腔癌、肝癌、肺癌、非ホジキンリンパ腫、及び原発性中枢神経系リンパ腫などの疾患を治療するために使用される。一実施形態では、本発明の組成物及び方法は、ワルデンシュトレームマクログロブリン血症(リンパ形質細胞性リンパ腫)、骨の悪性線維性組織球腫及び骨肉腫、髄芽腫、髄様上皮腫、メラノーマ、メルケル細胞癌、中皮腫、原発不明転移性扁平上皮頸部癌、多発性内分泌腫瘍症候群、口癌、多発性骨髄腫/形質細胞新生物、菌状息肉腫、骨髄異形成症候群、骨髄異形成/骨髄増殖性腫瘍、多発性骨髄腫、及び骨髄増殖性疾患などの疾患を治療するために使用される。一実施形態では、本発明の組成物及び方法は、癌を治療するために使用される。一実施形態では、本発明の組成物及び方法は、鼻腔癌及び副鼻腔癌、上咽頭癌、及び神経芽細胞腫などの疾患を治療するために使用される。一実施形態では、本発明の組成物及び方法は、口腔癌(oral cancer)、口唇及び口腔癌(oral Cabity cancer)、口腔咽頭癌、骨肉腫及び骨の悪性線維性組織球腫、卵巣癌、卵巣胚細胞腫瘍、卵巣上皮癌、及び卵巣低悪性度腫瘍などの疾患を治療するために使用される。一実施形態では、本発明の組成物及び方法は、膵臓癌、乳頭腫症、副鼻腔癌及び鼻腔癌、副甲状腺癌、陰茎癌、咽頭癌、中間分化型松果体実質腫瘍及び松果体芽細胞腫、テント上原始神経外胚葉腫瘍、下垂体腫瘍、胸膜肺芽、妊娠中の癌及び乳癌、原発性中枢神経系リンパ腫、並びに前立腺癌などの疾患を治療するために使用される。一実施形態では、本発明の組成物及び方法は、直腸癌、腎細胞(腎臓)癌、腎盂及び尿管、染色体15上のNUT遺伝子が関与する気道癌、網膜芽細胞腫、及び横紋筋肉腫からなる群から選択される癌を治療するために使用される。一実施形態では、本発明の組成物及び方法は、高悪性度の前立腺癌を治療するために使用される。一実施形態では、本発明の組成物及び方法は、中悪性度前立腺癌を治療するために使用される。一実施形態では、本発明の組成物及び方法は、低悪性度の前立腺癌を治療するために使用される。一実施形態では、本発明の組成物及び方法は、去勢抵抗性前立腺癌を治療するために使用される。
ド、ニトログリセリン、ノラトレキセド、ノレリン、N-アセチルシステイン、06-ベンジルグアニン、オブリメルセン、オメプラゾール、オンコファージ、オンコVEXGM-CSF、オルミプラチン(ormiplatin)、オルタタキセル、OX44抗体、OSI-027、OSI-906(リンシチニブ)、4-IBB抗体、オキサトラゾール、エストロゲン、パニツムマブ、パツピロン(patupilone)、ペグフィルグラスチム、PCK-3145、ペグフィルグラスチム、PBI-1402、PBI-05204、PDO325901、PD-1抗体、PEG-パクリタキセル、アルブミン安定化パクリタキセル、PEP-005、PF-05197281、PF-05212384、PF-04691502、PHT-427、P-04、PKC412、P54、PI-88、ペリチニブ、ペメトレキセド、ペントリクス(pentrix)、ペリホシン、ペリリルアルコール、ペルツズマブ、PI3K阻害剤、PI3K/mTOR阻害剤、PG-TXL、PG2、PLX-4032/RO-5185426(ベムラフェニブ)、PLX-3603/RO-5212054、PT-100、PWT-33597、PX-866、ピコプラチン、ピバロイルオキシメチルブチレート(pivaloyloxymethylbutyrate)、ピクサントロン、フェノキソジオール O、PKI166、プレビトレキセド、プリカマイシン、ポリプレン酸、ポルフィロマイシン、プレドニゾン、プレドニゾロン、キナメド、キヌプリスチン、R115777、RAF-265、ラモセトロン、ランピルナーゼ、RDEA-119/BAY 869766、RDEA436、レベッカマイシン類似体、受容体チロシンキナーゼ(RTK)阻害剤、レビミッド、RG-7167、RG-7304、RG-7421、RG-7321、RG 7440、リゾキシン、rhu-MAb、リンファベート、リセドロネート、リツキシマブ、ロバツムマブ、ロフェコキシブ、RO-31-7453、RO-5126766、RO-5068760、RPR 109881 A、ルビダゾン、ルビテカン、R-フルルビプロフェン、RX-0201、S-9788、サバルビシン、SAHA、サルグラモスチム、サトラプラチン、SB 408075、Se-015/Ve-015、SU5416、SU6668、SDX-101、セムスチン、セオカルシトール、SM-11355、SN-38、SN-4071、SR-27897、SR-31747、SR-13668、SRL-172、ソラフェニブ、スピロプラチン、スクアラミン、スベラニロヒドロキサミン酸(suberanilohydroxamic acid)、ステント、T 900607、T 138067、TAK-733、TAS-103、タセジナリン、タラポルフィン、タルセバ、タリキダル(tariquitar)、タシスラム(tasisulam)、タキソテール、タクサオプレキシン、タザロテン、テガフール、テモゾラミド、テスミリフェン、テストステロン、プロピオン酸テストステロン、テスミリフェン、テトラプラチン、テトロドトキシン、テザシタビン、サリドマイド、テラルクス(theralux)、テラルビシン、チマルファシン、チメクタシン、チアゾフリン、チピファルニブ、チラパザミン、トクラデシン、トムデックス、トレモフィン、トラベクテジン、トランスMID-107、トランスレチン酸、トラスツズマブ、トレメリムマブ、トレチノイン、トリアセチルウリジン、トリアピン、トリシリビン、トリメトレキサート、TLK-286TXD 258、タイケルブ/タイバーブ、ウロシジン、バルルビシン、バタラニブ、ビンクリスチン、ビンフルニン、ビルリジン、WX-UK1、WX-554、ベクティビックス、ゼローダ、XELOX、XL-147、XL-228、XL-281、XL-518/R-7420/GDC-0973、XL-765、YM-511、YM-598、ZD-4190、ZD-6474、ZD-4054、ZD-0473、ZD-6126、ZD-9331、ZD1839、ZSTK-474、ゾレドロネート、ゾスキダル、及びそれらの組み合わせからなる群から選択される。
(i)化合物(1):
(ii)対象への第1の治療物質の投与の時間後に所定の待機時間が経過するまで、かつ/又は有害事象が解消されるか若しくは解消しているまで待つことと、
(iii)対象に第2の治療物質を投与することと、を含み、
第1の治療物質と第2の治療物質の可能性のある組み合わされた毒性効果のリスクを増加させることなく第1の治療物質の遅延治療効果を達成するために、所定の待機時間が選択される方法を提供する。治療方法のいくつかの実施形態では、所定の待機時間は、化合物(1)又はその薬学的に許容される塩のクリアランス速度に基づいて決定される。治療方法のいくつかの実施形態では、所定の待機時間は、腎機能及び腎臓パラメータの定量的評価によって決定される。治療方法のいくつかの実施形態では、所定の待機時間は、腎機能の決定のためのアッセイにより決定され、このアッセイは、化合物(1)又はその薬学的に許容される塩の血清レベル、化合物(1)又はその薬学的に許容される塩のクリアランス速度、化合物(1)又はその薬学的に許容される塩あるいはその代謝物の24時間の尿クリアランスからなる群から選択される。
(i)化合物(1):
(ii)薬物動態学的プロファイルを用いて、対象における化合物(1)又はその薬学的に許容される塩あるいはその代謝物のレベルを監視することと、
(iii)対象における第1の治療物質のレベル次第で第2の治療物質を投与することと、
を含む方法を提供する。方法のいくつかの実施形態では、監視するステップは、薬物動態学的プロファイルを構築するのに適する時点で対象から取得される少なくとも2種類の試料中の化合物(1)又はその薬学的に許容される塩あるいはその代謝物の濃度を用いて、対象についての化合物(1)又はその薬学的に許容される塩あるいはその代謝物の薬物動態プロファイルを構築することを含む。方法のいくつかの実施形態では、少なくとも2種類の試料が、実験室での化合物(1)又はその薬学的に許容される塩あるいはその代謝物の定量化前に、ポイント・オブ・ケア装置若しくはポイント・オブ・ユース装置上で、又は少なくとも2種類の試料保管に適するマトリックス上での収集又は自己収集によって、ポイント・オブ・ケア又はポイント・オブ・ユースにて収集される。方法のいくつかの実施形態では、ポイント・オブ・ケア装置又はポイント・オブ・ユース装置のそれぞれは、化合物(1)又はその薬学的に許容される塩あるいはその代謝物を定量することができる。方法のいくつかの実施形態では、薬物動態プロファイルは、対象のための化合物(1)又はその薬学的に許容される塩の投与を導くのに適する薬物動態パラメータを含む。方法のいくつかの実施形態では、少なくとも2種類の試料は2~12種類の試料を含む。方法のいくつかの実施形態では、少なくとも2種類の試料は、8時間、24時間、48時間、又は72時間までの期間にわたって収集される。方法のいくつかの実施形態では、薬物動態パラメータは、AUC、AUCinf、Tmax、Cmax、閾値を超える時間、定常状態濃度、吸収速度、クリアランス速度、分配速度、半減期T-1/2又は非コンパートメント薬物動態(PK)分析若しくは生理学的モデルベースコンパートメントPK解析を含むコンパートメントPK分析から導き出されるパラメータからなる群から選択される、少なくとも1つのパラメータを含む。方法のいくつかの実施形態では、治療方法は、対象の薬物動態プロファイルを含むレポートを生成することをさらに含む。方法のいくつかの実施形態では、レポートは、対象の薬物動態プロファイルに基づく投薬に関する推奨を含む。方法のいくつかの実施形態では、化合物(1)又はその薬学的に許容される塩の投与量の減少が、1以上の薬物動態パラメータに基づいて、毒性リスクを減少させるために指示される。方法のいくつかの実施形態では、化合物(1)又はその薬学的に許容される塩の投与量の減少が閾値を超える時間に基づいて示され、閾値は、それを超えると毒性が生じる薬物濃度、又は薬物動態プロファイルを適切に説明するためのAUC、AUCinf、平均滞留時間(MRT)、薬物動態プロファイルを定義する指数、定常状態での分布容積(Vss)、終末相の分布容積(Vz)若しくは薬物動態学的変数のグループの組み合わせのうちの1以上である。方法のいくつかの実施形態では、化合物(1)又はその薬学的に許容される塩の用量調節が、1以上の薬物動態パラメータに基づいて、有効性を増加させるように示される。方法のいくつかの実施形態では、化合物(1)又はその薬学的に許容される塩の投与量の増加が、薬物動態プロファイルを適切に説明するためのAUC、AUCinf、MRT、薬物動態プロファイルを定義する指数、定常状態での分布容積(Vss)、終末相の分布容積(Vz)又は薬物動態学的変数のグループの組み合わせのうちの1以上に基づいて示される。方法のいくつかの実施形態では、化合物(1)又はその薬学的に許容される塩の用量は、所望の目標値の5%~25%以内に調整される。方法のいくつかの実施形態では、少なくとも2種類の試料のそれぞれが、化合物(1)又はその薬学的に許容される塩あるいはその代謝物の濃度を決定するためのポイント・オブ・ケア装置又はポイント・オブ・ユース装置に適用され、ポイント・オブ・ケア装置又はポイント・オブ・ユース装置は、少なくとも2種類の試料のうちの1以上の側方流動ストリップへの適用が試料中の薬物の画分を側方流動ストリップの構成要素と結合させ、適用される試料中の薬物濃度に比例する検出可能なシグナルを生成するような構造及び組成を有する、側方流動ストリップを含む。方法のいくつかの実施形態では、実験室での定量化前に、少なくとも2種類の試料が、少なくとも2種類の試料の保管に適するマトリックスに適用される。方法のいくつかの実施形態では、少なくとも2種類の試料は、乾燥した血液スポットとして保管される。方法のいくつかの実施形態では、薬物濃度は、ELISA、LC MS MS、LC UV又はLCMSによって測定される。方法のいくつかの実施形態では、薬物動態パラメータは、定常状態濃度、吸収、及び半減期Tl/2のうちの少なくとも1つを含む。方法のいくつかの実施形態では、少なくとも2種類の試料のうちの少なくとも1種類は全血である。
TRAILタンパク質は、化合物(1)又はその薬学的に許容される塩によって誘導されるTRAIL発現を検出するために、対象から取得した試験試料においてアッセイできる。免疫アッセイ法が試料中のTRAILをアッセイするために用いられ、非限定的に、酵素結合免疫吸着測定法(ELISA)、酵素結合免疫濾過測定法(ELIFA)、フローサイトメトリー、免疫ブロット、免疫沈降、免疫組織化学、免疫細胞化学、発光免疫測定法(LIA)、蛍光免疫測定法(FIA)、及びラジオイムノアッセイを含む。アッセイ方法を用いて、定性的及び/又は定量的結果を得てもよい。試料の定性分析と定量分析の両方に適するアッセイ法の具体的詳細は標準的な参考文献に記載されており、代表的なものとしては、E.Harlow及びD.Lane、抗体:実験室マニュアル、Cold Spring Harbor Laboratory Press、1988;F.Breitling及びS.Diibel、組み換え抗体、John Wiley & Sons、ニューヨーク、1999;H.Zola、モノクローナル抗体:モノクローナル抗体及び改変された抗体誘導体の調製及び使用(Preparation and Use of Monoclonal Antibodies and Engineered Antibody Derivatives)、基礎:バックグラウンドからベンチまで(From Background to Bench)、BIOS Scientific Publishers、2000;B.K.C.Lo、抗体操作 Antibody Engineering):方法とプロトコル、分子生物学の方法、Humana Press、2003;F.M.Ausubelら(編)、分子生物学のショートプロトコル(Short Protocols in Molecular Biology)、カレント・プロトコール、Wiley、2002;S.Klussman(編)、アプタマーのハンドブック(The Aptamer Handbook):機能オリゴヌクレオチド及びその応用(Functional Oligonucleotides and Their Applications)、Wiley、2006;Ormerod,M.G.、フローサイトメトリー:実践的なアプローチ、Oxford University Press、2000;Givan,A.L.,フローサイトメトリー:第一原理(first principles)、Wiley、ニューヨーク、2001;Gorczyca,W.、腫瘍性血液学におけるフローサイトメトリー(Flow Cytometry in Neoplastic Hematology):形態-免疫表現型の相関(morphologic-immunophenotypic correlation)、Taylor & Francis、2006;Crowther,J.R.,ELISAガイドブック(The ELISA Guidebook)分子生物学の方法、Humana Press、2000;Wild,D.,免疫測定法ハンドブック(The Immunoassay Handbook)、第3版、Elsevier Science、2005、並びにJ.Sambrook及びD.W.Russell、分子クローニング(Molecular Cloning):実験室マニュアル、Cold Spring Harbor Laboratory Press、第3版、2001が含まれる。
一態様では、本発明は、そのような治療を必要とする対象への化合物(1)又はその薬学的に許容される塩の投与が他の治療様式の投与によって補われる、マルチモーダル治療方法に関する。一実施形態では、本発明のマルチモーダル治療方法は、放射線療法と併用して、又は放射線が有効ではなかったと判定された後に、化合物(1)又はその薬学的に許容される塩を含む医薬組成物を対象に投与することを含む。一実施形態では、本発明のマルチモーダル治療方法は、放射線療法と併用して、化合物(1)又はその薬学的に許容される塩を含む医薬組成物を対象に投与することを含み、化合物(1)又はその薬学的に許容される塩を含む医薬組成物及び放射線療法は、任意の順序で、同時に又は連続的に投与される。一実施形態では、マルチモーダル治療方法は、化合物(1)又はその薬学的に許容される塩を含む医薬組成物を、連続的な設定で放射線療法と併用して対象に投与することを含む。一実施形態では、マルチモーダル治療方法は、そのような治療を必要とする対象に、化合物(1)又はその薬学的に許容される塩を含む医薬組成物を放射線療法と同時に投与することを含む。一実施形態では、本発明のマルチモーダル治療方法は、癌の治療のために使用される。一実施形態では、マルチモーダル治療方法は、そのような治療を必要とする癌対象に、化合物(1)又はその薬学的に許容される塩を含む医薬組成物を投与することと、放射ビームを癌細胞に照射することと、を含む。一実施形態では、マルチモーダル治療方法は、癌対象に処方される線量体積ヒストグラム(DVH)を供給するために等角放射線療法(CRT)技術を使用する。一実施形態では、マルチモーダル治療方法は、癌細胞に放射線を供給するために強度変調放射線治療(IMRT)技術を使用する。一実施形態では、マルチモーダル治療方法は、治療中に対象中の腫瘍の動きを補償する技術を使用する(例えば、放射線の用量が、患者が呼吸するのにつれて移動する胸部腫瘍に投与されなければならない場合)。一実施形態では、マルチモーダル治療方法は、呼吸サイクルにわたって腫瘍の動きを補償するために、4次元コンピュータ断層撮影法(4D CT)スキャン技術を使用して供給される放射線場を調整する。
上記の化合物(1)で表される化合物は、以下のスキーム1に示す合成法により調製できる。
一形態では、本発明は、化合物(1)の類似体及び関連する塩、並びにその製造方法を提供する。当業者なら、方法及び医薬組成物に関連する原理並びに概念を含む、化合物(1)及びその塩と組み合わせて上で記載される同じ一般的な原理及び概念が、化合物(1)の誘導体及び類似体並びに化合物(1)の塩並びにそれらの塩に均等に適用されると理解するであろう。
以下に提供する説明及び特定の実施例は、単なる例示のためのものであり、本開示の範囲を限定することを意図するものではないことを理解されたい。実施例1~2は、化合物(1)から始まる化合物(1)のジ塩酸塩の合成を示す。これらの実施例において、かつ本願を通して、化合物(1)のジ塩酸塩を化合物(2)と呼ぶ。以下の実施例は、開示される実施形態を例示するためのものであり、それらに限定されるものとして解釈されるべきではない。以下に記載のもの以外の追加の化合物は、上記の続きの反応スキーム又はその適切な変形若しくは修正を用いて調製できる。
乾燥ジオキサン(2.0mL)中の2-メチルチオ-2-イミダゾリンヨウ化水素酸塩(244mg、1.00ミリモル)の撹拌溶液に2-クロロベンジルアミン(141mg、1.0ミリモル)を添加した。反応混合物をアルゴン雰囲気下70℃で90分間撹拌した。この溶液を室温まで冷却し、焼結漏斗で濾過し、冷ジオキサン(2mL)で洗浄し、真空下で乾燥させた。白色固体の化合物4・ΗΙ(R2=2-クロロベンジル)(242mg、72%)を取得し、さらに精製することなく使用した。
水(3mL)中の2-クロロベンジルアミノ-2-イミダゾリンヨウ化水素酸塩の撹拌溶液(242mg、0.72ミリモル)に、7℃で1.0Nの水酸化ナトリウム(2mL)を添加した。反応混合物をアルゴン下7℃で30分間撹拌した。その後、塩化メチレン(5mL)を添加し、混合物をさらに5分間撹拌した。反応混合物を塩化メチレン(2×2.5mL)で抽出し、有機層を無水Na2SO4上で乾燥させ、濾過して、蒸発させた。生じた遊離塩基(150mg、100%)を粘稠な液体として取得し、さらに精製することなく次の反応に用いた。MS(ESI)210(M+H)。
酢酸エチル(50mL)中の攪拌メチル-1-ベンジル-4-オキソ-3-ピペリジンカルボキシレート塩酸塩(5.7g、20ミリモル)に、7℃でトリエチルアミン(6mL)を添加した。反応混合物をアルゴン雰囲気下7℃で30分間撹拌した。この反応混合物を酢酸エチル(2×50mL)で抽出し、水(50mL)で洗浄した。有機層を無水Na2SO4上で乾燥させ、濾過し、蒸発させた。粘性油状物として生じた遊離塩基残基(5、R1=ベンジル)を、さらに精製せずに次の反応に使用した。MS(ESI)248(M+H)。
1-ブタノール(2mL)中の2-クロロベンジルアミノ-2-イミダゾリン(150mg、0.72ミリモル)、メチル-1-ベンジル-4-オキソ-3-ピペリジンカルボキシレート(5、R1=ベンジル)(195mg、0.79ミリモル)の溶液に、PPTS(10mg)を添加し、混合物を室温で48時間撹拌した。その後、この反応混合物を2時間125℃~130℃で還流した。溶媒を真空下で除去し、酢酸エチル(10mL)で抽出し、飽和重炭酸ナトリウム溶液(2×10mL)及び水(10mL)で洗浄した。有機層を無水Na2SO4上で乾燥させ、濾過し、蒸発させた。粗製遊離塩基をRP HPLC(10%~40%アセトニトリル/水)により精製し、白色固体としてONC902 TFA塩を取得した(228mg、50%収率)。MS(ESI)407(M+H)。
乾燥トルエン(50mL)中の60%水素化ナトリウム(3.5g、88ミリモル)の懸濁液に、炭酸ジメチル(4.32g、48.0ミリモル)を窒素雰囲気下にて室温で0.5時間かけて滴下した。メタノールを数滴添加した後、乾燥トルエン(20mL)に溶解した1-tert-ブトキシカルボニル-4-ピペリドン(4.8g、24ミリモル)の溶液を、1時間かけて80℃で撹拌しながら反応混合物に滴下した。この反応混合物を同じ温度で3時間撹拌し、次いで0℃(氷浴)まで冷却し、酢酸でPHを6~6.5に調整した。生じた冷混合物を水(10mL)で希釈し、5%水酸化ナトリウム溶液でpH8に調整した。トルエン層を分離し、水層をトルエン(20mL)で抽出した。合わせた有機層を無水硫酸ナトリウムで乾燥させ、減圧下で濃縮した。この化合物を真空中で乾燥させ、メチル-1-tertブトキシカルボニル-4-オキソ-3-ピペリジンカルボキシレート(5.0g、80%)を得た。得られた化合物をさらに精製することなく次の反応に用いた。
N,N-ジメチルホルムアミド(3mL)中のONC907(100mg、0.2ミリモル)、フェニルエチルブロミド(55.0mg、0.28ミリモル)及び炭酸カリウム(150mg、1.0ミリモル)の混合物を、12時間、70℃まで加熱した。溶媒を真空下で除去し、酢酸エチル(10mL)で抽出し、水(5mL)で洗浄した。有機層を無水Na2SO4上で乾燥させ、濾過し、蒸発させた。粗製遊離塩基をRP HPLC(10%~40%アセトニトリル/水)により精製し、白色固体としてONC909(62mg、50%)TFA塩を得た。MS(ESI)401(M+H)。
1-ブタノール(2.0mL)中の2-メチルベンジルアミノ-2-イミダゾリン(190.0mg、1.0ミリモル)、メチル-1-メチル-4-オキソ-3-ピペリジンカルボキシレート(185.0mg、1.0ミリモル)の溶液にPPTS(10.0mg)を添加し、混合物を室温で48時間撹拌した。その後、この反応混合物を2時間、125℃~130℃で還流した。溶媒を真空下で除去し、酢酸エチル(10mL)で抽出し、飽和重炭酸ナトリウム溶液(2×10mL)及び水(10mL)で洗浄した。有機層を無水Na2SO4上で乾燥させ、濾過し、蒸発させた。粗製遊離塩基をHPLC 10%~40%のアセトニトリル及び水により精製し、白色固体としてONC908(270.0mg、50%)TFA塩を得た。MS(ESI)311(M+H)。
2Lの丸底フラスコ中の800mLの攪拌飽和NaHCO3に、化合物(3)(239.7g、0.845モル、1.6当量)を少量ずつ添加した。n-ブタノール(500mL)を得られた混合物に添加し、混合物を30分間撹拌し、次いで分液漏斗に移した。化合物(4)を含む有機相を分離し、機械的撹拌、N2入口、熱電対、冷却器及びDean-starkトラップを備える2Lの三首丸底フラスコに移した。化合物(5)(100g、0.528モル、1当量)及びP-トルエンスルホン酸ピリジニウム(PPTS)(6.63g、0.026モル、5モル%)をこのフラスコの内容物に添加した。生じた混合物を6時間、加熱還流した。反応混合物中の水は、必要に応じて、Dean-starkトラップ中に分離した。還流温度を93℃から118℃に上昇させた。反応の進行をHPLCによって監視した。HPLC上の化合物(1)のピーク面積が反応時間に対して一定のままになったときに、反応を停止した。
化合物(1)を単離しないで、実施例8からの反応混合物を水500mLで洗浄し、メチルtert-ブチルエーテル(MTBE)(800mL)で希釈した。有機相を水(500mLで、2回)で洗浄し、機械的撹拌、N2入口、熱電対、冷却器及びDean-starkトラップを備える3Lの三首丸底フラスコに移した。反応混合物を撹拌しながら、HClの添加時に反応混合物から固形物が沈殿しなくなるまで、ジオキサン-MTBE溶液中の1NのHClを滴加した(ジオキサン中の4N HCl:300mL、1.2モル、2.27当量;MTBE:1200mL)。反応混合物を2時間、60~65℃で加熱還流した。必要に応じて、水をDean-starkトラップ中に分離した。室温まで冷却し、固形沈殿物を焼結ガラス漏斗を通して濾過し、n-ブタノール-MTBE(1:2、600mL)及びMTBE(600mL)でそれぞれ洗浄した。固体を、一晩65℃で、真空オーブン中で乾燥させ(16時間)、黄色固体200gを得た。
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