JP2020500175A - 亜鉛結合部分を有するホスホイノシチド3−キナーゼ阻害剤を用いる併用療法 - Google Patents
亜鉛結合部分を有するホスホイノシチド3−キナーゼ阻害剤を用いる併用療法 Download PDFInfo
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- JP2020500175A JP2020500175A JP2019523093A JP2019523093A JP2020500175A JP 2020500175 A JP2020500175 A JP 2020500175A JP 2019523093 A JP2019523093 A JP 2019523093A JP 2019523093 A JP2019523093 A JP 2019523093A JP 2020500175 A JP2020500175 A JP 2020500175A
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 229960004747 ubidecarenone Drugs 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
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Abstract
Description
本出願は2016年11月2日出願の米国仮出願第62/416,329号の利益を主張する。上記出願の全体の教示が参照により本明細書に援用される。
本発明を説明するために用いる種々の用語の定義を以下に列挙する。これらの定義は、特定の場合において別段の限定がなされない限り、個々にまたはより大きな群の一部としてのいずれかで、本明細書及び特許請求の範囲の全体を通して用いられる用語に適用される。
本発明の医薬組成物は、1種または複数種の薬学的に許容される担体または賦形剤と共に製剤化された、ベネトクラクスまたはその薬学的に許容される塩などのBcl阻害剤との組み合わせで、治療有効量の式Iの化合物、例えば化合物1またはその薬学的に許容される塩を含む。
ステップa:(Z)−2−(エトキシメチル)−3−メトキシアクリル酸エチル(化合物202)
エタノール(750mL)にナトリウム(40.9g、1.78mol)を少しずつ慎重に加え、全てのナトリウム金属が消失した後にこの溶液を濃縮して、NaOEt粉末を得た。撹拌下でヘキサン(1.0L)を加え、この混合物を氷水浴で冷却した。0〜5℃で201(130g、0.89mol)とギ酸エチル(131g、1.78mol)の混合物を滴加した。この反応混合物を室温で終夜撹拌した。氷水浴で冷却しながら硫酸ジメチル(224g、1.78mol)を滴加した。得られた混合物を50℃で2時間加熱した。この混合物に塩化トリエチルアンモニウム(122g)及び水酸化ナトリウム(20g)を添加した。次いでこの混合物を室温で4時間撹拌し、ろ過した。ろ液を水洗し、Na2SO4上で脱水した。これを濃縮して標記化合物(140g、37%)を無色油状物として得て、これを更に精製することなく次のステップに用いた。
エタノール(500mL)中の化合物202(140g、0.745mol)、尿素(40.0g、0.697mol)、及び濃塩酸(34mL)の混合物を終夜加熱還流した。反応物の約50容量%を留去した後、得られた懸濁液をろ過し、少量のエタノールで洗浄し、乾燥して化合物203(47g、37%)を白色固体として得た。LCMS: 171 [M+1]+。1H NMR (400 MHz, CDCl3): δ1.19 (t, J = 7.2 Hz, 3H), 3.92 (s, 2H), 4.08 (q, J = 7.2 Hz, 2H), 7.0 (s, 1H), 7.08 (d, J = 6.0 Hz, 1H), 8.83 (d, br, J = 4.8 Hz, 1H)。
化合物203(47g、280mmol)の酢酸(500mL)溶液に、臭素(49.0g、307mmol)を添加した。この混合物を2時間加熱還流し、室温に冷却し、更に0〜5℃に冷却し、ろ過して、標記化合物204を黄色固体として得た(38g、54%)。LCMS: 169 [M+1]+。1H NMR (400 MHz, D2O): δ 1.28 (t, J = 7.2 Hz, 3H), 4.32 (q, J = 7.2 Hz, 2H), 9.00 (br, s, 2H)。
化合物204(38.0g、153mmol)及び三塩化ホスホリル(300mL)及びN,N−ジメチルアニリン(3mL)の混合物を2時間加熱還流し、室温に冷却し、濃縮した。残渣を氷水で慎重にクエンチし、炭酸ナトリウムでpHを7〜8に調整し、EtOAcで抽出した。1つにまとめた有機分を氷水及び飽和食塩水で洗浄し、Na2SO4上で脱水し、留去し、カラムクロマトグラフィー(EtOAc/ヘキサン、10%で溶離)により精製して、化合物R−2−1(15g、52%)を白色固体として得た。LCMS: 187 [M+1]+。1H NMR (400 MHz, CDCl3): δ 1.36 (t, J = 7.5 Hz, 3H), 4.39 (q, J = 7.5 Hz, 2H), 9.08 (s, 2H)。
無水1,2−ジメトキシエタン(300mL)中のNaH(27g、鉱油中60%、0.675mol)の混合物を40〜50℃に加熱し、3,3−ジメトキシプロピオン酸メチル(205)(100g、0.675mol)を滴加した。得られた混合物を0.5時間撹拌し、40〜50℃で無水ギ酸メチル(81g、1.35mol)を滴加した。得られた混合物を40〜50℃(内部温度)で2時間撹拌した後、これを0℃に冷却した。この反応混合物をゆっくりと25℃まで加温し、終夜撹拌した。Et2O(150mL)を加え、30分間撹拌した。得られた懸濁液をろ過した。固体をEt2O(100mL)で洗浄し、回収し、乾燥して、標記化合物206(82g、61%)を灰白色固体として得た。LCMS (m/z): 130.8 [M+1]+。1HNMR (400 MHz, CD3OD): δ3.36 (s, 6H), 3.60 (s, 3H), 5.34 (s, 1H), 8.92 (s, 1H)。
DMF(300mL)中のグアニジン塩酸塩(42.2g、0.44mol)の混合物に、化合物206(80g、0.40mol)を添加した。得られた混合物を100℃で1時間加熱した。この反応混合物をろ過した後に冷却した。ろ過ケーキを50mLのDMFで洗浄し、1つにまとめたろ液を濃縮して残渣を得、これを冷EtOH中に懸濁させ、冷EtOH(50mL)で洗浄して、化合物207(38g、61.5%)を黄色固体として得た。LCMS (m/z): 154.2 [M+1]+, 195.1[M+42]+。1H NMR (400 MHz, CD3OD): δ 3.88 (s, 3H), 8.77 (s, 2H)。
濃塩酸(15.2mL)とCH2Cl2(60mL)の混合物に化合物207(7g、0.046mol)を添加した。冷却後、15〜20℃でZnCl2(18.6g、0.138mol)を添加した。この混合物を15〜20℃で0.5時間撹拌し、5〜10℃に冷却した。内部温度を5〜10℃に維持しながら、NaNO2(9.5g、0.138mol)を少しずつ添加した。反応を約2時間継続した。この反応混合物を氷水(50mL)に注ぎ込んだ。有機層を分離し、水相をCH2Cl2(30mL×2)で抽出した。1つにまとめた有機抽出液を濃縮して粗生成物(4.2g)を得た。この粗化合物をヘキサン(20mL)中に懸濁させ、60℃で30分間加熱し、ろ過した。ろ液を濃縮して、標記化合物R−2−2(3.5g、44.4%)を灰白色固体として得た。LCMS (m/z): 214.1[M+42]+。1HNMR (400 MHz, CDCl3): δ4.00 (s, 3H), 9.15 (s, 2H)。
2−メトキシ−ピリジン(100g、0.92mol)、NBS(180g、1.0mol)のアセトニトリル(1.0L)溶液を還流下で21時間撹拌した。TLCにより反応が完結したことが明らかになった。この反応混合物を室温に冷却し、濃縮した。約900mlの溶媒を回収した。得られた懸濁液をろ過し、n−ヘキサン(約400mL)で洗浄した。ろ液を再度濃縮して粗生成物を得た。この粗生成物を減圧下で蒸留して(30℃/約0.3mmHg)、標記化合物を透明な油状物として得た(146g、84%)。LCMS (m/z): 190.0 [M+1]+。1H NMR (400 MHz, CDCl3): δ 3.90 (s, 3H), 6.65 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 8.8 Hz, 2.4Hz, 1H), 8.19 (s, 1H)。
化合物303(20g、0.11mol)の無水THF(180ml)溶液に、−78℃でn−BuLi(59mL、2MのTHF溶液)を滴加し、得られた混合物を1時間撹拌した。−78℃でホウ酸トリイソプロピル(37mL)を添加し、この反応混合物を室温に加温し、終夜撹拌を継続した。TLC(ヘキサン/酢酸エチル=5:1)により反応が完結したことが明らかになった。この混合物を4N HCl(90ml)でpH3〜4に調整した。沈殿物をろ過により回収して、粗化合物R−3−1(21g、128%)を得た。この粗化合物R−3−1(21g)を水(200ml)に溶解し、この溶液を濃アンモニア溶液でpH8〜9に調整し、沈殿物をろ過により回収して、純粋な標記化合物R−3−1を白色固体として得た(11g、67%)。LCMS (m/z): 154.1 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ3.86 (s, 3H), 6.76 (d, J = 8.4 Hz, 1H), 7.99 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 8.05 (br, 2H), 8.52 (d, J = 2.0 Hz, 1H)。
無水ジオキサン(500mL)中の化合物303(55g、0.29mol)、4,4,4’,4’,5,5,5’,5’−オクタメチル−2,2’−ビ(1,3,2−ジオキサボロラン)(90g、0.35mol)、酢酸カリウム(57g、0.58mol)、及びビス(トリフェニルホスフィン)パラジウム(II)クロリド(2.2g、3mmol)の混合物を、N2雰囲気下、108℃で終夜加熱した。この反応混合物を濃縮し、ヘキサン/酢酸エチルで溶離させるカラムクロマトグラフィーにより精製して、標記化合物R−3−2(58g、84%)を得た。1H NMR (400 MHz, DMSO−d6): δ 1.30 (s, 12H), 3.88 (s, 3H), 6.81 (d, J = 8.0 Hz, 1H), 7.88 (dd, J = 8.0 Hz, 2.0Hz, 1H), 8.41 (d, J = 2.0Hz, 1H)。
尿素法:3−アミノチオフェン−2−カルボン酸メチル(101)(90.0g、573mmol、1.0当量)及び尿素(277.6g、4.6mol、8.0当量)の混合物を190℃で3〜4時間加熱し、室温に冷却した。この反応混合物にNaOH水溶液(10%、800mL)を添加した。周囲温度で1時間撹拌した後、固体をろ過により除去した。ろ液をHClでpH3〜4に酸性化し、沈殿した固体をろ過により回収し、水洗し、減圧下で乾燥して、所望の生成物である化合物102を灰白色固体として得た(87g、89%)。融点:280〜285℃。LCMS (m/z): 169.0 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ 6.92 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 5.2 Hz, 1H), 11.0−11.5 (br, 2H)。
化合物102(40g、238mmol、1.0当量)及びN,N−ジメチルアニリン(22.5mL、179mmol、0.75当量)の冷却したアセトニトリル(250mL)溶液に、温度を20℃より低温に維持しながら、オキシ塩化リン(152mL、1.67mol、7.0当量)をゆっくりと添加した。次いでこの混合物を85℃に加熱し、24時間撹拌した。この反応混合物を15℃に冷却し、次いで氷と冷水の混合物(360mL)上にゆっくりと注ぎ込んだ。得られたスラリーをろ過し、冷水(200mL)ですすいだ。ケーキを真空オーブン中40℃で24時間乾燥し、化合物103(40.5g、83%)を灰白色固体として得た。融点:245〜250℃。LCMS (m/z): 205.0 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ 7.75 (d, J = 5.2 Hz, 1H), 8.71 (d, J = 5.2 Hz, 1H)。
化合物103(34.2g、167mmol、1.0当量)及びメタノール(500mL)の混合物にモルホリン(31.2mL、367mmol、2.2当量)をゆっくりと添加した。この反応混合物を室温で終夜撹拌した。沈殿物をろ過により回収し、メタノールで洗浄し、減圧下で乾燥して、所望の生成物である化合物104を淡黄色固体として得た(39g、91%)。融点:250〜255℃。LCMS (m/z): 256.0 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ 3.76 (t, J = 5.2 Hz, 4H), 3.92 (t, J = 5.2 Hz, 4H), 7.42 (d, J = 5.2 Hz, 1H), 8.32 (d, J = 5.2 Hz, 1H)。
窒素下で、−78℃の化合物104(20g、78.4mmol、1.0当量)のTHF(無水、320mL)懸濁液に、n−BuLi(ヘキサン溶液、2.4M、40.8mL、102mmol、1.3当量)をゆっくりと添加した。得られたスラリーを−60℃まで加温したところ、透明な褐色の溶液に変化した。次いでこの反応混合物を再度−78℃に冷却し、DMF(無水、9.1mL、118mmol、1.5当量)をゆっくりと添加した。得られた溶液を−78℃で0.5時間撹拌し、1時間かけて0℃まで加温し、HCl水溶液(0.25M、660mL)と氷水(320mL)の混合物にゆっくりと注ぎ込んだ。得られたスラリーを0〜10℃で0.5時間撹拌し、ろ過し、冷水で洗浄し、減圧下で乾燥して、化合物105を黄色固体として得た(22g、98%)。融点:260〜265℃。LCMS (m/z): 284.0 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ 3.77 (t, J = 5.2 Hz, 4H), 3.96 (t, J = 5.2 Hz, 4H), 8.30 (s, 1H), 10.21 (s, 1H)。
窒素雰囲気下で、化合物105(20.0g、70.4mmol、1.0当量)のメタノール(125mL)溶液に、メチルアミンのメタノール溶液(27%v/v、75mL、563.2mmol)を添加した。この反応混合物を室温で終夜撹拌し、溶媒を減圧下で除去して、粗固体生成物を得、これを窒素下でメタノール(550mL)及びTHF(220mL)に溶解した。水素化ホウ素ナトリウム(8g、211.2mmol)を少しずつ添加し、この反応混合物を室温で終夜撹拌した。この反応混合物を減圧下で留去し、水(300mL)を加えた。この水性混合物を塩化メチレンで抽出し、1つにまとめた抽出液をNa2SO4上で脱水し、濃縮した。残渣を6M HCl(230mL)に溶解し、30分間撹拌した。この水溶液を塩化メチレンで数回洗浄し、NaOH(4N)でpH9〜10に調整した。沈殿した固体をろ過により回収し、乾燥して(60℃、6時間)、淡黄色固体を得た(18g、85%)。融点:240〜245℃。LCMS (m/z): 299 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ2.32 (s, 3H), 3.74 (t, J = 5.2 Hz, 4H), 3.88 (t, J = 5.2 Hz, 4H), 3.96 (s, 2H), 7.24 (s, 1H)。
室温のCH3CN(400mL)中の106(10g、33.6mmol)及びR−2−1(6.8g、36.4mmol)の混合物に、ジイソプロピルエチルアミン(220mL、1.26mol)を添加した。得られた混合物を室温で終夜撹拌した。次いでこの混合物を留去し、続いて塩化メチレン(300mL)を加えた。有機相を水洗し、Na2SO4上で脱水し、減圧下で濃縮して残渣を得た。この残渣に酢酸エチルを加え、得られた混合物を氷/水浴温度で50分間撹拌した。得られた固体をろ過により回収して、標記生成物107−1を白色固体として得た(10.6g、70%)。LCMS: 449 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ 1.30 (t, J = 7.2 Hz, 3H), 3.25 (s, 3H), 3.71 (t, J = 5.2 Hz, 4H), 3.83 (t, J = 4.8 Hz, 4H), 4.29 (m, 2H), 5.21 (s, 2H), 7.39 (s, 1H), 8.87 (s, 2H)。
化合物106(25g、84mmol)、CH3CN(500mL)、及びR−2−2(16g、92mmol)の混合物を室温で撹拌した。ジイソプロピルエチルアミン(DIPEA)(500mL、2.9mol)を添加した。この溶液を終夜撹拌し、留去した。塩化メチレン(500mL)を加えた後、有機相を水洗し、Na2SO4で脱水し、減圧下で濃縮した。残渣に酢酸エチル(200mL)を加え、この混合物を氷/水浴中で50分間撹拌した。標記生成物を白色固体として回収した(29.4g、81%)。LCMS (m/z): 435.2 [M+1]+。1HNMR (400 MHz, DMSO−d6): 3.25 (s, 3H), 3.71 (t, J = 5.2 Hz, 4H), 3.82−3.84 (m, 7H), 5.21 (s, 2H), 7.39 (s, 1H), 8.87 (s, 2H)。
方法A:トルエン(80ml)、エタノール(50ml)、及び水(10ml)の混合溶媒中の化合物107−1(12g、26.7mmol)、R−3−1(4.9g、32mmol)、NaHCO3(6.7g、80.1mmol)、及びビス(トリフェニルホスフィン)パラジウム(II)クロリド(188mg、0.267mmol)の混合物を、N2雰囲気下、108℃で4.5時間加熱した。TLCにより反応が完結したことが明らかになった。次いでこの反応混合物を室温に冷却し、水(20ml)を加えた。得られた固体をろ過により回収し、次いでこれをエタノール(100mL)中に懸濁させた。この懸濁液を室温で30分間撹拌し、ろ過した。回収した固体をエタノールで洗浄し、減圧下で乾燥して、標記化合物108−1を白色固体として得た(10g、72%)。
室温のジオキサン(540mL)中の化合物107−2(20g、46.0mmol)、B−3−1(9.2g、60.2mmol、1.3当量)の混合物に、固体のNaHCO3(11.6g、138.1mmol、3当量)を添加し、続いて水(40mL)を加えた。得られた混合物を、溶液の表面を通してN2を流すことによって脱気した。次いでビス(トリフェニルホスフィン)パラジウム(II)クロリド(323mg、0.46mmol、0.01当量)を添加し、得られた混合物を108℃で15時間加熱した。TLC及びLCMSにより反応が完結したことが明らかになった。この反応混合物がまだ熱い(>90℃)うちにセライトを通してろ過し、ジオキサン(70mL)で洗浄した。ろ液を徐々に室温に冷却すると、冷却期間中に白色の微細結晶が生成した。この懸濁液をろ過し、ジオキサン(80mL)で洗浄して、標記化合物108−2を白色固体として得た(18g、78%)。LCMS (m/z): 508.3 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ3.28 (s, 3H), 3.76 (t, J = 4.8 Hz, 4H), 3.82 (s, 3H);3.92 (m, 4H), 3.93 (s, 3H), 5.20 (s, 2H), 6.91 (d, J = 8.8Hz, 1H), 7.47 (s, 1H), 8.57 (dd, J = 8.8Hz, 2.4Hz, 1H), 8.88 (s, 2H), 9.15 (d, J = 2.0Hz, 1H)。
ヒドロキシルアミンメタノール溶液の調製
MeOH(400mL)中のNH2OH・HCl(80g、1.12mol)の混合物を60〜65℃で1時間加熱して、透明な溶液を生成させた。次いでこの溶液を氷水浴中で冷却した。冷却したこの混合物に、反応温度を0〜10℃に維持しながら、KOH(96g、1.68mol)のMeOH(240mL)溶液を滴加した。得られた混合物を0℃で30分間撹拌し、次いで無水Na2SO4(700g)を充填した定圧ロートを通してろ過した。ろ液を氷浴下で回収し、使用するまで冷蔵庫に保存した。
上記調製してすぐのヒドロキシルアミンメタノール溶液(1.79M、350ml)に化合物108−1(10g、19mmol)を懸濁させた。この混合物にジクロロメタン(100mL)を加えた。反応フラスコを密封し、この混合物を室温で5時間撹拌したところ、該混合物は透明な溶液に変化した。反応混合物を更に9時間撹拌し、ろ過して不溶な固体を全て除去した。酢酸を添加してろ液をpH6〜7に調整し、固体の沈殿物を生成させた。この固体をろ過により回収し、水及び最小限の量のメタノールで洗浄し、減圧下、60℃で5時間乾燥して、化合物1を白色固体として得た(9.2g、96%)。融点:177〜180℃。LCMS: 509.3 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ 3.24 (s, 3H), 3.76 (t, J = 5 Hz, 4H), 3.92 (t, J = 5 Hz, 4H), 3.92 (s, 3H), 5.20 (s, 2H), 6.90 (d, J = 8.8 Hz, 1H), 7.44 (s, 1H), 8.57 (dd, J = 8.8 Hz, 2.4Hz, 1H), 8.75 (s, 2H), 9.01 (s, 1H), 9.14 (d, J = 2.0 Hz, 1H), 11.08 (s,1H)。
室温の化合物108−2(31g、61.1mmol)のジクロロメタン(310mL)懸濁液に、上記調製してすぐのヒドロキシルアミンメタノール溶液(1.79M、744ml)を添加した。反応フラスコを密封し、この反応混合物を室温で5時間撹拌した。反応混合物は透明な溶液に変化した。この反応溶液をろ過して不溶な固体を全て除去した。次いでろ液に水(310mL)を加えたところ、添加中に固体は生成しなかった。撹拌しながら酢酸(18.5mL)を加えてpHを10.20に調整した(pH計で連続的に監視した)。酢酸添加中に内部温度の変化はなかった。得られた反応混合物を更に4時間撹拌し続けた。白色固体が徐々に生成した。この懸濁液をろ過し、最小限の量のメタノール(100mL×3)で洗浄した。回収した白色固体をメタノール(620mL)及び水(124mL)中に再懸濁させて懸濁液を形成した。上記懸濁液に更に酢酸(11g)を添加してpHを5〜6に調整した。固体の形態の変化が観察された。この懸濁液を更に2時間撹拌し続け、ろ紙を通してろ過し、最小限の量のメタノール(100mL×3)で洗浄した。回収した白色固体をオーブン(50℃)中で12時間乾燥して、標記化合物1を白色固体として得た(23.6g、76.0%)。融点:255〜259℃。LCMS (m/z): 509.3 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ3.24 (s, 3H), 3.76 (t, J = 5.2 Hz, 4H), 3.92 (t, J = 5.2Hz, 4H), 3.92 (s, 3H), 5.20 (s, 2H), 6.91 (d, J = 8.4Hz, 1H), 7.45 (s, 1H), 8.57 (dd, J = 8.4Hz, 2.4Hz, 1H), 8.75 (s, 2H), 9.07 (s, 1H), 9.14 (d, J = 2.4Hz, 1H), 11.14 (s,1H)。
方法A:0℃で、化合物1(300mg、0.59mmol)とMeOH/Et2O(3/1、40mL)の混合物に、メタンスルホン酸(114mg、1.18mmol)のMeOH(3mL)溶液を添加した。得られた混合物を0℃で3時間撹拌した。沈殿物をろ過により回収し、Et2Oで洗浄して、化合物2を白色固体として得た(260mg、73%)。
0℃の化合物1(300mg、0.59mmol)のメタノール(30mL)懸濁液に、t−BuONa(85mg、0.88mmol)をゆっくりと添加した。得られた混合物を室温に加温し、2時間撹拌を継続した。この反応物を濃縮し、残渣をエタノールで粉体化及び洗浄し、続いてろ過して、化合物3を白色固体として得た(230mg、73%)。融点:178〜183℃。LCMS: 509.3 [M+1] +。1H NMR (400 MHz, DMSO−d6): δ3.17 (s, 3H), 3.75 (s, 4H), 3.92 (s, 7H), 5.16 (s, 2H), 6.90 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.65 (s, 2H), 9.14 (s, 1H)。
N2下、0℃で、メタノール(50mL)中の化合物1(400mg、0.78mmol)の混合物に、t−BuOK(132mg、1.17mmol)を添加した。この混合物を0℃で1時間撹拌し、室温で1.5時間撹拌を継続した。ろ過により不溶な固体を除去し、ろ液を−20℃に冷却した。このろ液にEt2O(100mL)を加えた。得られた混合物を−20℃で1時間撹拌した。ヘキサン(70mL)を加え、この混合物を−20℃で2時間撹拌し続けた。固体をろ過により回収し、減圧下で乾燥して、化合物4を白色固体として得た(150mg、35%)。融点:174〜179℃。LCMS: 509.3[M+1]+。1H NMR (400 MHz, DMSO−d6): δ 3.16 (s, 3H), 3.74−3.76 (m, 4H), 3.90−3.93 (m, 7H), 5.15 (s, 2H), 6.90 (d, J = 8.4Hz, 1H), 7.43 (s, 1H), 8.39 (br, 1H), 8.58 (d, J = 8.8Hz, 1H), 8.62 (s, 2H), 9.15 (s, 1H)。
化合物1(200mg、0.39mmol)のDCM/MeOH(60mL/12mL)溶液に、水酸化コリン(106mg、0.39mmol、MeOH中45%)を添加した。この混合物を室温で2時間撹拌し、次いで濃縮して約30mLの溶媒を除去した。酢酸エチル(60mL)を加え、この混合物を室温で2時間撹拌した。少量の沈殿物が生じた後、この混合物を濃縮して約40mLの溶媒を除去し、更に酢酸エチル(60mL)を加えた。この混合物を室温で2時間撹拌し、ろ過して、化合物5を白色固体として得た(180mg、76%)。融点:181〜185℃。LCMS: 509.3[M+1]+。1H NMR (400MHz, DMSO−d6): δ 3.11 (s, 9H), 3.17 (s, 3H), 3.40 (t, J = 4.8Hz, 2H), 3.75 (t, J = 4.8Hz, 4H), 3.84 (br, 2H), 3.90−3.93 (m, 7H), 5.15 (s, 2H), 6.89 (d, J = 8.8Hz, 1H), 7.41 (s, 1H), 8.57 (dd, J = 8.8Hz, 2.4Hz, 1H), 8.64 (s, 2H), 9.14 (d, J = 2.0Hz, 1H)。
化合物1(200mg、0.39mmol)のDCM/MeOH(30mL/7.5mL)懸濁液に、硫酸(77mg、0.79mmol、1mLのMeOH溶液)を添加して、透明な溶液を形成した。この反応混合物を室温で終夜撹拌した。沈殿が生じ、次いでtert−ブチルメチルエーテル(60mL)を加えた。得られた混合物を室温で1時間撹拌し続けた。固体をろ過により回収して、化合物6を白色固体として得た(180mg、76%)。融点:243〜246℃。LCMS: 509.3 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ 3.26 (s, 3H), 3.78 (t, J = 4.8 Hz, 4H), 3.96 (s, 3H), 4.03 (t, J = 4.4 Hz, 4H), 5.24 (s, 3H), 6.98 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 8.54 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 8.76 (s, 2H), 9.12 (d, J = 2.0 Hz, 1H), 11.06 (br, 1H)。
ステップ7a:(2−クロロ−4−モルホリン−4−イル−チエノ[3,2−d]ピリミジン−6−イルメチル)−メチル−アミン(化合物0503)
窒素雰囲気下で、0112(20.0g、70.4mmol)のメタノール(125mL)溶液にメチルアミンのメタノール溶液(27%v/v、75mL、563.2mmol)を添加した。この反応混合物を室温で終夜撹拌し、溶媒を減圧下で除去して粗固体生成物を得、これを窒素下でメタノール(550mL)及びTHF(220mL)に溶解した。水素化ホウ素ナトリウム(8g、211.2mmol)を少しずつ添加し、反応混合物を室温で終夜撹拌した。この反応混合物を減圧下で留去し、水(300mL)を加えた。この水性混合物を塩化メチレンで抽出し、1つにまとめた抽出液をNa2SO4上で脱水し、濃縮した。残渣を6M HCl(230mL)に溶解し、30分間撹拌した。この水溶液を塩化メチレンで数回洗浄し、NaOH(4N)でpH=9〜10に調整した。沈殿した固体をろ過により回収し、乾燥して(60℃、6時間)、淡黄色固体を得た(18g、85%)。LCMS: 299 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ 2.32 (s, 3H), 3.74 (t, J = 5.2 Hz, 4H), 3.88 (t, J = 5.2 Hz, 4H), 3.96 (s, 2H), 7.24 (s, 1H)。
0503(10g、33.6mmol)、CH3CN(400mL)、及び0305(6.8g、36.4mmol)の混合物を室温で撹拌した。次いでジイソプロピルエチルアミン(DIPEA)(220mL、1.26mol)を添加し、この溶液を終夜撹拌し、留去した。塩化メチレン(300mL)を加えた後、有機相を水洗し、Na2SO4上で脱水し、減圧下で濃縮して残渣を得た。この残渣に酢酸エチルを加え、この混合物を氷/水浴中で50分間撹拌した。標記生成物0504を白色固体として回収した(10.6g、70%)。LCMS: 449 [M+1]+。1HNMR (400 MHz, DMSO−d6): δ1.30 (t, J = 7.2 Hz, 3H), 3.25 (s, 3H), 3.71 (t, J = 5.2 Hz, 4H), 3.83 (t, J = 4.8 Hz, 4H), 4.29 (m, 2H), 5.21 (s, 2H), 7.39 (s, 1H), 8.87 (s, 2H)。
N−メチル−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ピリジン−2−アミン(0602−227)(351mg、1.5mmol)、0504(314mg、0.7mmol)、NaHCO3(176mg、2.1mmol)、及びPd(PPh3)2Cl2(24.6mg、0.035mmol)の混合物をトルエン/EtOH/H2O(2.5mL/1.6mL/0.7mL)に溶解した。次いでこの反応物をマイクロ波中、120℃で2時間撹拌した。この混合物に水(8mL)を加え、酢酸エチル(15mL×3)で抽出した。有機層を脱水し、濃縮し、カラムクロマトグラフィー(メタノール/ジクロロメタン、5%v/v)により精製して、標記化合物0603−111(150mg、41%)を白色固体として得た。LCMS: 521 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ1.28 (t, J = 7.2 Hz, 3H), 2.81 (d, J = 4.4 Hz, 3H), 3.24 (s, 3H), 3.73 (d, J = 4.4 Hz, 4H), 3.86 (d, J = 4.4 Hz, 4H), 4.27 (q, J = 7.2 Hz, 2H), 5.20 (s, 2H), 6.48 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 4.4 Hz, 1H), 7.39 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.86 (s, 2H), 8.90 (s, 1H)。
0603−236(150mg、0.29mmol)及び調製してすぐのヒドロキシルアミンメタノール溶液(6mL)から、実施例1に記載の手順と同様の手順を用いて、化合物2を褐色固体として調製した(21mg、14%)。融点:193〜195℃。LCMS: 508 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ2.83 (d, J = 4.8 Hz, 3H), 3.23 (s, 3H), 3.74 (m, 4H), 3.89 (m, 4H), 5.20 (s, 2H), 6.50 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 5.2 Hz, 1H), 7.39 (s, 1H), 8.27 (dd, J = 8.8, 2.0 Hz, 1H), 8.75 (s, 2H), 9.01 (d, J = 2.0 Hz, 1H), 9.07 (br, 1H)。
ステップ8a:N−(4−ブロモフェニル)アセトアミド(化合物0601−150)
0℃で、4−ブロモアニリン(6.3g、63.7mmol)のCH2Cl2(50mL)溶液に、塩化アセチル(3.75g、47.7mmol)及びTEA(7.4g、73.4mmol)を添加し、2時間撹拌した。この反応混合物を水、飽和食塩水で洗浄し、Na2SO4上で脱水し、ろ過し、減圧下で濃縮して、標記化合物0601−150(3.6g、46%)を褐色固体として得た。LCMS: 214 [M+1]+。1H NMR (400 MHz, DMSO−d6) δ2.05 (s, 3H), 7.46 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 10.12 (s, 1H)。
0601−150(2.0g、9.3mmol)、ビス(ピナコラト)ジボロン(4.4g、17.5mmol)、酢酸カリウム(3.5g、14mmol)、及びPdCl2(dppf)2(76mg、0.088mmol)から、化合物0602−107(実施例34)について記載した手順と同様の手順を用いて、標記化合物0602−150を白色固体として調製した(2.3g、94%)。LCMS: 262 [M+1]+。1H NMR (400 MHz, DMSO−d6) δ1.27 (d, J = 6.8 Hz, 12H), 2.04 (s, 3H), 7.58 (s, 4H), 10.03 (s, 1H)。
トルエン(4mL)、エタノール(2mL)、及び水(1mL)中の、化合物0504−54(210mg、0.46mmol)、0602−150(159mg、0.60mmol)、炭酸水素ナトリウム(118mg、1.4mmol)、及びビス(トリフェニルホスフィン)パラジウム(II)クロリド(17mg、0.02mmol)の混合物を窒素でフラッシュし、マイクロ波照射下、120℃で2時間加熱した。この反応混合物を酢酸エチルと水との間で分配させ、有機層を飽和食塩水で洗浄し、硫酸マグネシウム上で脱水し、ろ過し、減圧下で留去した。残渣をジクロロメタンで洗浄し、2−(((2−(4−アセトアミドフェニル)−4−モルホリノチエノ−[3,2−d]ピリミジン−6−イル)メチル)(メチル)アミノ)ピリミジン−5−カルボン酸エチル(136mg、53%)を白色固体として得た。LCMS: 548 [M+1]+。1H NMR (400 MHz, DMSO−d6): δ1.29 (t, J = 7.2 Hz, 3H), 2.06 (s, 6H), 3.26 (s, 3H), 3.75 (m, 4H), 3.91 (m, 4H), 4.28 (q, J = 7.2 Hz, 2H), 5.22 (s, 2H), 7.45 (s, 1H),7.67 (d, J = 8.8 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.87 (s, 1H), 10.10 (s, 1H)。
0603−150(170mg、0.3mmol)及び調製してすぐのヒドロキシルアミンメタノール溶液(4mL)から、実施例1に記載の手順と同様の手順を用いて、化合物3を黄色固体として調製した(43mg、26%)。融点:183〜186℃。
LCMS: 493 [M+1]+。1H NMR (400 MHz, DMSO−d6) δ 3.22 (s, 3H), 3.74 (m, 4H), 3.87 (m, 4H), 4.27 (q, J = 6.8 Hz, 2H), 5.20 (s, 2H), 5.50 (s, 2H), 6.59 (d, J = 8.8 Hz, 2H), 7.36 (s, 1H), 8.07 (d, J = 8.0 Hz, 2H), 8.86 (s, 2H)。
以下のアッセイを用いて、化合物1のPI3Kの種々のアイソフォーム及び変異体を阻害する能力を測定した。
PI3Kα活性をADP−Glo発光キナーゼアッセイを用いて測定した。N末端GSTタグ付き組換え全長ヒトp110αとタグなし組換全長ヒトp85αとの複合体であるPI3Kαを、バキュロウイルス感染Sf9細胞発現系において同時発現させた。(GenBank受入番号は、p110αがU79143、p85αがXM_043865である)。グルタチオン−アガロースを用いたワンステップアフィニティークロマトグラフィーにより上記タンパク質を精製した。競合アッセイを行って、精製した組換えPI3Kα(p110α/p85α)及びPIP2の存在下でATPから生成したADPの量を測定した。PI3Kαを、反応緩衝液(50mM HEPES、pH7.4、150mM NaCl、5mM MgCl2、3μM オルトバナジン酸Na、1mM DTT、10μM 超純粋ATP、及び0.5% DMSO)中で20μM PIP2基質と共に30℃で30分間インキュベートした。次いで反応中に生成したADPをADP−Gloアッセイにより測定した。このアッセイは2ステップで実施し、最初に等容量のADP−GLO(商標)Reagent(Promega)を添加してキナーゼ反応を停止させ、残ったATPを枯渇させた。第2のステップで、Kinase Detection Reagentを添加し、これは同時にADPをATPに変換もする。ルシフェラーゼ/ルシフェリン共役反応を用いて、新たに合成されたATPを測定した。このアッセイにおいて化合物1に関して測定されたIC50は100nM未満であった。
均一時間分解蛍光(HTRF)技術を利用した時間分解蛍光共鳴エネルギー移動(TR−FRET)アッセイを用いてPI3Kβの活性を測定した。N末端ヒスチジンタグ付き組換え全長ヒトp110βとタグなし組換え全長ヒトp85αとの複合体であるPI3Kβを、バキュロウイルス感染Sf21細胞発現系において同時発現させた。(GenBank受入番号は、p110βがNM_006219、p85αがXM_043865である)。グルタチオン−アガロースを用いたワンステップアフィニティークロマトグラフィーにより上記タンパク質を精製する。競合アッセイを行って、精製した組換えPI3Kβ(p110β/p85α)の存在下でPIP2から生成したPIP3の量を測定した。PI3Kβを反応緩衝液(20mM HEPES、pH7.5、10mM NaCl、4mM MgCl2、2mM DTT、10μM ATP、及び1% DMSO)中で10μM PIP2基質と共に30℃で30分間インキュベートした。次いでこの反応生成物をPIP3検出タンパク質、ユーロピウム標識抗体、ビオチン標識PIP3プローブ、及びアロフィコシアニン標識ストレプトアビジンと混合した。反応混合物中にセンサー複合体が形成され、安定なTR−FRETシグナルを発生する。このシグナル強度は、上記PIP3検出タンパク質に結合するビオチン標識プローブが酵素活性によって産生されるPIP3によって置換され、上記混合物中の未結合ビオチン標識PIP3プローブの量が増加するにつれて低下する。マイクロプレートリーダーを用い、バックグラウンドを差し引いてTR−FRETシグナルを測定した。
蛍光偏光アッセイを用いてPI3Kδの活性を測定した。N末端ヒスチジンタグ付き組換え全長ヒトp110δとタグなし組換え全長ヒトp85αとの複合体であるPI3Kδを、バキュロウイルス感染Sf9細胞発現系において同時発現させた。(p110δのGenBank受入番号はNM_005026である)。グルタチオン−アガロースを用いたワンステップアフィニティークロマトグラフィーにより上記タンパク質を精製する。競合アッセイを行って、精製した組換えPI3Kδ(p110δ/p85α)の存在下でPIP2から生成したPIP3の量を測定した。PI3Kδを反応緩衝液(20mM HEPES(pH7.5)、10mM NaCl、4mM MgCl2、2mM DTT、10μM ATP、及び1% DMSO)中で10μM PIP2基質と共に30℃で1時間インキュベートした。次いでこの反応生成物をPIP3検出タンパク質及び上記蛍光PIP3プローブと混合した。偏光(mP)値は、上記PIP3検出タンパク質に結合する蛍光プローブが酵素活性によって産生されるPIP3によって置換され、上記混合物中の未結合蛍光プローブの量が増加するにつれて低下する。マイクロプレートリーダーを用い、バックグラウンドを差し引いて偏光度(mP)の値を測定した。
均一時間分解蛍光(HTRF)技術を利用した時間分解蛍光共鳴エネルギー移動(TR−FRET)アッセイを用いてPI3Kγの活性を測定した。N末端ヒスチジンタグ付きヒトPI3Kδを、バキュロウイルス感染Sf9細胞発現系において発現させた。(GenBank受入番号はAF327656である)。グルタチオン−アガロースを用いたワンステップアフィニティークロマトグラフィーにより上記タンパク質を精製する。競合アッセイを行って、精製した組換えPI3Kγ(p120γ)の存在下でPIP2から生成したPIP3の量を測定した。PI3Kγ(2nM)を反応緩衝液(20mM HEPES、pH7.5、10mM NaCl、4mM MgCl2、2mM DTT、10μM ATP、及び1% DMSO)中で10μM PIP2基質と共に30℃で30分間インキュベートした。次いでこの反応生成物をPIP3検出タンパク質、ユーロピウム標識抗体、ビオチン標識PIP3プローブ、及びアロフィコシアニン標識ストレプトアビジンと混合した。反応混合物中にセンサー複合体が形成され、安定なTR−FRETシグナルを発生する。このシグナル強度は、上記PIP3検出タンパク質に結合するビオチン標識プローブが酵素活性によって産生されるPIP3によって置換され、上記混合物中の未結合ビオチン標識PIP3プローブの量が増加するにつれて低下する。マイクロプレートリーダーを用い、バックグラウンドを差し引いてTR−FRETシグナルを測定した。
Biomol Color de Lysシステム(AK−500, Biomol, Plymouth Meeting, PA)を用いてHDAC阻害活性を評価した。簡単に説明すると、HeLa細胞核抽出物をHDACの供給源として用いた。種々の濃度の被験化合物をジメチルスルホキシド(DMSO)で段階希釈し、比色人工基質の存在下でHeLa細胞核抽出物に添加した。最終的なアッセイ条件は、50mM Tris/Cl、pH8.0、137mM NaCl、2.7mM KCl、及び1mM MgCl2を含有していた。反応を室温(25℃)で1時間実施した後、停止用の現像液を添加した。相対的酵素活性を、WALLAC Victor II 1420マイクロプレートリーダーで蛍光強度として測定した(励起:350〜380nm、発光:440〜460nm)。GraphPad Prism(v4.0a)を用い、シグモイド用量反応曲線近似によりデータを解析して、IC50を算出した。このアッセイにおいて化合物1に関して測定されたIC50は100nM未満であった。
試薬
ベネトクラクス(ABT−199)はSelleck Chemicals(Houston, TX)から購入した。インビトロアッセイに関しては、化合物をジメチルスルホキシド(DMSO)に溶解して1000倍のストック液を作製し、−80℃で保存して1回のみ使用した。
DLBCL癌細胞株をアメリカ培養細胞系統保存機関(American TypeCulture Collection)(Manassas, VA)及びドイツ微生物細胞培養コレクション(German Collection of Microorganisms and Cell Cultures)(Braunschweig, Germany)から購入した。細胞を製造上の推奨に従って維持し、5% CO2の加湿雰囲気中、37℃でインキュベートした。増殖培地を2〜3日毎に交換し、細胞を2×106〜4×106細胞/mLの密度に維持した。指数関数的に増殖する細胞培養物を下記の全ての実験に用いた。
増殖アッセイに推奨される培養培地を用いて、細胞を96ウェル平底プレートに2×104の密度で播種した。次いで、細胞を、10%(v/v)のFBSを添加した培養培地中で、種々の濃度の表示した化合物と共に、表示した時間インキュベートした。CELLTITER−GLO(登録商標)Luminescent Cell Viability Assay (Promega, Madison, WI)を用いて細胞生存率を評価した。GraphPad Prism 5.0 (Graphpad Software, La Jolla, CA)を用いて曲線近似及びIC50の算出を行った。各実験について、2回の独立した実験を2回繰り返しで実施した。
薬物併用の相乗作用を、処理の24時間後の細胞増殖として得られた、用量−効果曲線に基づいて判定した。相乗性に対するそれぞれの薬剤の相対的な寄与を調べるために、ベネトクラクスの単独でのまたは固定した濃度の化合物1との併用での段階希釈液を試験した。相乗性、相加性、または拮抗を、式E(d1,d2)=E(d1)+E(d2)−E(d1)×E(d2)(式中、E(d1,d2)は、化合物1及びベネトクラクスの個々の効果E(d1)及びE(d2)によって予測される化合物1及びベネトクラクスの相加効果である)で定義されるBliss独立モデルによって判定した。
Charles River Laboratories(Wilmington, MA)から入手した6〜9週齢のメスの免疫不全Fox Chase SCID Beigeマウスの右後側腹部領域に100〜200μLの培地懸濁液中の5×106細胞を皮下注射した。平均の腫瘍の大きさが約100〜200mm3に達した時点で治療を開始した。化合物1を30% Captisol(ビヒクル1;Ligand Pharmaceuticals, Inc, La Jolla, CA)中で製剤化した。ベネトクラクスを、60% Phosal 50PG、30% PEG400、10% エタノール(ビヒクル2;Sigma Aldrich, St. Louis, MO)中で製剤化した。
異なる実験条件で治療した腫瘍において得られた値の間の差異は、GraphPad Prism 5.0(Graphpad Software)上でスチューデントt検定を用いて判定した。p<0.05を統計的に有意と見なした。
インビボDOHH2びまん性大細胞型B細胞リンパ腫モデルの結果を図2に示す。グラフAでは、ビヒクル対照、化合物1単独(50mg/kg)、ベネトクラクス単独(100mg/kg)、及び化合物1(50mg/kg)とベネトクラクス(100mg/kg)の併用を比較している。グラフBでは、ビヒクル対照、化合物1単独(初回用量100mg/kg、その後の用量75mg/kg)、ベネトクラクス単独(100mg/kg)、及び化合物1(初回用量100mg/kg、その後の用量75mg/kg)とベネトクラクス(100mg/kg)の併用を比較している。両方の実験において、化合物1とベネトクラクスの併用の効果は、各薬剤による単剤療法の結果に基づいて予測される相加効果よりも顕著に大きかった。
Charles River Laboratories(Wilmington, MA)から入手した7〜9週齢のメスの免疫不全Fox Chase SCID Beigeマウス(15〜24g)の右後側腹部領域に100μLの冷PBSの培地懸濁液中の5×106のSU−DHL−4細胞を皮下注射した。移植の29日後に治療を開始し、到達した平均の腫瘍の大きさは126mm3であった。化合物1を7.5mg/mLの濃度となるようにビヒクル1(30% Captisol)に溶解した。ベネトクラクス(ABT−199)を20mg/mLの濃度となるようにビヒクル2(60% Phosal 50PG、30% PEG400、10% エタノール)に溶解した。
異なる実験条件で治療した腫瘍において得られた値の間の差異は、GraphPad Prism 5.0(Graphpad Software)上でスチューデントt検定を用いて判定した。p<0.05を統計的に有意と見なした。
インビボSUD−HL4びまん性大細胞型B細胞リンパ腫モデルの結果を図3及び4に示す。図3では、ビヒクル対照(群A)、化合物1単独(群D)、ベネトクラクス単独(群F及びG)、ならびに化合物1とベネトクラクスの併用(群I及びJ)を比較している。図4では、ビヒクル対照(群B)、化合物1単独(群E)、ベネトクラクス単独(群F)、及び化合物1とベネトクラクスの併用(群K)を比較している。両方の実験において、化合物1とベネトクラクスの併用の効果は、各薬剤による単剤療法の結果に基づいて予測される相加効果よりも顕著に大きかった。
Claims (31)
- RがR1C(O)−であり、
但し、
R1は、置換もしくは非置換C1〜C24アルキル、置換もしくは非置換C2〜C24アルケニル、好ましくはC2〜C10アルケニル、より好ましくはC2〜C6アルケニル、置換もしくは非置換C2〜C24アルキニル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールである
請求項1に記載の方法。 - Rが水素またはアセチルである、請求項1に記載の方法。
- Rが水素である、請求項3に記載の方法。
- 前記BCL−2阻害剤が、ベネトクラクス、オバトクラクス、ナビトクラクス、サブトクラクス、ガンボギン酸、HA14−1、ABT−737、TW−37、AT101、及びそれらの薬学的に許容される塩からなる群より選択される、請求項1〜7のいずれか1項に記載の方法。
- 前記BCL−2阻害剤がベネトクラクスまたはその薬学的に許容される塩である、請求項8に記載の方法。
- 前記BCL−2阻害剤がベネトクラクスまたはその薬学的に許容される塩である、請求項7に記載の方法。
- (a)前記式Iの化合物及びBCL−2阻害剤が、前記対象に別個の組成物として同時に投与される、または
(b)前記式Iの化合物及びBCL−2阻害剤が、前記対象に別個の組成物として逐次的に投与される、
請求項1〜7及び10のいずれか1項に記載の方法。 - 前記式Iの化合物及びBCL−2阻害剤が単一の組成物で投与される、請求項1〜10のいずれか1項に記載の方法。
- 前記がんが血液がんである、請求項12に記載の方法。
- 前記がんが白血病またはリンパ腫である、請求項13に記載の方法。
- 前記リンパ腫がB細胞リンパ腫、T細胞リンパ腫、またはNK細胞リンパ腫である、請求項14に記載の方法。
- 前記リンパ腫がびまん性大細胞型B細胞リンパ腫である、請求項14に記載の方法。
- 前記がんが血液がんである、請求項10に記載の方法。
- 前記がんが白血病またはリンパ腫である、請求項17に記載の方法。
- 前記リンパ腫がB細胞リンパ腫、T細胞リンパ腫、またはNK細胞リンパ腫である、請求項17に記載の方法。
- 前記リンパ腫がびまん性大細胞型B細胞リンパ腫である、請求項18に記載の方法。
- RがR1C(O)−であり、
但し、
R1は、置換もしくは非置換C1〜C24アルキル、置換もしくは非置換C2〜C24アルケニル、好ましくはC2〜C10アルケニル、より好ましくはC2〜C6アルケニル、置換もしくは非置換C2〜C24アルキニル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールである、
請求項21に記載の医薬組成物。 - Rが水素またはアセチルである、請求項22に記載の医薬組成物。
- Rが水素である、請求項23に記載の医薬組成物。
- 前記BCL−2阻害剤が、ベネトクラクス、オバトクラクス、ナビトクラクス、サブトクラクス、ガンボギン酸、HA14−1、ABT−737、TW−37、AT101、及びそれらの薬学的に許容される塩からなる群より選択される、請求項21〜27のいずれか1項に記載の医薬組成物。
- 前記BCL−2阻害剤がベネトクラクスまたはその薬学的に許容される塩である、請求項27に記載の医薬組成物。
- 前記BCL−2阻害剤がベネトクラクスまたはその薬学的に許容される塩である、請求項28に記載の医薬組成物。
- 錠剤またはカプセル剤の形態である、請求項21〜30のいずれか1項に記載の医薬組成物。
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PCT/US2017/059464 WO2018085342A1 (en) | 2016-11-02 | 2017-11-01 | Combination therapy with a phosphoinositide 3-kinase inhibitor with a zinc binding moiety |
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EP3849554A4 (en) * | 2018-09-11 | 2022-06-01 | Curis, Inc. | POLYTHERAPY WITH A PHOSPHOINONOSITIDE 3-KINASE INHIBITOR HAVING A ZINC-BINDING METAL |
CN112778212B (zh) * | 2021-01-28 | 2022-03-15 | 苏州莱克施德药业有限公司 | 库潘尼西中间体2-胺基嘧啶-5-羧酸甲酯的合成方法 |
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JP2014509653A (ja) * | 2011-04-01 | 2014-04-21 | キュリス,インコーポレイテッド | 亜鉛結合部分を有するホスホイノシチド3−キナーゼインヒビター |
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US20130102595A1 (en) * | 2011-04-15 | 2013-04-25 | Curis, Inc. | Treatment of cancers having k-ras mutations |
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MX2019004842A (es) | 2019-06-20 |
CN109923117A (zh) | 2019-06-21 |
CA3040727A1 (en) | 2018-05-11 |
EP3535272A1 (en) | 2019-09-11 |
SG11201903723RA (en) | 2019-05-30 |
BR112019008698A2 (pt) | 2019-07-16 |
EA201991069A1 (ru) | 2019-10-31 |
US20180133223A1 (en) | 2018-05-17 |
KR20190077040A (ko) | 2019-07-02 |
MA46728A (fr) | 2019-09-11 |
IL266135A (en) | 2019-06-30 |
AU2020227036A1 (en) | 2020-09-17 |
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