JP2015505308A - 癌の治療のためのピペラジニル誘導体 - Google Patents
癌の治療のためのピペラジニル誘導体 Download PDFInfo
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- JP2015505308A JP2015505308A JP2014549488A JP2014549488A JP2015505308A JP 2015505308 A JP2015505308 A JP 2015505308A JP 2014549488 A JP2014549488 A JP 2014549488A JP 2014549488 A JP2014549488 A JP 2014549488A JP 2015505308 A JP2015505308 A JP 2015505308A
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- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 20
- 201000011510 cancer Diseases 0.000 title claims abstract description 20
- 238000011282 treatment Methods 0.000 title claims abstract description 13
- 125000004193 piperazinyl group Chemical group 0.000 title abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 14
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- 229940079593 drug Drugs 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 58
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 39
- -1 alkyl sulfonic acids Chemical class 0.000 claims description 35
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
- 125000005843 halogen group Chemical group 0.000 claims description 29
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
Description
本発明は、特に癌の治療に有用なピペラジニル化合物、それを含有する組成物およびそれらの製造方法に関する。
寿命が延びるにつれ、世界の死亡数の主因の一つである癌はますます多くの人々に影響を及ぼし、依然として治療が困難である。
Xは、(C1−C6)アルキル、フェニル、ベンジル、C(O)OR5またはC(O)NHR5基であり、
R1は、水素原子、またはC(O)H、C(O)R6もしくはC(O)OR6基であり、
R2は、水素原子または(C1−C6)アルキル基であるか、
あるいはR2は、R1またはXと共に、飽和炭化水素鎖を形成して、5員環または6員環、特に、5員環を形成し、
R3は、水素もしくはハロゲン原子、または(C1−C6)アルキルもしくは(C1−C6)アルコキシ基であり、
R4は、水素もしくはハロゲン原子、CN、NO2、または(C1−C6)アルキル、(C1−C6)アルコキシ、アリールオキシ、ベンジルオキシまたはヘテロアリールオキシ基であり、該基は1以上のハロゲン原子で置換されていてもよく、
Arは、チオフェニル基、または1以上のハロゲン原子で置換されていてもよいフェニル基であり、かつ
R5およびR6は、互いに独立して、(C1−C6)アルキル、アリール−(C1−C6)アルキルまたはアリール基であり、該基は1以上のハロゲン原子で置換されていてもよい]。
(1)水和物および溶媒和物、
(2)塩酸、臭化水素酸、硫酸、硝酸、およびリン酸などの無機酸を伴って形成される、または酢酸、ベンゼンスルホン酸、安息香酸、カンファースルホン酸、クエン酸、エタンスルホン酸、フマル酸、グルコヘプタン酸、グルコン酸、グルタミン酸、グリコール酸、ヒドロキシナフトエ酸、2−ヒドロキシエタンスルホン酸、乳酸、マレイン酸、リンゴ酸、マンデル酸、メタンスルホン酸、ムコン酸、2−ナフタレンスルホン酸、プロピオン酸、サリチル酸、コハク酸、ジベンゾイル−L−酒石酸、酒石酸、p−トルエンスルホン酸、トリメチル酢酸、およびトリフルオロ酢酸などの有機酸を伴って形成される酸付加塩(有利にはそれは塩酸である)、および
(3)親化合物中に存在する酸が金属イオン、例えば、アルカリ金属イオン(例えば、Na+、K+またはLi+)、アルカリ土類金属イオン(例えば、Ca2+またはMg2+)またはアルミニウムイオンで置換されているか、または有機または無機塩基が配位しているかのいずれかの場合に形成される塩
を含んでなる。許容される有機塩基は、ジエタノールアミン、エタノールアミン、N−メチルグルカミン、トリエタノールアミン、およびトロメタミンなどを含んでなる。許容される無機塩基は、水酸化アルミニウム、水酸化カルシウム、水酸化カリウム、炭酸ナトリウムおよび水酸化ナトリウムを含んでなる。
(i)上記で定義されるような少なくとも一つの式(I)の化合物および
(ii)少なくとも一つの他の有効成分
を、同時に、個別に、または時間差で使用するための組合せ物として含んでなる医薬組成物である。
a)下記式(II):
のアミンと、塩化クロロアセチルとを塩基の存在下で反応させて、R1≠Hである式(I)の化合物を得る工程、および
b)場合によりR1≠H基を有する窒素原子を脱保護して、R1=Hである式(I)の化合物を得る工程
を含んでなる方法に関する。
この工程に使用される塩基は、好ましくは、NaHCO3などの弱塩基である。
のピペラジンと、下記式(IV):
との酸との反応によって得ることができる。
i)下記式(V):
のケトエステルと、下式(VI):
のアニリンとを反応させて、下記式(VII):
のイミンを得る工程、
ii)前工程で得られた式(VII)のイミンを還元して、下記式(VIII):
のアミンを得る工程、
iii)前工程で得られた式(VIII)の化合物のエステル官能基を鹸化して、式(IV)の酸を得る工程
を用いて製造することができる。
この工程は好ましくは、HClなどの酸で処理することにより、CO2tBuなどのR1=CO2R6である式(I)の化合物を用いて行われる。
以下の節では、本発明の化合物の2つのジアステレオ異性体が分離された場合には、2つの異なる命名法が採用された。
・それぞれ単一のジアステレオ異性体の特定の構造を表すa/b
・それぞれ使用したクロマトグラフィー系で最小極性および最大極性のジアステレオ異性体を表すdia1/dia2
TLC 薄層クロマトグラフィー
DCM ジクロロメタン
DIEA ジイソプロピルエチルアミン
HBTU 2−(1H−ベンゾトリアゾール−1−yl)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスフェート
LCMS 質量分析計に連結した液体クロマトグラフィー
NMR 核磁気共鳴
RT 室温
アルゴン下、0℃で、DCM(200mL)中、塩化アルミニウム(21.13g、160mmol)の溶液に、塩化エチルオキサリル(17.9mL、160mmol)を10分間滴下した。この媒体を10分間振盪下に置いた。30mLのDCM中に希釈したフルオロベンゼン(14.7mL、160mmol)を0℃で滴下した。この媒体を室温で12時間、振盪下に置いた。媒体を水で洗浄し、有機相をMgSO4で乾燥させた。蒸発後、回収した油状物を、シクロヘキサン−酢酸エチル90:10で溶出するシリカゲルでのフラッシュクロマトグラフィーにより精製した。
黄色油状物を回収した(17.08g、54%)。
1H NMR (300 MHz, CDCl3):δ8.04-8.14 (m; 1.8 H); 7.15-7.24 (m; 1.9 H); 4.46 (q; J = 7.2 Hz; 2.0 H); 1.44 (t; J = 7.2 Hz; 3.0 H)。
トルエン(25mL)中、1(3.92g、20mmol)の溶液に、モレキュラーシーブの存在下で、パラ−トルエンスルホン酸(200 mg、1mmol)および4−フェノキシフェニル−アニリン(3.70g、20mmol)を順次加えた。この媒体を20時間、ディーンスターク装置中、還流下に置いた。この媒体を水で洗浄し、有機相をMgSO4で乾燥させた。蒸発後、回収した油状物を、シクロヘキサン−酢酸エチル90:10で溶出するフラッシュシリカゲルクロマトグラフィーにより精製した。
黄色油状物(6.27g、86%)の回収
LCMS [M+H] = 364 (C22H18FNO3)
メタノール(75mL)および酢酸(7.5mL)中、2(6.27g、17.26mmol)の溶液に、シアノ水素化ホウ素ナトリウム(1.63g、26mmol)を加えた。この媒体を室温で1時間、振盪下に置いた。メタノールを一部蒸発させ、この溶液を、必要であれば水を加えたNa2CO3で中和した。この媒体をDCMで抽出し、有機相をMgSO4で乾燥させた。蒸発後、回収した油状物をシクロヘキサン−酢酸エチル95:5で溶出するシリカゲルでのフラッシュクロマトグラフィーにより精製した。
黄色油状物の回収(5.91g、93%)。
LCMS [M+H] = 366 (C22H20FNO3)
1H NMR (300 MHz, CDCl3):δ7.45-7.54 (m; 1.9 H); 7.23-7.31 (m; 1.9 H); 6.97-7.11 (m; 2.9 H); 6.81-6.94 (m; 3.9 H); 6.54 (d; J = 9.0 Hz; 2.0 H); 5.01 (br; 1.0 H); 4.90 (br; 0.9 H); 4.10-4.32 (m; 2.0 H); 1.23 (t; J = 7.0 Hz; 3.0 H)。
130mLのアセトニトリル中、3(8.04g、22mmol)の溶液に、66mLの1M LiOH溶液(3当量)を加えた。この反応媒体を2〜3時間、振盪下に置き、反応の完了をTLC(シクロヘキサン−酢酸エチル60:40)で管理した。アセトニトリルを一部蒸発させ、この媒体を200mLの水を加えた1M HCl溶液で酸性化した。この媒体を濾過し、回収した固体を水中で3回洗浄し、乾燥オーブン中、P2O5の存在下で真空乾燥させた。
白色粉末の回収(7.17g、97%)。
LCMS [M+H] = 338 (C20H16FNO3)
1H NMR (300 MHz, DMSO):δ7.55 (dd; J = 8.5 Hz; J = 5.6 Hz; 2.1 H); 7.28 (t; J = 7.9 Hz; 2.1 H); 7.20 (t; J = 8.5 Hz; 2.1 H); 6.99 (t; J = 7.0 Hz; 1.1 H); 6.74-6.90 (m; 4.0 H; 6.62-6.70 (m; 2.0 H); 5.10 (s 1.0 H)。
DCM(150mL)中、1当量のDIEA(3.7mL)の存在下、4(7.17g、21.2mmol)の溶液に、50mLのDCM中、1当量のDIEA(3.7mL)の存在下、Boc−α−(S)−イソプロピル−ピペラジンヒドロクロリド(5.63g、21.26mmol)の溶液を、次いで、HBTU(8.06g、21.2mmol)を加えた。この媒体を12時間、振盪下に置いた。この媒体を水で洗浄し、有機相をMgSO4で乾燥させた。蒸発後、回収した油状物を、シクロヘキサン−酢酸エチル80:20で溶出するシリカゲルでのフラッシュクロマトグラフィーにより精製した。
白色泡沫の回収(11.90g、100%)。
LCMS [M+H] = 548 (C32H38FN3O4)
NaHCO3(7.30g、87.0mmol)の存在下、250mLのDCM中、5(11.86g、22.66mmol)の溶液に、塩化クロロアセチル(3.45mL、43.3mmol)を加えた。この媒体を12時間、振盪下に置いた。この媒体を水で洗浄し、有機相をMgSO4で乾燥させた。蒸発後、回収した油状物を、95−5’〜50−50のシクロヘキサン−酢酸エチル勾配を用いるシリカゲルでのフラッシュクロマトグラフィーにより精製し、無色の泡沫の形態で2種類のジアステレオ異性体を別個に得た。
(3.80g、28%)
LCMS [M+H] = 625 (C34H39ClFN3O5)
1H NMR (300 MHz, CDCl3):δ7.92-8.01 (m; 1.0 H); 7.30-7.40 (m; 2.0 H); 7.10-7.18 (m; 1.1 H); 7.01-7.09 (m; 1.1 H); 6.84-7.00 (m; 6.1 H); 6.55-6.65 (m; 1.1 H); 6.32-6.48 (m; 2.1 H); 4.72 (d; J = 13.5 Hz; 0.5 H) 4.63 (d; J = 13.5 Hz; 0.4 H); 3.52-3.96 (m; 4.0 H); 3.10-3.27 (m; 0.5 H); 2.85-3.07 (m; 0.4 H); 2.23-2.85 (m; 0.5 H + 0.7 H + 0.4 H); 1.87-2.14 (m; 0.6 H); 1.42 (s; 8.7 H); 1.17 (d; J = 6.6 Hz; 1.0 H); 1.03 (d; J = 6.6 Hz; 1.3 H); 0.88 (d; J = 6.6 Hz; 1.1 H); 0.69 (d; J = 6.6 Hz; 1.3 H)。
(3.29g、24%)
LCMS [M+H] = 625 (C34H39ClFN3O5)
1H NMR (300 MHz, CD2Cl2):δ7.85-8.00 (m; 1.0 H); 7.36 (t; J = 7.6 Hz; 2.1 H); 6.99-7.21 (m; 3.2 H); 6.81-6.98 (m; 5.2 H); 6.63 (br; 1.1 H); 6.35-65.5 (m; 2.1 H); 4.65 (d; J = 13.1 Hz; 0.6 H) 4.42 (d; J = 13.1 Hz; 0.3 H); 3.50-4.16 (m; 4.9 H); 3.00-3.43 (m; 0.9 H); 2.57-2.90 (m; 1.9 H); 1.98-2.18 (m; 0.7 H); 1.36-1.49 (m; 10.0 H); 1.73 (d; J = 6.5 Hz; 2.1 H); 0.90 (d; J = 6.5 Hz; 2.1 H); 0.63 (d; J = 6.5 Hz; 1.0 H); 0.20 (d; J = 6.5 Hz; 0.9 H)。
DCM(10mL)中、1当量のDIEA(131μL)の存在下、(4−フルオロ−フェニル)−(4−フェノキシ−フェニルアミノ)−酢酸4(253mg、0.75mmol)の溶液に、5mLのDCM中、1当量のDIEA(131μL)の存在下、Boc−α−(R)−イソプロピル−ピペラジン(171mg、0.75mmol)の溶液を、次いで、HBTU(285mg、0.75mmol)を加えた。この媒体を12時間、振盪下に置いた。この媒体を水で洗浄し、有機相をMgSO4で乾燥させた。蒸発後、回収した油状物を、シクロヘキサン−酢酸エチル80:20で溶出するシリカゲルでのフラッシュクロマトグラフィーにより精製した。
白色泡沫の回収(369mg、90%)。
LCMS [M+H] = 548 (C32H38FN3O4)
両ジアステレオ異性体を、実施例1(工程6)の製造と同様の操作様式に従って6から製造した。
最小極性ジアステレオ異性体(I−2 dia1)(195mg、42%)
LCMS [M+H] = 625 (C34H39ClFN3O5)
1H NMR (300 MHz, CD2Cl2):δ7.85-8.00 (m; 1.0 H); 7.36 (t; J = 7.6 Hz; 2.0 H); 6.99-7.21 (m; 3.1 H); 6.81-6.98 (m; 4.9 H); 6.63 (br; 1.0 H); 6.35-6.55 (m; 2.1 H); 4.65 (d; J = 13.0 Hz; 0.7 H) 4.42 (d; J = 13.0 Hz; 0.2 H); 3.50-4.16 (m; 4.9 H); 3.00-3.43 (m.; 0.8 H); 2.57-3.90 (m; 2.0 H); 1.98-2.18 (m; 0.8 H); 1.36-1.49 (m; 10.5 H); 1.73 (d; J = 6.5 Hz; 2.0 H); 0.90 (d; J = 6.5 Hz; 2.0 H); 0.63 (d; J = 6.5 Hz; 0.8 H);0.20 (d; J = 6.5 Hz; 0.8 H)。
LCMS [M+H] = 625 (C34H39ClFN3O5)
1H NMR (300 MHz, CDCl3):δ7.92-8.01 (m; 1.0 H); 7.30-7.40 (m; 2.0 H); 7.10-7.18 (m; 1.0 H); 7.01-7.09 (m; 1.1 H); 6.84-7.00 (m; 6.0 H); 6.55-6.65 (m; 1.1 H); 6.32-6.48 (m; 2.1 H); 4.72 (d; J = 13.5 Hz; 0.4 H) 4.63 (d; J = 13.5 Hz; 0.3 H); 3.52-3.96 (m; 4.7 H); 3.10-3.27 (m; 0.7 H); 2.85-3.07 (m; 0.5 H); 2.23-2.85 (m; 0.5 H + 0.6 H + 0.8 H); 1.87-2.14 (m; 0.9 H); 1.42 (s; 8.6 H); 1.17 (d; J = 6.6 Hz; 1.4 H); 1.03 (d; J = 6.6 Hz; 2.1 H); 0.88 (d; J = 6.6 Hz; 2.1 H); 0.69 (d; J = 6.6 Hz; 1.6 H)。
LCMS [M+H] = 524 (C29H32Cl2FN3O3)
1H NMR (300 MHz, DMSO):δ8.60-9.35 (m; 1.6 H); 7.77 (br; 0.8 H); 7.30-7.40 (m; 2.0 H); 7.00-7.23 (m; 5.1 H); 6.80-7.00 (m; 3.1 H); 6.54-6.76 (m; 3.0 H); 4.56 (d; J = 13.3 Hz; 1.0 H); 3.88-4.16 (m; 3.0 H); 3.00-3.30 (m; 3.1 H); 2.65-2.96 (m; 1.7 H); 1.52-2.00 (m; 1.6 H); 1.00 (t; J = 7.4 Hz; 2.4 H); 0.59 (dd; J = 15.6 Hz; J = 6.7 Hz; 3.5 H)。
LCMS [M+H] = 524 (C29H32Cl2FN3O3)
1H NMR (300 MHz, DMSO):δ8.65-9.6 (br; 1.2 H); 7.77 (br.; 0.8 H); 7.30-7.40 (m; 2.0 H); 6.36-7.25 (m; 11.7 H); 4.40-4.60 (m; 0.8 H); 4.00-4.12 (m; 2.0 H); 3.76-3.98 (m; 0.9 H); 3.37-3.63 (m; 0.9 H); 2.65-3.30 (m; 4.0 H); 1.77-2.06 (m; 1.6 H); 0.89-1.06 (m; 6.1 H)。
濾過後の白色粉末の回収:(95mg)
LCMS [M+H] = 524 (C29H32Cl2FN3O3)
1H NMR (300 MHz, DMSO):δ8.65-9.6 (br; 1.3 H).; 7.77 (br; 0.4 H); 7.30-7.40 (m; 2.0 H); 6.36-7.25 (m; 11.8 H); 4.40-4.60 (m; 0.9 H); 4.00-4.12 (m; 2.0 H); 3.76-3.98 (m; 1.0 H); 3.37-3.63 (m; 1.0 H); 2.65-3.30 (m; 3.8 H); 1.77-2.06 (m; 1.8 H); 0.89-1.06 (m; 6.1 H)。
濾過後の白色粉末の回収:(95mg)
LCMS [M+H] = 524 (C29H32Cl2FN3O3)
1H NMR (300 MHz, DMSO):δ8.60-9.35 (m; 1.7 H); 7.77 (br; 0.9 H); 7.30-7.40 (m; 2.0 H); 7.00-7.23 (m; 5.0 H); 6.80-7.00 (m; 3.0 H); 6.54-6.76 (m; 2.9 H); 4.56 (d; J = 13.3 Hz; 1.0 H); 3.88-4.16 (m; 3.0 H); 3.00-3.30 (m; 3.1 H); 2.65-2.96 (m; 1.7 H); 1.52-2.06 (m; 1.9 H); 1.00 (t; J = 7.2 Hz; 2.4 H); 0.59 (dd; J = 15.4 Hz; J = 6.7 Hz; 3.3 H)。
DCM(150mL)中、1当量のDIEA(4.6mL)の存在下、(4−フルオロ−フェニル)−(2−メチル−4−フェノキシ−フェニルアミノ)−酢酸(9.29g、26.4mmol)の溶液に、50mLのDCM中、1当量のDIEA(4.6mL)の存在下、Boc−α−(S)−イソプロピル−ピペラジンヒドロクロリド(7.00g、26.4mmol)の溶液を、次いで、HBTU(10.00g、26.4mmol)を加えた。この媒体を12時間、振盪下に置いた。この媒体を水で洗浄し、有機相をMgSO4で乾燥させた。蒸発後、回収した油状物を、シクロヘキサン−酢酸エチル80:20で溶出するシリカゲルでのフラッシュクロマトグラフィーにより精製した。
白色泡沫の改修(14.13g、95%)
LCMS [M+H] = 562 (C33H40FN3O4)
250mLのDCM中、NaHCO3(8.40g、100.0mmol)の存在下、8(14.13g、25.1mmol)の溶液に、塩化クロロアセチル(4.00mL、50.0mmol)を加えた。この媒体を12時間、振盪下に置いた。この媒体を水で洗浄し、有機相をMgSO4で乾燥させた。蒸発後、回収した油状物を、90:10から段階的に50:50とするシクロヘキサン−酢酸エチルで溶出するシリカゲルでのフラッシュクロマトグラフィーにより精製した。
最小極性ジアステレオ異性体(I−5 dia1)(3.83g、24%)
LCMS [M+H] = 639 (C35H41ClFN3O5)
1H NMR (300 MHz, CD2Cl2):δ7.94-8.57 (m; 1.0 H); 7.35 (t; J = 7.9 Hz; 2.0 H); 7.07-7.27 (m; 3.0 H); 6.74-6.95 (m; 5.0 H); 6.58 (br d; J = 2.6 Hz; 1.1 H); 6.51 (br s; 0.2 H); 6.41 (s; 0.8 H); 6.31 (br s; 0.3 H); 4.62 (d; J = 13.5 Hz; 0.7 H) 4.39 (d; J = 13.5 Hz; 0.3 H); 3.53-4.05 (m; 4.8 H); 3.04-3.46 (m; 0.8 H); 2.41-2.96 (m; 2.1 H); 2.04-2.23 (m; 0.8 H); 1.82-1.95 (m; 2.2 H); 1.43 (br s; 10.1 H); 1.07 (d; J = 6.5 Hz; 2.1 H); 0.90 (d; J = 6.5 Hz; 2.3 H); 0.63 (d; J = 6.5 Hz; 1.0 H); 0.29 (d; J = 6.5 Hz; 0.8 H)。
LCMS [M+H] = 639 (C35H41ClFN3O5)
1H NMR (300 MHz, CDCl3):δ8.00-8.10 (m; 1.0 H); 7.30-7.40 (m; 2.1 H); 6.98-7.18 (m; 3.2 H); 6.73-6.90 (m; 5.3 H); 6.52-6.58 (m; 1.0 H); 6.34-6.39 (m; 1.0 H); 4.71 (d; J = 13.5 Hz; 0.7 H); 4.49 (d; J = 13.5 Hz; 0.4 H); 3.50-4.00 (m; 4.7 H); 3.10-3.30 (m; 0.7 H); 2.86-3.07 (m; 0.4 H); 2.54-2.85 (m; 1.5 H); 2.30-2.47 (m; 0.4 H); 1.80-1.87 (m; 2.8 H); 1.54-1.60 (m; 2.5 H); 1.42 (br s; 8.8 H); 1.19 (d; J = 6.6 Hz; 1.1 H); 1.00 (d; J = 6.6 Hz; 1.5 H); 0.88 (d; J = 6.6 Hz; 1.2 H); 0.64 (d; J = 6.6 Hz; 1.5 H)。
LCMS [M+H] = 639 (C35H41ClFN3O5)
1H NMR (300 MHz, CD2Cl2):δ7.94-8.57 (m; 0.9 H); 7.35 (t; J = 7.9 Hz; 1.9 H); 7.05-7.25 (m; 3.1 H); 6.72-6.93 (m; 5.0 H); 6.58 (br d; J = 2.6 Hz; 1.1 H); 6.41 (s; 0.8 H); 6.31 (br s; 0.3 H); 4.63 (d; J = 13.5 Hz; 0.8 H) 4.40 (d; J = 13.5 Hz; 0.3 H); 3.51-4.06 (m; 4.8 H); 3.03-3.45 (m; 1.0 H); 2.41-2.96 (m; 1.6 H); 2.02-2.21 (m; 0.8 H); 1.82-1.95 (m; 2.1 H); 1.43 (br s; 10.1 H); 1.07 (d; J = 6.5 Hz; 2.1 H); 0.90 (d; J = 6.5 Hz; 2.3 H); 0.63 (d; J = 6.5 Hz; 1.0 H); 0.29 (d; J = 6.5 Hz; 0.8 H)。
LCMS [M+H] = 639 (C35H41ClFN3O5)
1H NMR (300 MHz, CDCl3):δ8.00-8.10 (m; 1.0 H); 7.30-7.40 (m; 2.1 H); 6.98-7.18 (m; 3.1 H); 6.73-6.90 (m; 5.1 H); 6.52-6.58 (m; 1.0 H); 6.34-6.39 (m; 1.0 H); 4.70 (d; J = 13.5 Hz; 0.7 H); 4.49 (d; J = 13.5 Hz; 0.4 H); 3.50-4.00 (m; 4.8 H); 3.10-3.30 (m; 0.7 H); 2.86-3.07 (m; 0.4 H); 2.54-2.85 (m; 1.5 H); 2.30-2.47 (m; 0.4 H); 1.80-1.87 (m; 2.8 H); 1.54-1.60 (m; 2.6 H); 1.42 (br s; 8.6 H); 1.20 (d; J = 6.6 Hz; 1.1 H); 1.01 (d; J = 6.6 Hz; 1.5 H); 0.89 (d; J = 6.6 Hz; 1.2 H); 0.64 (d; J = 6.6 Hz; 1.5 H)。
濾過後の白色粉末の回収:(26mg)
LCMS [M+H] = 538 (C30H34Cl2FN3O3)
1H NMR (300 MHz, DMSO):δ8.79-9.33 (m; 1.3 H); 7.83 (t; J = 9.0 Hz; 1.0 H); 7.24-7.40 (m; 4.0 H); 6.97-7.15 (m; 3.1 H); 6.73-6.89 (m; 3.2 H); 6.64 (d; J = 2.7 Hz; 0.9 H); 6.51-6.59 (m; 1.0 H); 4.40-4.55 (br m; 1.1 H); 3.86-4.09 (m; 3.6 H); 3.45-3.60 (m; 0.7 H); 2.78-3.05 (m; 2.8 H); 1.79-2.00 (m; 4.5 H); 1.61-1.77 (m; 0.7 H); 0.97 (d; J = 6.7 Hz; 6.0 H)。
濾過後の白色粉末の回収:(2.62g)
LCMS [M+H] = 538 (C30H34Cl2FN3O3)
1H NMR (300 MHz, DMSO) :δ8.78-9.51 (m; 1.9 H); 7.82 (t; J = 8.9 Hz; 0.9 H); 7.20-7.41 (m; 4.0 H); 6.97-7.16 (m; 3.1 H); 6.71-6.90 (m; 3.1 H); 6.61-6.70 (m; 1.9 H); 4.46-4.60 (br m; 1.0 H); 3.85-4.15 (m; 3.1 H); 3.00-3.30 (m; 3.0 H); 2.57-2.96 (m; 1.8 H); 1.43-1.98 (m; 4.3 H); 1.00 (dd; J = 8.8 Hz; J = 7.0 Hz; 2.7 H); 0.71 (d; J = 6.8 Hz; 1.6 H); 0.65 (d; J = 6.8 Hz; 1.5 H)。
濾過後の白色粉末の回収:(34mg、56%)
LCMS [M+H] = 538 (C30H34Cl2FN3O3)
1H NMR (300 MHz, DMSO):δ8.79-9.33 (m; 1.3 H); 7.83 (t; J = 9.0 Hz; 0.9 H); 7.24-7.40 (m; 4.0 H); 6.97-7.15 (m; 3.1 H); 6.73-6.89 (m; 3.1 H); 6.64 (d; J = 2.7 Hz; 1.0 H); 6.51-6.59 (m; 1.0 H); 4.41-4.56 (br m; 1.1 H); 3.86-4.09 (m; 3.4 H); 3.45-3.60 (m; 0.7 H); 2.78-3.05 (m; 2.8 H); 1.79-2.00 (m; 4.4 H); 1.61-1.77 (m; 0.8 H); 0.97 (d; J = 6.7 Hz; 6.0 H)。
濾過後の白色粉末の回収:(30mg、54%)
LCMS [M+H] = 538 (C30H34Cl2FN3O3)
1H NMR (300 MHz, DMSO):δ8.78-9.51 (m; 1.5 H); 7.82 (t; J = 8.9 Hz; 1.0 H); 7.20-7.41 (m; 4.0 H); 6.97-7.16 (m; 3.1 H); 6.71-6.90 (m; 3.2 H); 6.61-6.70 (m; 1.9 H); 4.46-4.60 (br m; 1.0 H); 3.85-4.15 (m; 3.1 H); 3.00-3.30 (m; 2.9 H); 2.57-2.96 (m; 1.8 H); 1.43-1.98 (m; 4.3 H); 1.00 (dd; J = 8.8 Hz; J = 7.0 Hz; 2.7 H); 0.71 (d; J = 6.8 Hz; 1.6 H); 0.65 (d; J = 6.8 Hz; 1.5 H)。
1)細胞傷害性試験
癌細胞の増殖に対する本発明の化合物の効果を、組織起源の異なる様々なヒト癌細胞株(MCF−7:乳癌、MCF−7/adr:アドリアマイシン耐性乳癌、HL−60:急性前骨髄球性白血病、HL−60/R10:ドキソルビシン耐性急性前骨髄球性白血病、HT29:結腸腺癌、Mia Paca2:膵臓腫瘍、Panc−1:膵外分泌腫瘍、SK−OV−3:シスプラチンおよびアドリアマイシン耐性卵巣癌)に対して検討した。本研究に用いた癌細胞を、種々の濃度で培養培地に加えた本発明の化合物の一つの存在下、37℃でインキュベートした。
水溶解度は、ある分子のADME特性(吸収、分布、代謝および排泄)を改善するための主要な物理化学的パラメーターである(Drug-like properties: concepts, structure design and methods, Edward Harvel Kerns, Li Di、 Academic Press, 2008)。
化合物の薬物動態挙動は、in vivo実験でのその合理的使用のための前提条件である。化合物をDMSO溶液として、静脈経路(IV)または経口経路(PO)でbalb/cマウスに与えた。5分〜6時間の範囲の複数の時点で血液サンプルを採取し、血漿を回収し、各サンプル中の化合物の濃度をLC/MS/MSによりアッセイした。得られたデータから、時間−濃度曲線のプロット、ならびに化合物の血漿半減期(T1/2)ある時点での曲線下面積(AUCt)および最大濃度(Cmax)などの基本パラメーターの決定がかのうであった。表6は、静脈経路を介して10mg/kgの用量で投与した化合物の薬物動態パラメーターに対してピペラジン置換が寄与した増加を示す。
Claims (17)
- 下記一般式(I)で表される化合物およびその薬学的に許容可能な塩、その立体異性体または任意の割合の立体異性体の混合物、特に鏡像異性体混合物、および特にラセミ混合物:
Xは、(C1−C6)アルキル、フェニル、ベンジル、C(O)OR5、またはC(O)NHR5基であり、
R1は、水素原子、またはC(O)H、C(O)R6もしくはC(O)OR6基であり、
R2は、水素原子または(C1−C6)アルキル基であるか、
あるいはR2は、R1またはXと共に、飽和炭化水素鎖を形成して、5員環または6員環、特に5員環を形成し、
R3は、水素もしくはハロゲン原子、または(C1−C6)アルキルもしくは(C1−C6)アルコキシ基であり、
R4は、水素もしくはハロゲン原子、CN、NO2、または(C1−C6)アルキル、(C1−C6)アルコキシ、アリールオキシ、ベンジルオキシまたはヘテロアリールオキシ基であり、該基は1以上のハロゲン原子で置換されていてもよく、
Arは、チオフェニル基、または1以上のハロゲン原子で置換されていてもよいフェニル基であり、および
R5およびR6は、互いに独立して、(C1−C6)アルキル、アリール−(C1−C6)アルキルまたはアリール基であり、該基は1以上のハロゲン原子で置換されていてもよい]。 - Arがチオフェニル基、または1以上のフッ素原子で置換されたフェニル基、例えば4−フルオロ−フェニルである、請求項1または2に記載の化合物。
- R4が水素もしくはハロゲン原子、または(C1−C6)アルキル、(C1−C6)アルコキシもしくはアリールオキシ基であり、該基が1以上のハロゲン原子、特にフッ素で置換されていてもよい、請求項1〜3のいずれか一項に記載の化合物。
- R3が水素原子または(C1−C6)アルキル基、例えばメチルである、請求項1〜4のいずれか一項に記載の化合物。
- Xが(C1−C6)アルキル、フェニル、またはベンジル基であり、R1およびR2が水素原子であり、R3が水素原子または(C1−C6)アルキル基、特に(C1−C3)アルキルであり、R4がハロゲン原子、または(C1−C6)アルキル、(C1−C6)アルコキシ、アリールオキシもしくはベンジルオキシ基であり、該基は1以上のハロゲン原子で置換されていてもよく、Arがチオフェニル基、またはフッ素原子で置換されていてもよいフェニル基、例えば4−フルオロ−フェニルであり、かつR5およびR6が互いに独立して、(C1−C6)アルキル、アリール−(C1−C6)アルキル、またはアリール基であり、該基は1以上のフッ素原子で置換されていてもよい、請求項1〜5のいずれか一項に記載の化合物。
- 薬物として使用するための、請求項1〜7のいずれか一項に記載の一般式(I)で表される化合物。
- 癌および化学療法耐性癌の治療または予防に用いるための、請求項1〜7のいずれか一項に記載の一般式(I)の化合物。
- 請求項1〜7のいずれか一項に記載の一般式(I)の少なくとも一つの化合物を、一以上の薬学的に許容可能な賦形剤とともに含んでなる、医薬組成物。
- 抗癌剤などの少なくとも一つの他の有効成分を含んでなる、請求項10に記載の医薬組成物。
- 有効成分が、シスプラチンおよびその誘導体(カルボプラチンおよびオキサリプラチンなど)、タキソール、タキソテール、パクリタキセルおよびドセタキセルなどのタキサン、ビンブラスチン、ビンクリスチンおよびビノレルビンなどのビンカアルカロイド、メルカプトプリン、チオグアニン、ペントスタチンおよび2−クロロデオキシアデノシンなどのプリン類似体、カンプトテシン化合物、例えばイリノテカンおよびトポテカンなどのトポイソメラーゼI阻害剤、エピポドフィロトキシン、ポドフィロトキシンおよびその誘導体(エトポシドおよびテニポシドなど)などのトポイソメラーゼII阻害剤、5−フルオロウラシル、ロイコボリン、ゲムシタビンまたはカペシタビンなどの抗腫瘍ヌクレオシド誘導体、ナイトロジェンマスタード(例えば、シクロホスファミド、メクロレタミン、クロラムブシルおよびメルファラン)、ニトロソ尿素(カルムスチン(carmustin)、ロムスチン(lomustin)およびストレプトゾシンなど)、アルキルスルホン酸(ブスルファン、エチレンイミンおよびメチルメラミン(チオテパおよびヘキサメチルメラミンなど))、ならびにテトラジン(ダカルバジンなど)などのアルキル化剤、ダウノルビシン、アドリアマイシン、ドキシル、イダルビシンおよびミトキサントロンなどの抗腫瘍アントラサイクリンの誘導体、ピクロポドフィリンなどのIGF−I受容体標的分子、テトロカルシンAなどのテトラカルシン誘導体、プレドニゾンなどのコルチコステロイド、トラスツズマブ(抗HER2抗体)、リツキシマブ(抗CD20抗体)、ゲムツザマブ(gemtuzamab)、セツキシマブ、ペルツズマブおよびベバシズマブなどの抗体、タモキシフェン、フルベストラント、トレミフェン、ドロロキシフェン、ファスロデックスおよびラロキシフェンなどのエストロゲン受容体の拮抗薬または選択的調節薬、エキセメスタン、アナストロゾール、レトロゾールおよびボロゾールなどのアロマターゼ阻害剤、レチノイド(例えば、レチノイン酸およびビタミンD)およびアキュテインなどのレチノイン酸の代謝遮断薬などの分化薬、アザシチジンおよびデシタビンなどのDNAメチルトランスフェラーゼ阻害剤、ペルメトレキセド(permetrexed)二ナトリウムなどの葉酸拮抗薬、アンチノマイシン(antinomycin)D、ブレオマイシン、マイトマイシンC、アクチノマイシンD、カルミノマイシン、ダウノマイシンおよびプリカマイシンなどの抗生物質、クロファラビン(chlofarabine)、アミノプテリン、シトシンアラビノシド、フロクスウリジンおよびメトトレキサートなどの代謝拮抗物質、YC 137、BH 312、ABT 737、ゴシポール、HA 14−1、TW 37およびデカン酸などのBcl−2阻害剤の、アポトーシス誘導薬および抗血管新生薬、コンブレスタチン、コルヒチン誘導体およびノコダゾールなどのチューブリン結合剤、フラボペリドール(flavoperidol)、メシル酸イマチニブ、エルロチニブおよびゲフィチニブなどのキナーゼ阻害剤、チピファルニブなどのファルネシルトランスフェラーゼ阻害剤、酪酸ナトリウム、ヒドロキサミン酸サブエロイルアニリド、デプシペプチド、NVP−LAQ824、R306465、JNJ−26481585およびトリコスタチンAなどのヒストンデアセチラーゼ阻害剤、MLN.41、ボルテゾミブおよびヨンデリスなどのユビキチン−プロテアソーム系阻害剤、およびテロメスタチンなどのテロメラーゼ阻害剤の中から選択される、請求項11に記載の医薬組成物。
- (i)請求項1〜7のいずれか一項に記載の少なくとも一つの式(I)で表される化合物および
(ii)抗癌剤などの少なくとも一つの他の有効成分
を、同時に、個別に、または時間差で使用するための組合せ物として含んでなる、医薬組成物。 - 有効成分が、シスプラチンおよびその誘導体(カルボプラチンおよびオキサリプラチンなど)、タキソール、タキソテール、パクリタキセルおよびドセタキセルなどのタキサン、ビンブラスチン、ビンクリスチンおよびビノレルビンなどのビンカアルカロイド、メルカプトプリン、チオグアニン、ペントスタチンおよび2−クロロデオキシアデノシンなどのプリン類似体、カンプトテシン化合物、例えばイリノテカンおよびトポテカンなどのトポイソメラーゼI阻害剤、エピポドフィロトキシン、ポドフィロトキシンおよびその誘導体(エトポシドおよびテニポシドなど)などのトポイソメラーゼII阻害剤、5−フルオロウラシル、ロイコボリン、ゲムシタビンまたはカペシタビンなどの抗腫瘍ヌクレオシド誘導体、ナイトロジェンマスタード(例えば、シクロホスファミド、メクロレタミン、クロラムブシルおよびメルファラン)、ニトロソ尿素(カルムスチン(carmustin)、ロムスチン(lomustin)およびストレプトゾシンなど)、アルキルスルホン酸(ブスルファン、エチレンイミンおよびメチルメラミン(チオテパおよびヘキサメチルメラミンなど))、ならびにテトラジン(ダカルバジンなど)などのアルキル化剤、ダウノルビシン、アドリアマイシン、ドキシル、イダルビシンおよびミトキサントロンなどの抗腫瘍アントラサイクリンの誘導体、ピクロポドフィリンなどのIGF−I受容体標的分子、テトロカルシンAなどのテトラカルシン誘導体、プレドニゾンなどのコルチコステロイド、トラスツズマブ(抗HER2抗体)、リツキシマブ(抗CD20抗体)、ゲムツザマブ(gemtuzamab)、セツキシマブ、ペルツズマブおよびベバシズマブなどの抗体、タモキシフェン、フルベストラント、トレミフェン、ドロロキシフェン、ファスロデックスおよびラロキシフェンなどのエストロゲン受容体の拮抗薬または選択的調節薬、エキセメスタン、アナストロゾール、レトロゾールおよびボロゾールなどのアロマターゼ阻害剤、レチノイド(例えば、レチノイン酸およびビタミンD)およびアキュテインなどのレチノイン酸の代謝遮断薬などの分化薬、アザシチジンおよびデシタビンなどのDNAメチルトランスフェラーゼ阻害剤、ペルメトレキセド(permetrexed)二ナトリウムなどの葉酸拮抗薬、アンチノマイシン(antinomycin)D、ブレオマイシン、マイトマイシンC、アクチノマイシンD、カルミノマイシン、ダウノマイシンおよびプリカマイシンなどの抗生物質、クロファラビン(chlofarabine)、アミノプテリン、シトシンアラビノシド、フロクスウリジンおよびメトトレキサートなどの代謝拮抗物質、YC 137、BH 312、ABT 737、ゴシポール、HA 14−1、TW 37およびデカン酸などのBcl−2阻害剤の、アポトーシス誘導薬および抗血管新生薬、コンブレスタチン、コルヒチン誘導体およびノコダゾールなどのチューブリン結合剤、フラボペリドール(flavoperidol)、メシル酸イマチニブ、エルロチニブおよびゲフィチニブなどのキナーゼ阻害剤、チピファルニブなどのファルネシルトランスフェラーゼ阻害剤、酪酸ナトリウム、ヒドロキサミン酸サブエロイルアニリド、デプシペプチド、NVP−LAQ824、R306465、JNJ−26481585およびトリコスタチンAなどのヒストンデアセチラーゼ阻害剤、MLN.41、ボルテゾミブおよびヨンデリスなどのユビキチン−プロテアソーム系阻害剤、およびテロメスタチンなどのテロメラーゼ阻害剤の中から選択される、請求項13に記載の医薬組成物。
- 癌の治療または予防、特に化学療法耐性癌の治療を意図する薬物として使用するための、請求項10〜14のいずれか一項に記載の医薬組成物。
- 下記の一連の工程を含んでなる、請求項16に記載の方法:
i)下記式(V)で表されるケトエステル:
と、下記式(VI)で表されるアニリン:
とを反応させて、下記式(VII)で表されるイミン:
を得る工程、
ii)前工程で得られた式(VII)で表されるイミンを還元して、下記式(VIII)で表されるアミン:
を得る工程、
iii)前工程で得られた式(VIII)で表される化合物のエステル官能基を鹸化して、下記式(IV)で表される酸:
を得る工程、
iv)前工程で得られた式(IV)で表される酸と、下記式(III)で表されるピペラジン:
とを反応させて、請求項16に記載の式(II)で表されるアミンを得る工程、
v)前工程で得られた式(II)で表されるアミンと、塩化クロロアセチルとを塩基の存在下で反応させて、R1≠Hである式(I)で表される化合物を得る工程、および
vi)場合により、R1≠H基を有する窒素原子を脱保護して、R1=Hである式(I)で表される化合物を得る工程。
Applications Claiming Priority (3)
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FR1162586A FR2985256B1 (fr) | 2011-12-30 | 2011-12-30 | Derives piperazinyles pour le traitement de cancers |
PCT/EP2012/077059 WO2013098393A1 (fr) | 2011-12-30 | 2012-12-28 | Derives piperazinyles pour le traitement de cancers |
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US20060058296A1 (en) * | 2003-12-24 | 2006-03-16 | Scios, Inc. | Treatment of osteolytic lesions associated with multiple myeloma by inhibition of p38 map kinase |
WO2010091164A1 (en) * | 2009-02-06 | 2010-08-12 | Exelixis, Inc. | Inhibitors of glucosylceramide synthase |
JP2011523956A (ja) * | 2008-06-13 | 2011-08-25 | シトミク システム | 癌の治療のために用いることができる化合物 |
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DE10358539A1 (de) * | 2003-12-15 | 2005-07-07 | Merck Patent Gmbh | Carbonsäureamidderivate |
MXPA06012394A (es) * | 2004-04-30 | 2007-01-31 | Bayer Pharmaceuticals Corp | Derivados de pirazolilurea sustituidos utiles en el tratamiento de cancer. |
US7615556B2 (en) * | 2006-01-27 | 2009-11-10 | Bristol-Myers Squibb Company | Piperazinyl derivatives as modulators of chemokine receptor activity |
JP2010526048A (ja) * | 2007-05-04 | 2010-07-29 | アストラゼネカ アクチボラグ | アミノ−チアゾリル−ピリミジン誘導体、および癌の治療のための該誘導体の使用 |
CA2760766A1 (en) * | 2009-05-21 | 2010-11-25 | Nicholas James Bennett | Novel pyrimidine derivatives and their use in the treatment of cancer and further diseases |
MX342951B (es) * | 2010-07-16 | 2016-10-18 | Agios Pharmaceuticals Inc * | Composiciones terapeuticamente activas y su metodo de uso. |
WO2012129452A2 (en) | 2011-03-22 | 2012-09-27 | University Of Southern California | Propynoic acid carbamoyl methyl-almides and pharmaceutical compositions and methods based thereon |
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Publication number | Priority date | Publication date | Assignee | Title |
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US20060058296A1 (en) * | 2003-12-24 | 2006-03-16 | Scios, Inc. | Treatment of osteolytic lesions associated with multiple myeloma by inhibition of p38 map kinase |
JP2011523956A (ja) * | 2008-06-13 | 2011-08-25 | シトミク システム | 癌の治療のために用いることができる化合物 |
WO2010091164A1 (en) * | 2009-02-06 | 2010-08-12 | Exelixis, Inc. | Inhibitors of glucosylceramide synthase |
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US20140356360A1 (en) | 2014-12-04 |
IL233414A0 (en) | 2014-08-31 |
NZ627149A (en) | 2015-08-28 |
RU2629115C2 (ru) | 2017-08-24 |
EP2797898B1 (fr) | 2016-09-14 |
FR2985256A1 (fr) | 2013-07-05 |
US9321778B2 (en) | 2016-04-26 |
CA2859721A1 (fr) | 2013-07-04 |
EP2797898A1 (fr) | 2014-11-05 |
BR112014015991A8 (pt) | 2017-07-04 |
IL233414A (en) | 2015-11-30 |
CA2859721C (fr) | 2020-01-07 |
HK1202118A1 (en) | 2015-09-18 |
FR2985256B1 (fr) | 2016-03-04 |
KR102086732B1 (ko) | 2020-03-09 |
KR20140117456A (ko) | 2014-10-07 |
CN104053648B (zh) | 2016-09-28 |
CN104053648A (zh) | 2014-09-17 |
EP2797898B9 (fr) | 2021-05-26 |
ES2606289T3 (es) | 2017-03-23 |
WO2013098393A1 (fr) | 2013-07-04 |
BR112014015991A2 (pt) | 2017-06-13 |
RU2014131001A (ru) | 2016-02-20 |
ZA201405068B (en) | 2015-11-25 |
BR112014015991B1 (pt) | 2022-11-16 |
AU2012360815A1 (en) | 2014-07-31 |
SG11201403727YA (en) | 2014-09-26 |
JP6105625B2 (ja) | 2017-03-29 |
AU2012360815B2 (en) | 2017-02-02 |
PL2797898T3 (pl) | 2017-03-31 |
HUE030951T2 (en) | 2017-06-28 |
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