JP2007291110A - 新規の有効な末端分化誘発剤およびその使用方法 - Google Patents
新規の有効な末端分化誘発剤およびその使用方法 Download PDFInfo
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- JP2007291110A JP2007291110A JP2007114876A JP2007114876A JP2007291110A JP 2007291110 A JP2007291110 A JP 2007291110A JP 2007114876 A JP2007114876 A JP 2007114876A JP 2007114876 A JP2007114876 A JP 2007114876A JP 2007291110 A JP2007291110 A JP 2007291110A
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- hydroxylamino
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- 238000000034 method Methods 0.000 title claims description 18
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Classifications
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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Abstract
Description
セベリン酸モノメチルエステル(1.9g;0.01mol)、塩化オキザロイル(1.75mL;2.54g;0.02mol)及び0.1mLのDMFのベンゼン(200mL)溶液を室温で一夜撹拌した。溶媒をエバポレートし、オイル状の残渣をクロロホルム(約20mL)に溶解し、o−ベンジルヒドロキシルアミン(2.46g;0.02mol)及びピリジン(1.6mL;1.68g;0.02mol)のクロロホルム(100mL)溶液と混合した。反応混合物を室温で一夜撹拌した。クロロホルム溶液を水(50mL)、10%塩酸、及び再度水(2×50mL)で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、エバポレートした。個体の残渣をヘキサン(約100mL)中でスラリーにし、濾過した。PhCH2ONHOC(CH2)6COOCH3の収率は2.61g(89%)であった。
(o−ベンジルヒドロキシルアミン(2.46g;0.02mol)、相当するアミン(0.02mol)及び塩化スベロイルのピリジン(500mL)溶液を室温で一夜撹拌した。溶媒をエバポレートし、半固体の残渣を1000mLのクロロホルム−メタノール(4:1)に溶解した。得られた溶液を水(2×100mL)10%塩酸(3×100mL)、及び再度水(2×100mL)で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、エバポレートした。固体の残渣をメタノール(100mL)に溶解し、5%Pd-Cを加えた。黒色の懸濁液を水素圧(約50psi)下で一夜振蘯した。触媒を濾過によって除き、濾液をエバポレートした。酢酸エチル−テトラヒドロフランを用いシリカゲルカラムクロマトグラフィーで標的化合物を単離した。
1H NMR(DMSO-D6,200MHz),δ(ppm)10.93(s,NHOCH3,1H);10.32(s,NHOH,1H);8.66(s,NHOH,1H);3.55(s,CH3,3H);1.91(t,J=7.6Hz,CH2CO-,4H);1.45(m,4H);1.20(m,4H)。
1H NMR(DMSO-D6,200MHz),δ(ppm)10.31(s,NHOH,1H);8.60(s,ブロード,NHOH,1H);7.57(d,J=7.6Hz,NH-C6H11,1H);3.40(m,CH-NH,1H);1.99(t,J=7Hz,CH2CONHC6H11,2H);1.91(t,J=7.6Hz,CH2CONHOH,2H);1.63(m,4H);1.44(m,4H);1.20(m,4H)。
1H NMR(DMSO-D6,200MHz),δ(ppm)10.31(s,NHOH,1H);8.67(s,ブロ一ド,NHOH,1H);2.85(d,J=30Hz,N(CH3)2,6H);2.24(t,J=7.4Hz,CH2CON(CH3),2H);1.91(t,J=7.4Hz,CH2COONHOH,2H);1.50(m,4H);1.20(m,4H)。
1H NMR(DMSO-D6,200MHz),δ(ppm)10.31(s,NHOH,1H);8.67(s,NHOH,1H);3.40(2t,CH2N,4H);2.20(t,J=7.4Hz,CH2CON(CH2)5,2H);1.91(t,J=7.4Hz,CH2CONOH,2H);1.10-1.60(m,ブロード,14H)。
二酸ジクロリド(diacid dichloride)(0.01mol)を、水酸化カリウム(1.12g;0.02mol)及び相当するアミン(0.01mol)の30mLテトラヒドロフラン−水(1:1)の冷混合溶液(0℃)に加えた。反応混合物を室温で約1時間撹拌し、溶媒をエバポレートし、固体の残渣をクロロホルム(300mL)及び水(300mL)の間で分配した。幾つかの場合には、すべての固体を溶解するのに小量のメタノールが必要である。有機層を10%水酸化カリウム(3×30mL)で洗浄した。塩基性の水抽出物を10%塩酸で酸性化した。沈殿を濾過によって集め、乾燥し、酢酸エチルからの結晶化、又は酢酸エチル−テトラヒドロフラン(4:1)によるシリカゲルカラムクロマトグラフィーで精製した。収率は20〜37%である。
2−、3−、及び4−シアノ;2−、3−、及び4−ニトロ;2−、3−、及び4−メチルシアノ;2−、3−、及び4−トリフルオロメチル;2−、3−、及び4−フルオロである。
o−ベンジルヒドロキシルアミン塩酸塩(3.2g;0.02mol)及び相当する二酸ジクロリド(0.04mol)のピリジン(500mL)懸濁液を室温で3日間撹拌した。水(10mL)を加え、撹拌を一夜続けた。溶媒をエバポレートし、固体の残渣を、テトラヒドロフラン−メタノールでシリカゲルカラムクロマトグラフィーにより精製した。二酸の生成物をメタノール(100mL)に溶解し、5%Pd-C(100mg)を加えた。反応懸濁液を水素圧(約50psi)下で一夜振蘯した。触媒を濾過によって除き、固体の残渣を熱メタノール(5×50mL)で洗浄した。メタノール性の濾液を合わせ、エバポレートした。固体の残渣をアセトン中でスリー化し、濾過した。収率は10〜20%であった。
o−ベンジルヒドロキシルアミン(2.46g;0.02mol)及び相当するジカルボン酸モノベンジルエステルモノ酸クロリド(0.04mol)のピリジン(500mL)溶液を室温で一夜撹拌した。溶媒をエバポレートした。半固体の残渣をクロロホルム(300mL)に溶解し、5%塩酸(2×50mL)、10水酸化カリウム(3×100mL)及び水(2×100mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、エバポレートした。固体の残渣を酢酸エチルでシリカゲルカラムクロマトグラフィーにより精製した。トリベンジル生成物をメタノール(100mL)に溶解し、5%Pd-C(100mg)を加えた。反応懸濁液を水素圧(約50psi)下室温で一夜振蘯した。固体を濾過によって除き、熱メタノール(5×50mL)で洗浄した。メタノール濾過液を合わせ、固体の残渣になるまでエバポレートした。該固体残渣を冷却したアセトンでスラリー化し、濾過した。標的化合物の収率は30〜60%であった。
二酸ジクロリド(0.01mol)を、水酸化カリウム(1.68g;0.03mol)ヒドロキシルアミン塩酸塩(0.7g;0.01mol)及び相当するアニリン(0.01mol)の50%テトラヒドロフラン(100mL)の撹拌溶液に加えた。得られた反応混合物を30分室温で撹拌し、溶媒を固体の残渣になるまでエバポレートした。この固体の浅渣をメタノール(約100mL)中でスラリー化し、無水硫酸マグネシウムで乾燥した。メタノール溶液を濾過によって分離し、固体の残渣になるまでエバポレートした。生成物を、酢酸エチル−テトラヒドロフラン(ほとんどの場合3:1)でシリカゲルカラムクロマトグラフィーにより生成した。
相当する二酸のモノメチルエステル(0.01mol)、塩化オキサリル(0.03mol)、及び数滴のDMFのベンゼン(500mL)溶液を室温で一夜撹拌した。溶媒をエバポレートし、オイル状の残渣を乾燥ベンゼン(3×50mL)に溶解し、再度エバポレートした。対応するジカルボン酸のモノエステルモノ酸クロリドのテトラヒドロフラン(50mL)溶液を相当するアミン(0.01mol)及びピリジン(1.6mL;1.6g;0.02mol)のテトラヒドロフラン(200mL)冷溶液に加えた。反応混合物を室温で1時間撹拌した。反応混合物を室温で1時間撹拌した。溶媒をエバポレートし、残渣をクロロホルム(300mL)に溶解し、クロロホルム溶液を10%塩酸(3×50mL)、10%水酸化カリウム(3×50mL)及び水(3×50mL)で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、エバポレートして純粋なジカルボン酸のモノエステルモノアミドを得た。生成物を水酸化カリウム(0.56g;0.01mol)を含有する80%メタノールに溶解した。反応混合物を2時間還流し、固体の残渣になるまでエバポレートした。残渣を水(約20mL)に溶解し、10%塩酸で約pH5に酸性化した。ジカルボン酸のモノ酸モノアミド(monoacid monoamide)を沈殿物の濾過、又はクロロホルムでの水溶液の抽出によって単離した。単離されたジカルボン酸のモノ酸モノアミドを、ピリジン(o−ベンジルヒドロキシルアミン0.01mol当たり約100mL)中において当量のo−ベンジルヒドロキシルアミン及び1,3−ジシクロヘキシルカルボシイミドと混合し、室温で一夜撹拌した。溶媒をエバポレートし、固体の残渣をクロロホルム(500mL)及び10%塩酸(300mL)の問で分配した。有機層を水(3×100mL)で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を固体の残渣になるまでエバポレートした。この固体の残渣を大量のテトラヒドロフランに溶解し、短いシリカゲルカラムを通して濾過した。粗生成物をメタノール(100mL)に溶解し、5%Pd-Cを加えた。反応懸濁液を水素圧(約50psi)下で一夜振蘯した。触媒を濾過によって分離し、濾液を固体の残渣になるまでエバポレートした。固体の残渣をヘキサン中でスラリー化し、濾過した。ほぼ純粋な生成物をこの方法で単離した。必要であれば、酢酸エチル−テトラヒドロフランを用いてシリカゲルカラムクロマトグラフィーで、更に精製を行った。収率は35%から65%であった。
o−ベンジルヒドロキシルアミン(1.23;0.01mol)、相当するアミン(0.01mol)、及びジカルボン酸ジクロリド(0.01mol)のピリジン(500mL)溶液を室温で一夜撹拌した。溶媒をエバポレートした。白色の固体残渣は、1H NMRの判定により、2種類の対称なアミン及び目的の非対称アミンを含有していた。固体の残渣をメタノール中でスラリー化し、無水硫酸マグネシウムで乾燥した。濾液をエバポレートし、固体の残渣をメタノール(約100mL)に溶解した。このメタノール溶液に、5%Pd-C(100mg)を加え、黒色の懸濁液を水素圧(約50psi)下で一夜振蘯した。触媒を濾過によって分離し、濾液をエバポレートした。生成物を酢酸エチル−テトラヒドロフランを用いたシリカゲルカラムクロマトグラフィーで単離した。収率は20から35%であった。
トリエチルアミン(3mL;2.18g;0.021.5mol)、相当するアミン(0.01mol)、o−(トリメチルシリル)ヒドロキシルアミン(1.05g、0.01mol)、及び相当するジカルボン酸の二酸クロリド(0.01mol)のクロロホルム溶液を室温で一夜撹拌した。溶媒をエバポレートし、残渣を、メタノール(約10mL)に溶解し、このメタノール溶液に、10%塩化アンモニウム(約10mL)を加えた。得られた懸濁液を50℃で2時間撹拌した。溶媒をエバポレートした。固体の残渣をメタノール(300mL)中でスラリー化し、無水硫酸マグネシウムで乾燥した。メタノール溶液を濾過によって分離し、固体の残渣になるまでエバポレートした。生成物を、酢酸エチル−テトラヒドロフランを用いシリカゲルカラムクロマトグラフィーで単離した。収率は20から33%であった。
実測値 63.58 7.59 10.48
1H NMR(DMSO-D6,200MHz),δ(ppm)10.31(s,NHOH,1H);9.83(s,NHPh,1H);8.64(s,NHOH,1H);7.57(d,J=8.2Hz,オルト芳香族プロトン,2H);7.26(t,J=8.4Hz,メタ芳香族プロトン,2H);6.99(t,パラ芳香族プロトン,2H);2.27(t,J=7.4Hz,CH2CONHPh,1H);1.93(t,J=7.2Hz,CH2CONHOH,2H);1.52(m,4H);1.26(m,4H)。
Claims (22)
- 請求項1に記載の化合物であって、XおよびYの夫々がヒドロキシル基であり、mおよびnの夫々が5である化合物。
- 下記構造を有する化合物。
- 下記構造を有する化合物。
- 請求項5に記載の化合物であって、XおよびYの夫々がヒドロキシルアミノ基であり;R1 がメチル基であり;R2 は水素原子であり;mおよびnの夫々が2である化合物。
- 請求項5に記載の化合物であって、XおよびYの夫々がヒドロキシルアミノ基であり;R1 がカルボニルヒドロキシルアミノ基であり;R2 は水素原子であり;mおよびnの夫々が5である化合物。
- 請求項5に記載の化合物であって、XおよびYの夫々がヒドロキシルアミノ基であり;R1 およびR2 の夫々がフルオロ基であり;mおよびnの夫々が2である化合物。
- 請求項9に記載の化合物であって、R1 はフェニルアミノ基であり、R2 はヒドロキシルアミノ基である化合物。
- 請求項11に記載の化合物であって、R1 はフェニルアミノ基であり、R2 はヒドロキシルアミノ基である化合物。
- 請求項13に記載の化合物であって、R1 はヒドロキシルアミノ基である化合物。
- 請求項13に記載の化合物であって、R2 はヒドロキシルアミノ基である化合物。
- 下記構造を有する化合物。
- 腫瘍性細胞の末端分化を選択的に誘導し、それによってかかる細胞の増殖を阻害するための薬学的組成物を製造する方法であって、前記薬学的組成物は、末端分化を選択的に誘導するために有効な請求項1,3,4,5,9,11,13または16に記載の化合物の有効量を含有する方法。
- 腫瘍性細胞の増殖を特徴とする腫瘍を有する患者を治療するための薬学的組成物を製造する方法であって、前記薬学的組成物は、末端分化を選択的に誘導するために有効な請求項1,3,4,5,9,11,13または16に記載の化合物の有効量を含有する方法。
- 腫瘍性細胞の末端分化を選択的に誘導し、それによってかかる細胞の増殖を阻害するための薬学的組成物であって、薬学的に許容可能なキャリアと、治療的に有効な量の請求項1,3,4,5,9,11,13または16に記載の化合物とを含有する組成物。
- 腫瘍性細胞の増殖を特徴とする腫瘍を有する患者を治療するための薬学的組成物であって、薬学的に許容可能なキャリアと、治療的に有効な量の請求項1,3,4,5,9,11,13または16に記載の化合物とを含有する組成物。
- 請求項19または20に記載の薬学的組成物であって、前記有効量が、患者において毒性を生じる量未満である組成物。
- 請求項19または20に記載の薬学的組成物であって、抗腫瘍剤と組合された組成物。
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CN106397102A (zh) * | 2016-08-29 | 2017-02-15 | 山东同成医药股份有限公司 | 卤代烃产品及其密封保温增压式生产方法 |
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RU2128643C1 (ru) | 1999-04-10 |
FI941537A0 (fi) | 1994-03-31 |
CA2120619C (en) | 2006-11-21 |
DE69229800T2 (de) | 2000-04-27 |
AU668696B2 (en) | 1996-05-16 |
ATE183185T1 (de) | 1999-08-15 |
US5369108A (en) | 1994-11-29 |
ES2134815T3 (es) | 1999-10-16 |
HU9400959D0 (en) | 1994-06-28 |
JP2003226680A (ja) | 2003-08-12 |
JP2008069158A (ja) | 2008-03-27 |
US5932616A (en) | 1999-08-03 |
DE69229800D1 (de) | 1999-09-16 |
KR100258680B1 (en) | 2000-05-15 |
EP0642509A1 (en) | 1995-03-15 |
CA2120619A1 (en) | 1993-04-15 |
WO1993007148A1 (en) | 1993-04-15 |
EP0642509B1 (en) | 1999-08-11 |
EP0642509A4 (en) | 1995-01-31 |
KR100263264B1 (ko) | 2000-08-01 |
US6087367A (en) | 2000-07-11 |
AU2870392A (en) | 1993-05-03 |
HUT67421A (en) | 1995-04-28 |
FI941537A (fi) | 1994-05-31 |
HU225497B1 (en) | 2007-01-29 |
JPH07502494A (ja) | 1995-03-16 |
JP3432823B2 (ja) | 2003-08-04 |
CL2008002943A1 (es) | 2009-03-06 |
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