JP2012531416A - ベンズアミド誘導体 - Google Patents
ベンズアミド誘導体 Download PDFInfo
- Publication number
- JP2012531416A JP2012531416A JP2012517571A JP2012517571A JP2012531416A JP 2012531416 A JP2012531416 A JP 2012531416A JP 2012517571 A JP2012517571 A JP 2012517571A JP 2012517571 A JP2012517571 A JP 2012517571A JP 2012531416 A JP2012531416 A JP 2012531416A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- benzo
- ylamino
- imidazol
- benzamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000003936 benzamides Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 153
- 238000000034 method Methods 0.000 claims description 71
- -1 —C 1 -C 6 alkyl Chemical group 0.000 claims description 49
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims description 6
- 125000001475 halogen functional group Chemical group 0.000 claims description 6
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 claims description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 5
- UQEANKGXXSENNF-UHFFFAOYSA-N 4-bromo-1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(Br)=CC=C1F UQEANKGXXSENNF-UHFFFAOYSA-N 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 4
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical group NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims description 3
- WNCBDFZWSJVVPA-UHFFFAOYSA-N 4-[(1-cyclobutylbenzimidazol-2-yl)amino]-n-hydroxybenzamide Chemical compound C1=CC(C(=O)NO)=CC=C1NC1=NC2=CC=CC=C2N1C1CCC1 WNCBDFZWSJVVPA-UHFFFAOYSA-N 0.000 claims description 3
- SHEGAJWJWIINNE-UHFFFAOYSA-N 4-[(1-cyclopentylbenzimidazol-2-yl)amino]-n-hydroxybenzamide Chemical compound C1=CC(C(=O)NO)=CC=C1NC1=NC2=CC=CC=C2N1C1CCCC1 SHEGAJWJWIINNE-UHFFFAOYSA-N 0.000 claims description 3
- DZYXQHXFIZSETE-UHFFFAOYSA-N 4-[(5-bromo-1-propan-2-ylbenzimidazol-2-yl)amino]-n-hydroxybenzamide Chemical compound N=1C2=CC(Br)=CC=C2N(C(C)C)C=1NC1=CC=C(C(=O)NO)C=C1 DZYXQHXFIZSETE-UHFFFAOYSA-N 0.000 claims description 3
- WLPCJHLDUCIDIR-UHFFFAOYSA-N 4-[(6-bromo-1-propan-2-ylbenzimidazol-2-yl)amino]-n-hydroxybenzamide Chemical compound N=1C2=CC=C(Br)C=C2N(C(C)C)C=1NC1=CC=C(C(=O)NO)C=C1 WLPCJHLDUCIDIR-UHFFFAOYSA-N 0.000 claims description 3
- SGZXWXJXWGMEAX-UHFFFAOYSA-N 4-[[4-fluoro-1-(2-methoxyethyl)benzimidazol-2-yl]amino]-n-hydroxybenzamide Chemical compound N=1C2=C(F)C=CC=C2N(CCOC)C=1NC1=CC=C(C(=O)NO)C=C1 SGZXWXJXWGMEAX-UHFFFAOYSA-N 0.000 claims description 3
- GDXZBBWPBOJICG-UHFFFAOYSA-N 4-[[5-(3-fluorophenyl)-1-(2-methoxyethyl)benzimidazol-2-yl]amino]-n-hydroxybenzamide Chemical compound N=1C2=CC(C=3C=C(F)C=CC=3)=CC=C2N(CCOC)C=1NC1=CC=C(C(=O)NO)C=C1 GDXZBBWPBOJICG-UHFFFAOYSA-N 0.000 claims description 3
- FKXHVSMXYMRBLC-UHFFFAOYSA-N 4-[[5-bromo-1-(2-methoxyethyl)benzimidazol-2-yl]amino]-n-hydroxybenzamide Chemical compound N=1C2=CC(Br)=CC=C2N(CCOC)C=1NC1=CC=C(C(=O)NO)C=C1 FKXHVSMXYMRBLC-UHFFFAOYSA-N 0.000 claims description 3
- AEFALECJWRUSKI-UHFFFAOYSA-N 4-[[5-bromo-1-[2-(dimethylamino)ethyl]benzimidazol-2-yl]amino]-n-hydroxybenzamide Chemical compound N=1C2=CC(Br)=CC=C2N(CCN(C)C)C=1NC1=CC=C(C(=O)NO)C=C1 AEFALECJWRUSKI-UHFFFAOYSA-N 0.000 claims description 3
- CYTWMDWNAUNSLF-UHFFFAOYSA-N 4-[[5-cyclopropyl-1-(2-methoxyethyl)benzimidazol-2-yl]amino]-n-hydroxybenzamide Chemical compound N=1C2=CC(C3CC3)=CC=C2N(CCOC)C=1NC1=CC=C(C(=O)NO)C=C1 CYTWMDWNAUNSLF-UHFFFAOYSA-N 0.000 claims description 3
- ZOJRGOYJBICCBI-UHFFFAOYSA-N 4-[[5-fluoro-1-(2-methoxyethyl)benzimidazol-2-yl]amino]-n-hydroxybenzamide Chemical compound N=1C2=CC(F)=CC=C2N(CCOC)C=1NC1=CC=C(C(=O)NO)C=C1 ZOJRGOYJBICCBI-UHFFFAOYSA-N 0.000 claims description 3
- JORHHCVLNRZFRD-UHFFFAOYSA-N 4-[[6-fluoro-1-(2-methoxyethyl)benzimidazol-2-yl]amino]-n-hydroxybenzamide Chemical compound N=1C2=CC=C(F)C=C2N(CCOC)C=1NC1=CC=C(C(=O)NO)C=C1 JORHHCVLNRZFRD-UHFFFAOYSA-N 0.000 claims description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- SSNCMIDZGFCTST-UHFFFAOYSA-N 1,3-difluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=C(F)C=CC=C1F SSNCMIDZGFCTST-UHFFFAOYSA-N 0.000 claims description 2
- KSUXYANQIKCARL-UHFFFAOYSA-N 1-fluoro-4-(methoxymethyl)-2-nitrobenzene Chemical compound COCC1=CC=C(F)C([N+]([O-])=O)=C1 KSUXYANQIKCARL-UHFFFAOYSA-N 0.000 claims description 2
- RJXOVESYJFXCGI-UHFFFAOYSA-N 2,4-difluoro-1-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1F RJXOVESYJFXCGI-UHFFFAOYSA-N 0.000 claims description 2
- USECIYVEPXUVHT-UHFFFAOYSA-N 2-propan-2-yloxyethanamine Chemical compound CC(C)OCCN USECIYVEPXUVHT-UHFFFAOYSA-N 0.000 claims description 2
- FAXDZWQIWUSWJH-UHFFFAOYSA-N 3-methoxypropan-1-amine Chemical compound COCCCN FAXDZWQIWUSWJH-UHFFFAOYSA-N 0.000 claims description 2
- VQCWSOYHHXXWSP-UHFFFAOYSA-N 4-bromo-2-fluoro-1-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Br)C=C1F VQCWSOYHHXXWSP-UHFFFAOYSA-N 0.000 claims description 2
- KZZKOVLJUKWSKX-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1CCC1 KZZKOVLJUKWSKX-UHFFFAOYSA-N 0.000 claims description 2
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 claims description 2
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 claims description 2
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 claims description 2
- ABMYEXAYWZJVOV-UHFFFAOYSA-N pyridin-3-ylboronic acid Chemical compound OB(O)C1=CC=CN=C1 ABMYEXAYWZJVOV-UHFFFAOYSA-N 0.000 claims description 2
- HZFPPBMKGYINDF-UHFFFAOYSA-N pyrimidin-5-ylboronic acid Chemical compound OB(O)C1=CN=CN=C1 HZFPPBMKGYINDF-UHFFFAOYSA-N 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims 5
- 229940125773 compound 10 Drugs 0.000 claims 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
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- VZYCZNZBPPHOFY-UHFFFAOYSA-N thioproperazine Chemical compound C12=CC(S(=O)(=O)N(C)C)=CC=C2SC2=CC=CC=C2N1CCCN1CCN(C)CC1 VZYCZNZBPPHOFY-UHFFFAOYSA-N 0.000 description 1
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- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
Description
Xにより表される基は、H、ハロ、−C1−C6アルキル、アリール、−C3−C7シクロアルキル又は−3から10員の複素環のいずれであってもよく、それらのいずれも、置換されていなくても又は1つ若しくは複数の以下の基で置換されていてもよい:−ハロ、−C1−C6アルキル、−O−(C1−C6アルキル)、−OH、−CN、−COOR’、−OC(O)R’、NHR’、N(R’)2、−NHC(O)R’又は−C(O)NHR’、ここでR’は−H又は−C1−C6アルキルであってよい。
Qにより表される基は、H、F又はClであってよい。
N−(2−アミノフェニル)−4−(1−イソプロピル−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミドの合成。(化合物ID#1)
イソプロピルアミン(3mL)を1−フルオロ−2−ニトロベンゼン(500mg、3.55mmol)のエタノール溶液に加える。反応液は、室温で終夜攪拌して濃縮することができる。残渣は、例えばBiotageカラムクロマトグラフィーにより精製することができて、N−イソプロピル−2−ニトロアニリン(590mg)が得られる。
実施例2
N−ヒドロキシ−4−(1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミドの合成(化合物ID#4)
2−メトキシエタンアミン(3mL)を1−フルオロ−2−ニトロベンゼン(400mg、2.84mmol)のエタノール溶液に加える。反応液は、室温で適当な時間(終夜など)攪拌して濃縮することができる。Biotageカラムクロマトグラフィーを含む任意の適当な方法により残渣を精製して、N−(2−メトキシエチル)−2−ニトロアニリン(477mg)を得ることができる。
実施例3
4−(5−ブロモ−1−イソプロピル−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミドの合成(化合物ID#6)
イソプロピルアミン(3mL)を4−ブロモ−1−フルオロ−2−ニトロベンゼン(700mg、3.18mmol)のエタノール溶液に加える。反応液を室温で終夜など適当な温度で適当な時間攪拌して濃縮することができる。Biotageカラムクロマトグラフィーなどの任意の適当な方法により残渣を精製して、4−ブロモ−N−イソプロピル−2−ニトロアニリン(770mg)を得ることができる。
実施例4
N−ヒドロキシ−4−(1−(2−メトキシエチル)−5−フェニル−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミドの合成。(化合物ID#8)
ジオキサンを、窒素雰囲気下で4−ブロモ−1−フルオロ−2−ニトロベンゼン(220mg、1.00mmol)、ベンゼンボロン酸(143mg、1.20mmol)、リン酸カリウム(636mg、3.00mmol)及びテトラキス(トリフェニルホスフィン)パラジウム(0)(55mg、0.05mmol)の混合物に加える。反応液を90°Cなどの適当な温度に加熱して、終夜などの適当な時間攪拌して濃縮することができる。濾液を濃縮して、Biotageカラムクロマトグラフィーにより精製し、4−フルオロ−3−ニトロビフェニル(200mg)を得ることができる。
実施例5
N−ヒドロキシ−4−(1−メチル−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド。(化合物ID#2)
該化合物は、メチルアミンを使用する以外は実施例2の合成方法にしたがって調製した。MS(M+lに対する計算値:283;実測値 283)
実施例6
4−(1−シクロブチル−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド。(化合物ID#3)
該化合物は、シクロブチルアミンを使用する以外は実施例2の合成方法にしたがって調製した。MS(M+lに対する計算値:323;実測値 323)。
4−(1−シクロペンチル−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド。(化合物ID#5)
該化合物は、シクロペンチルアミンを使用する以外は実施例2の合成方法にしたがって調製した。MS(M+lに対する計算値:337;実測値 337)。
4−(6−ブロモ−1−イソプロピル−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド。(化合物ID#7)
化合物は、4−ブロモ−2−フルオロ−1−ニトロベンゼンを使用する以外は実施例4の合成方法にしたがって調製した。MS(M+lに対する計算値:390;実測値 390)。
N−ヒドロキシ−4−(1−(3−メトキシプロピル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド。(化合物ID#9)
化合物は、3−メトキシプロパン−1−アミンを使用する以外は実施例2の合成方法にしたがって調製した。MS(M+lに対する計算値:341;実測値 341)。
4−(5−ブロモ−1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド。(化合物ID#10)
化合物は、2−メトキシエタンアミンを使用する以外は実施例3の合成方法にしたがって調製した。MS(M+lに対する計算値:406;実測値 406)。
N−ヒドロキシ−4−(1−(2−ヒドロキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド。(化合物ID#11)
化合物は、2−アミノエタノールを使用する以外は実施例2の合成方法にしたがって調製した。MS(M+lに対する計算値:313;実測値 313)。
4−(5−フルオロ−1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド。(化合物ID#12)
化合物は、1,4−ジフルオロ−2−ニトロベンゼンを使用する以外は実施例2の合成方法にしたがって調製した。MS(M+lに対する計算値:345;実測値 345)。
N−ヒドロキシ−4−(1−(2−イソプロポキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド。(化合物ID#13)
化合物は、2−イソプロポキシエタンアミンを使用する以外は実施例2の合成方法にしたがって調製した。MS(M+lに対する計算値:355;実測値 355)。
4−(5−(3−フルオロフェニル)−1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド。(化合物ID#14)
化合物は、l,5−ジフルオロ−2−ニトロベンゼンを使用する以外は実施例2の合成方法にしたがって調製した。MS(M+lに対する計算値:345;実測値 345)。
N−ヒドロキシ−4−(1−(2−メトキシエチル)−5−(ピリミジン−5−イル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド。(化合物ID#15)
化合物は、5−ピリミジンボロン酸及び2−メトキシエタンアミンを使用する以外は実施例4の合成方法にしたがって調製した。MS(M+lに対する計算値:405;実測値 405)。
4−(5−シクロプロピル−1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド。(化合物ID#16)
化合物は、シクロプロピルボロン酸及び2−メトキシエタンアミンを使用する以外は実施例4の合成方法にしたがって調製した。MS(M+lに対する計算値:367;実測値 367)。
4−(5−ブロモ−1−(2−(ジメチルアミノ)エチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド。(化合物ID#17)
化合物は、N1,N1−ジメチルエタン−1,2−ジアミンを使用する以外は実施例3の合成方法にしたがって調製した。MS(M+lに対する計算値:419;実測値 419)。
N−ヒドロキシ−4−(1−イソプロピル−5−(ピリミジン−5−イル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド。(化合物ID#18)
化合物は、3−ピリミジンボロン酸を使用する以外は実施例4の合成方法にしたがって調製した。MS(M+lに対する計算値:389;実測値 389)。
N−ヒドロキシ−4−(1−イソプロピル−5−(ピリジン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド。(化合物ID#19)
化合物は、3−ピリジンボロン酸を使用する以外は実施例4の合成方法にしたがって調製した。MS(M+lに対する計算値:388;実測値 388)。
N−(2−アミノフェニル)−4−(1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド。(化合物ID#20)
化合物は、2−メトキシエタンアミンを使用する以外は実施例1の合成方法にしたがって調製した。MS(M+lに対する計算値:402;実測値 402)。
4−(6−フルオロ−1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド。(化合物ID#21)
化合物は、2,4−ジフルオロ−1−ニトロベンゼンを使用する以外は実施例2の合成方法にしたがって調製した。MS(M+lに対する計算値:345;実測値 345)。
4−(4−フルオロ−1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド。(化合物ID#22)
化合物は、1,3−ジフルオロ−2−ニトロベンゼンを使用する以外は実施例2の合成方法にしたがって調製した。MS(M+lに対する計算値:345;実測値 345)。
N−ヒドロキシ−4−(1−イソプロピル−5−(メトキシメチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド。(化合物ID#23)
化合物は、1−フルオロ−4−(メトキシメチル)−2−ニトロベンゼンを使用する以外は実施例2の合成方法にしたがって調製した。MS(M+lに対する計算値:355;実測値 355)。
細胞傷害性及び化合物の細胞増殖に対する効果を評価するために、さまざまな濃度の上でリストを挙げた化合物の存在下の異なった時点における細胞生存率を使用した。細胞ラインSKOV3及びA2780における開示した化合物についてのIC50(又はパーセント活性)データを表1にまとめてある。
細胞増殖率(%)=(ftest/fvehicle)×100
式中、ftestは、試験した試料の蛍光であり、及びfvehicleは薬剤が溶解しているビヒクルの蛍光である。用量応答グラフ及びIC50値を以下の式を使用するソフトウェアPrism4(GraphPad)を使用して発生させた:
表1
実施例の化合物のSKOV3細胞及びA2780細胞におけるIC50(IC50、μM)
Claims (24)
- 式:
(式中、Xは、H、ハロ、−C1−C6アルキル、アリール、−C3−C7シクロアルキル、及び−3から10員の複素環からなる群から選択され;
Yは、H、−C1−C6アルキル、及び−C3−C7シクロアルキルからなる群から選択され;
Zは、メチル、−NH2、−NHOH、及び構造
のフェニレンジアミン基(II)
からなる群から選択され;及び
Qは、H、F及びClからなる群から選択される)
の化合物、並びに全てのそれらの薬学的に許容される塩、溶媒和物、及び化学的に保護された形体。 - 化合物が:
N−(2−アミノフェニル)−4−(1−イソプロピル−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド、
N−ヒドロキシ−4−(1−メチル−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド、
4−(1−シクロブチル−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド、
N−ヒドロキシ−4−(1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド、
4−(1−シクロペンチル−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド、
4−(5−ブロモ−1−イソプロピル−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド、
4−(6−ブロモ−1−イソプロピル−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド、
N−ヒドロキシ−4−(1−(2−メトキシエチル)−5−フェニル−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド、
N−ヒドロキシ−4−(1−(3−メトキシプロピル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド、
4−(5−ブロモ−1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド、
N−ヒドロキシ−4−(1−(2−ヒドロキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド、
4−(5−フルオロ−1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド、
N−ヒドロキシ−4−(1−(2−イソプロポキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド、
4−(5−(3−フルオロフェニル)−1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド、
N−ヒドロキシ−4−(1−(2−メトキシエチル)−5−(ピリミジン−5−イル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド、
4−(5−シクロプロピル−1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド、
4−(5−ブロモ−1−(2−(ジメチルアミノ)エチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド、
N−ヒドロキシ−4−(1−イソプロピル−5−(ピリミジン−5−イル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド、
N−ヒドロキシ−4−(1−イソプロピル−5−(ピリジン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド、
N−(2−アミノフェニル)−4−(1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド、
4−(6−フルオロ−1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド、
4−(4−フルオロ−1−(2−メトキシエチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)−N−ヒドロキシベンズアミド、及び
N−ヒドロキシ−4−(1−イソプロピル−5−(メトキシメチル)−1H−ベンゾ[d]イミダゾール−2−イルアミノ)ベンズアミド
からなる群から選択される、請求項1の化合物。 -
- 化合物1が1−フルオロ−2−ニトロベンゼンである、請求項3に記載の方法。
- 化合物1が4−ブロモ−1−フルオロ−2−ニトロベンゼンである、請求項3に記載の方法。
- 化合物1が2,4−ジフルオロ−1−ニトロベンゼンである、請求項3に記載の方法。
- 化合物1が1,3−ジフルオロ−2−ニトロベンゼンである、請求項3に記載の方法。
- 化合物1が1−フルオロ−4−(メトキシメチル)−2−ニトロベンゼンである、請求項3に記載の方法。
- 化合物8が4−ブロモ−1−フルオロ−2−ニトロベンゼンである、請求項3に記載の方法。
- 化合物8が4−ブロモ−2−フルオロ−1−ニトロベンゼンである、請求項3に記載の方法。
- 化合物9が2−メトキシエタンアミンである、請求項4に記載の方法。
- 化合物9がメチルアミンである、請求項4に記載の方法。
- 化合物9がシクロブチルアミンである、請求項4に記載の方法。
- 化合物9がシクロペンチルアミンである、請求項4に記載の方法。
- 化合物9が3−メトキシプロパン−1−アミンである、請求項4に記載の方法。
- 化合物9が2−アミノエタノールである、請求項4に記載の方法。
- 化合物9が2−イソプロポキシエタンアミンである、請求項4に記載の方法。
- 化合物9がN1,N1−ジメチルエタン−1,2−ジアミンである、請求項4に記載の方法。
- 化合物9がイソプロピルアミンである、請求項5に記載の方法。
- 化合物9が2−メトキシエタンアミンである、請求項5に記載の方法。
- 化合物10がベンゼンボロン酸である、請求項9に記載の方法。
- 化合物10が5−ピリミジンボロン酸である、請求項9に記載の方法。
- 化合物10がシクロプロピルボロン酸である、請求項9に記載の方法。
- 化合物10が3−ピリジンボロン酸である、請求項9に記載の方法。
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JP2017505793A (ja) * | 2014-02-11 | 2017-02-23 | バイエル・ファルマ・アクティエンゲゼルシャフト | mIDH1阻害剤としてのベンズイミダゾール−2−アミン |
JP2017533206A (ja) * | 2014-10-23 | 2017-11-09 | バイエル・ファルマ・アクティエンゲゼルシャフト | 腫瘍の治療のためのmidh1阻害剤としての1−シクロヘキシル−2−フェニルアミノベンゾイミダゾール |
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JP2018522838A (ja) * | 2015-06-08 | 2018-08-16 | バイエル・ファルマ・アクティエンゲゼルシャフト | mIDH1阻害剤としてのN−メンチルベンズイミダゾール |
JP2018522939A (ja) * | 2015-05-22 | 2018-08-16 | トランスレイショナル・ドラッグ・ディベロップメント・エルエルシー | ベンズアミドおよび活性化合物組成物および使用方法 |
JP2018524371A (ja) * | 2015-07-16 | 2018-08-30 | バイエル・ファルマ・アクティエンゲゼルシャフト | mIDH1阻害剤としての5−ヒドロキシアルキルベンズイミダゾール |
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JP2019535772A (ja) * | 2016-11-23 | 2019-12-12 | トランスレイショナル・ドラッグ・ディベロップメント・エルエルシー | ベンズアミドおよび活性化合物組成物および使用方法 |
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US10555935B2 (en) | 2016-06-17 | 2020-02-11 | Forma Therapeutics, Inc. | 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors |
KR102117083B1 (ko) * | 2018-10-30 | 2020-05-29 | 계명대학교 산학협력단 | 벤조헤테로사이클 화합물 및 이를 유효성분으로 함유하는 암질환 예방 또는 치료용 조성물 |
CN112209884B (zh) * | 2019-07-12 | 2022-11-11 | 杭州梯诺医药科技有限公司 | 1-h苯并咪唑衍生物、制备方法及其应用 |
WO2023247715A1 (de) * | 2022-06-24 | 2023-12-28 | Basf Se | Neue carboxy-liganden sowie deren verwendung in katalysatoren |
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JP2017505793A (ja) * | 2014-02-11 | 2017-02-23 | バイエル・ファルマ・アクティエンゲゼルシャフト | mIDH1阻害剤としてのベンズイミダゾール−2−アミン |
JP2017505790A (ja) * | 2014-02-11 | 2017-02-23 | バイエル・ファルマ・アクティエンゲゼルシャフト | mIDH1阻害剤としてのベンズイミダゾール−2−アミン |
JP2017533206A (ja) * | 2014-10-23 | 2017-11-09 | バイエル・ファルマ・アクティエンゲゼルシャフト | 腫瘍の治療のためのmidh1阻害剤としての1−シクロヘキシル−2−フェニルアミノベンゾイミダゾール |
JP2017533205A (ja) * | 2014-10-23 | 2017-11-09 | バイエル・ファルマ・アクティエンゲゼルシャフト | mIDH1阻害剤としてのベンゾイミダゾール−2−アミン |
JP7028765B2 (ja) | 2015-05-22 | 2022-03-02 | トランスレイショナル・ドラッグ・ディベロップメント・エルエルシー | ベンズアミドおよび活性化合物組成物および使用方法 |
JP2018522939A (ja) * | 2015-05-22 | 2018-08-16 | トランスレイショナル・ドラッグ・ディベロップメント・エルエルシー | ベンズアミドおよび活性化合物組成物および使用方法 |
JP2018522838A (ja) * | 2015-06-08 | 2018-08-16 | バイエル・ファルマ・アクティエンゲゼルシャフト | mIDH1阻害剤としてのN−メンチルベンズイミダゾール |
JP2018524371A (ja) * | 2015-07-16 | 2018-08-30 | バイエル・ファルマ・アクティエンゲゼルシャフト | mIDH1阻害剤としての5−ヒドロキシアルキルベンズイミダゾール |
JP2019511485A (ja) * | 2016-03-02 | 2019-04-25 | トランスレイショナル・ドラッグ・ディベロップメント・エルエルシー | アミノベンゾイミダゾール誘導体 |
JP2019535772A (ja) * | 2016-11-23 | 2019-12-12 | トランスレイショナル・ドラッグ・ディベロップメント・エルエルシー | ベンズアミドおよび活性化合物組成物および使用方法 |
JP7080234B2 (ja) | 2016-11-23 | 2022-06-03 | トランスレイショナル・ドラッグ・ディベロップメント・エルエルシー | ベンズアミドおよび活性化合物組成物および使用方法 |
JP2020533316A (ja) * | 2017-09-06 | 2020-11-19 | トランスレイショナル・ドラッグ・ディベロップメント・エルエルシー | アミノベンゾイミダゾール誘導体、治療、およびヒストン脱アセチル化酵素を阻害する方法 |
US11780816B2 (en) | 2017-09-06 | 2023-10-10 | Translational Drug Development, Llc | Aminobenzimidazole derivatives, treatments, and methods of inhibiting histone deacetylase |
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EP2445345A4 (en) | 2013-04-24 |
IL217183A0 (en) | 2012-02-29 |
HK1204227A1 (en) | 2015-11-13 |
CN104219954B (zh) | 2017-03-22 |
US20190084940A1 (en) | 2019-03-21 |
JP5868851B2 (ja) | 2016-02-24 |
US20120142922A1 (en) | 2012-06-07 |
US20150284336A1 (en) | 2015-10-08 |
EP2445345A1 (en) | 2012-05-02 |
US9464059B2 (en) | 2016-10-11 |
CA2766550A1 (en) | 2010-12-29 |
WO2010151441A1 (en) | 2010-12-29 |
CA2766550C (en) | 2017-04-11 |
US9125901B2 (en) | 2015-09-08 |
CN104219954A (zh) | 2014-12-17 |
EP2445345B1 (en) | 2014-08-27 |
AU2010263113B2 (en) | 2015-11-26 |
IL217183A (en) | 2015-02-26 |
AU2010263113A1 (en) | 2012-02-16 |
US20160362382A1 (en) | 2016-12-15 |
US10590088B2 (en) | 2020-03-17 |
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