CN101130539B - Indole-substituteing imidazoline-2-ketones derivant, preparing method and uses of the same - Google Patents
Indole-substituteing imidazoline-2-ketones derivant, preparing method and uses of the same Download PDFInfo
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Abstract
The invention discloses an indole to replace imidazoline-2-ketones derivant, which is characterized by the following: choosing natural product Combretastatin A-4 as lead compound; replacing ethene chain with imidazoline-2-ketone five-membered hetero ring; replacing benzene ring in CA-4 with indole ring; getting a series of imidazoline ketones derivant. This invention can be used to prepare antitumor agent, which possesses the function to inhibit tumor cell propagation and simple preparing method.
Description
Technical field
The invention belongs to compound, relate generally to the Preparation method and use of indole-substituteing imidazoline-2-ketones derivant.
Background technology
The beginning of the eighties; Chemical research worker Pettit group separates from the plant Combretum caffrum in Africa and has obtained a series of Combretastatin compound, and diarylvinylene compound CombretastatinA-1, A-2, A-3, A-4, A-5, A-6 are wherein arranged; Dibenzyl Compound C ombretastatinB-1, B-2, B-3, B-4; Combretastatin C-1; Macrocyclic lactone compounds Combretastatin D-1, D-2 and Phenathrene and Dihydrophenathrene.External inhibition activity of tumor cells experiment shows that these compounds all have higher activity (ED
50=0.003～18 μ g/mL).Therefore, the simplicity of its structure and make them more and more receive people's attention in the distinctive activity aspect the anti-tumor aspect especially drug-resistant tumor.
Combretastatin A-4 as active best, the simplest compound of structure in the Combretastatin family, has been separated with its co-worker by Pettit early than nineteen eighty-two and has identified structure.Research shows, its antitumor mechanism possibly be through combining to realize its antimitotic effect with tubulin quick; On the other hand, also there is this compound of research report to destroy tumor vessel by target, and the blood vessel of healthy tissues is not had destruction.Although CA-4 has cytotoxic activity and a microtubulin-resisting polymerization activity external; But CA-4 only shows more weak anti-tumor activity in the activity research in vivo as a kind of antimitotic agent; Chief reason is its poorly water-soluble; The cis-stilbene structural instability is prone to be isomerizated into transconfiguration.In view of these reasons, people have carried out continuous structural modification in the hope of obtaining the anti-tumor agent comprising salmosin of high-efficiency low-toxicity to it.Its prodrug phosphoric acid salt CA-4-P has been in during clinical II and III phase study.
Structure activity study shows that it is to keep the active most important condition that two phenyl ring in the CA-4 structure are in cis-configuration.Therefore people utilize stiffening ring substituted ethylene bridge chains such as tetra-atomic ring, five-ring, six-ring, fused heterocycle can keep certain activity to a great extent.In next CA-4 structure 3; 4; The 5-trimethoxyphenyl also is to keep the cytotoxic activity of height necessary, and another phenyl ring 3-hydroxyl-4-p-methoxy-phenyl can be by indyl, and heterocyclic substituted such as naphthyl can keep certain activity; In addition on this phenyl ring, introduce water soluble groups such as amino, activity increases to some extent.
The Chinese patent of this seminar " imidazole-2-ketone compound " application number 200410052976.X.; Utilize the bioisostere principle design that tetrahydroglyoxaline-2-ketone five-ring is introduced in the CA-4 structure; A series of imidazoline-2-ketones CA-4 analogues have been synthesized; And carried out preliminary pharmacology test; It is active that the result shows that this compounds has an obvious suppression tumor cell proliferation, is promising anti-tumor agent comprising salmosin, for the research of tumor treatment medicine provides new thinking.
Summary of the invention
The purpose of this invention is to provide one type of indole-substituteing imidazoline-2-ketones derivant, can be used for preparing anti-tumor drug.
The present invention is on the basis of 200410052976.X in one Chinese patent application number; In conjunction with the CA-4 structure activity relationship; Above-claimed cpd is made further structure of modification, and design is introduced the pharmacophore indole ring on the female ring of tetrahydroglyoxaline-2-ketone, to obtain water-soluble better and active better candidate compound.
The present invention to substituent change in the above-mentioned imidazoline-2-ketones compound molecule mainly is; With application number is that 3 substituted-phenyl is changed into the substituted indole ring in the compound structure that provides of 200410052976.X; And hydrogen base, substituted-phenyl carbamyl on 1 nitrogen-atoms changed into hydrogen base, formyl radical, ethanoyl, substituted indyl carbamyl, thereby a series of new indole-substituteing imidazoline-2-ketones derivants have been obtained.
Indole-substituteing imidazoline-2-ketones derivant provided by the invention has following general structure:
Wherein
R
1Be H, 2 or, 3 or 4-F, 2 or, 3 or 4-Cl, 2 or, 3 or 4-Br, 2 or, 3 or 4-NO
4, 2 or, 3 or
4-OC
2H
5、2?or?3?or?4-OCH
3、2?or?3?or?4-CH
3、2?or?3?or?4-OH、2?or?3?or
4-N(CH
3)
2、3，4-(OCH
3)
2、3-NO
2-4-OCH
3、3-NH
2-4-OCH
3、
3-NH
3 +Cl
--4-OCH
3、3-OH-4-OCH
3、3-OCH
3-4-OH、4-OH-3，5-(OCH
3)
2、
3，4，5-(OCH
3)
3；
R
2Be H, CHO, COCH
3, CONH-(1H-indole-5-yl),
CONH-(1-methyl-1H-indole-5-yl)、CONH-(1-benzyl-1H-indole-5-yl)；
R
3Be H, CH
3, Bn.
Another object of the present invention provides the preparation method of indole-substituteing imidazoline-2-ketones derivant, makes through following steps:
Reaction formula 1:
Above-mentioned reaction formula is the reaction formula that is used to prepare target compound IVa and IVb, and wherein compound I (replacing the alpha-aminoacetophenone hydrochloride) can make (M.C.Rebstock etal, J.A.C.S. through corresponding alpha-brominated methyl phenyl ketone; 1995,77,24-26); Compound I I (substituted 5-isocyanic ester-indoles) can make (W.A.Gregory et al through corresponding 5-amino indole and solid phosgene reaction; J.Med.Chem., 1989,32; 1673-1681), the cyclization dehydration reaction takes place and obtains target compound IVa and target compound IVb in compound I and compound III in the inert solvent under nitrogen protection.In reaction, used solvent can be benzene, toluene, and YLENE etc., temperature of reaction is generally between 80-140 ℃, and gained target compound IVa and IVb can get pure products through column chromatography.And then process physiologically acceptable salts such as hydrochloride, acetate, oxalate.Reaction formula 2:
Above-mentioned reaction formula is the reaction formula that is used to prepare target compound IVc, and wherein the preparation method of compound I and compound I I is the same, and compound III (replaces the alpha-acetamido-methyl phenyl ketone, R
2=COCH
3Replace α-formamido group methyl phenyl ketone, R
2=CHO) can through corresponding compounds I by literature method make (M.A.Ghassan et al, J.Heterocyclic Chem., 1987,24,297-301 & A.Jack et al, J.Org.Chem., 1986,51,3374-3376).The cyclization dehydration reaction takes place and obtains target compound IVc (R in compound I I and compound III in inert solvent under nitrogen protection
2=CHO, COCH
3).In reaction, used solvent can be benzene, toluene, and YLENE etc., temperature of reaction is generally between 80-140 ℃, and gained target compound IVc can get pure products through column chromatography.And then process physiologically acceptable salts such as hydrochloride, acetate, oxalate.
The 3rd purpose of the present invention provides the application of indole-substituteing imidazoline-2-ketones derivant in the preparation antitumor drug.Preliminary in-vitro screening finds that they are to various tumor cell strains; Comprise that human leukemia cell K562, people's cancer of the stomach SGC-7901, people's small cell carcinoma of lung A549, Human Prostate Cancer Cells PC-3 etc. all have the inhibition proliferation function, wherein majority of compounds is to the half-inhibition concentration (IC of various tumor cell lines
50) all reach μ M level, compare with Docetaxel with the positive control drug NSC-757., indivedual compound exhibits higher inhibition tumor cell proliferation active.
Characteristics of the present invention are to be lead compound with natural product CombretastatinA-4, utilize tetrahydroglyoxaline-2-ketone five-membered ring to replace its ethylene chain, a series of imidazolones derivs that obtain with phenyl ring among the indole ring replaced C A-4.This is the brand-new compound of a class formation, and preliminary pharmacological activity screening experiment shows that most compounds have the vitro inhibition proliferation function to tumour cell, and part of compounds has significant inhibition proliferation function, IC
50Reach μ M level.The present invention is reasonable in design, and the preparation method is easy, is suitable for practicality.
Embodiment
The present invention combines embodiment to be further described.Following embodiment is that explanation is of the present invention, rather than limits the present invention by any way.
The preparation of embodiment 1:1-(1H-indoles-5-yl)-5-(4-bromophenyl)-4-tetrahydroglyoxaline-2-ketone (compound IV a1)
0.53g (4mmol) 5-amino-1H-indoles, 4mL dry toluene are added in the reaction flask, and cryosel is bathed cooling, slowly splashes into by 0.79g solid phosgene and the formulated solution of 6mL dry toluene, drips and finishes; Nitrogen protection continued stirring reaction down after 1 hour, removed cryosel and bathed, and room temperature reaction is after 30 minutes; Slowly heat temperature raising is to refluxing, and after 4 hours, reaction soln becomes clarification; Add 4-bromo-alpha-aminoacetophenone hydrochloride 0.38g (2mmol), add dry toluene 10mL, reflux is spent the night.Cooling, decompression and solvent recovery, residue washs with chloroform 20mL * 2, merging filtrate, saturated NaCl solution washing, organic layer is used anhydrous Na
2SO
4After the drying, decompression and solvent recovery gets brown solid, and silica gel column chromatography separates (eluent: ETHYLE ACETATE: sherwood oil=1: 3), get yellow solid (compound IV a1), yield 29.5%.Fusing point: 170-172 ℃.
1H?NMR(δ，CDCl
3)：6.57(s，1H，indole?H)，7.21(s，1H，indole?H)，7.28-7.31(dd，1H，J＝1.6Hz，8.8Hz，indole?H)，7.38-7.40(d，1H，J＝8.8Hz，indole?H)，7.42-7.44(d，2H，J＝8.8Hz，aromatic?H)，7.56-7.59(d，2H，J＝8.8Hz，aromatic?H)，7.61(s，1H，imidazolin-2-one?H)，7.89-7.90(d，1H，J＝2.4Hz，indole?H)，8.21(s，1H，imidazolin-2-one?N-H)，9.86(s，1H，indole?N-H).
Embodiment 2:N, the preparation of 3-two (1H-indoles-5-yl)-4-(2,4 difluorobenzene base)-4-tetrahydroglyoxaline-2-ketone-1-methane amide (compound IV b1)
0.58g (4mmol) 5-amino-1H-indoles, 4mL dry toluene are added in the reaction flask, and cryosel is bathed cooling, slowly splashes into by 0.79g solid phosgene and the formulated solution of 6mL dry toluene, drips and finishes; Nitrogen protection continued stirring reaction down after 1 hour, removed cryosel and bathed, and room temperature reaction is after 30 minutes, and slowly heat temperature raising is to refluxing; After 4 hours, reaction soln becomes clarification, adds 2; 4-two fluoro-alpha-aminoacetophenone hydrochloride 0.38g (2mmol) add dry toluene 10mL, and reflux is spent the night.Cooling, suction filtration, filter cake washs with chloroform 20mL * 2, merging filtrate, saturated NaCl solution washing, organic layer is used anhydrous Na
2SO
4After the drying, decompression and solvent recovery gets the tawny solid, and silica gel column chromatography separates (eluent: ETHYLE ACETATE: sherwood oil=1: 3), get yellow solid (compound IV b1), yield 55.5%.Fusing point: 115-117 ℃.
1H?NMR(δ，CDCl
3)：6.55(s，2H，indole?H)，6.7?1-6.76(m，2H，indole?H)，6.99-7.07(m，3H，indole?H)，7.23(s，1H，indole?H)，7.29-7.41(m，4H，indole?H，aromatic?H×3)，7.52(s，1H，imidazolin-2-one?H)，7.98(s，1H，indole?H)，8.21(s，1H，indole?N-H)，8.37(s，1H，indole?N-H).10.77(s，1H，-O＝C-N-H-).
Embodiment 3:N, the preparation of 3-two (1H-indoles-5-yl)-4-(4-chloro-phenyl-)-4-tetrahydroglyoxaline-2-ketone-1-methane amide (compound IV b2)
Operating process and embodiment 2 just replace 2 with 4-chloro-alpha-aminoacetophenone hydrochloride, 4-two fluoro-alpha-aminoacetophenone hydrochlorides together.Obtain faint yellow solid (compound IV b2), yield 49.6%.Fusing point: 239-241 ℃.
1H?NMR(δ，DMSO-d
6)：5.57-5.59(d，1H，J＝8.0Hz，indole?H)，6.43-6.48(d，2H，J＝20?Hz，indole?H)，6.95-6.97(d，1H，J＝8.4?Hz，indole?H)7.15-7.20(d，2H，J＝8.8Hz，aromatic?H)，7.29-7.31(d，2H，J＝8.8Hz，aromatic?H)，7.37-7.39(d，2H，J＝6.0Hz，indole?H)，7.41-7.45(m，3H，indole?H×2，imidazolin-2-one?H)，7.55(s，1H，indole?H)，7.83(s，1H，indole?H)，10.77(s，1H，-O＝C-N-H-)，11.14(s，1H，indoleN-H)，11.37(s，1H，indole?N-H).
Embodiment 4:N, the preparation of 3-two (1-Methyl-1H-indole-5-yl)-4-(2,4 difluorobenzene base)-4-tetrahydroglyoxaline-2-ketone-1-methane amide (compound IV b3)
Operating process and embodiment 2 just replace 5-amino-1H-indoles with 1-methyl-5-amino-1H-indoles together.Obtain yellow solid (compound IV b3), yield 58.6%.Fusing point: 220-222 ℃.
1H?NMR(δ，CDCl
3)：3.78-3.80(d，6H，J＝6.4Hz，N-CH
3×2)，6.46-6.47(d，1H，J＝2.8Hz，indole?H)，6.68-6.78(m，2H，aromatic?H，indole?H)，7.02-7.05(dd，1H，J＝2.0Hz，8.8Hz，indole?H)，7.05-7.06(d，1H，J＝2.8Hz，indole?H)，7.10-7.11(d，2H，J＝3.2Hz，indole?H)，7.27-7.35(m，3H，aromatic?H，indole?H×2)，7.40(s，1H，imidazolin-2-one?H)，7.48-7.49(d，1H，J＝1.6Hz，indole?H)，7.95-7.96(d，1H，J＝2.0Hz，indole?H)，10.91(s，1H，-O＝C-N-H-).
Embodiment 5:N, the preparation of 3-two (1-Methyl-1H-indole-5-yl)-4-(4-chloro-phenyl-)-4-tetrahydroglyoxaline-2-ketone-1-methane amide (compound IV b4)
Operating process and embodiment 2 just replace 5-amino-1H-indoles with 1-methyl 5-amino-1H-indoles together, and 4-chloro-alpha-aminoacetophenone hydrochloride replaces 2,4-two fluoro-alpha-aminoacetophenone hydrochlorides.Obtain yellow solid (compound IV b4), yield 46.1%.Fusing point: 230-232 ℃.
1H?NMR(δ，CDCl
3)：3.78(s，3H，N-CH
3)，3.82(s，3H，N-CH
3)，6.46-6.47(d，1H，J＝2.8Hz，indole?H)，6.49-6.50(d，1H，J＝2.4Hz，indole?H)，7.01-7.03(dd，1H，J＝2.0Hz，8.8Hz，indole?H)，7.05-7.06(d，2H，J＝2.8Hz，aromatic?H)，7.06-7.07(s，1H，indole?H)，7.13-7.14(d，1H，J＝3.2Hz，indole?H)，7.17-7.19(d，2H，J＝2.0Hz，aromatic?H)，7.29(s，1H，indole?H)，7.31-7.32(d，1H，J＝2.0Hz，indole?H)，7.34(s，1H，indole?H)，7.36(s，1H，imidazolin-2-one?H)，7.53-7.54(d，1H，J＝2.0Hz，indole?H)，7.94-7.95(d，1H，J＝1.6Hz，indole?H)，10.88(s，1H，-O＝C-N-H-).
Embodiment 6:N, the preparation of 3-two (1-benzyl-1H-indoles-5-yl)-4-(2,4 difluorobenzene base)-4-tetrahydroglyoxaline-2-ketone-1-methane amide (compound IV b5)
Operating process and embodiment 2 just replace 5-amino-1H-indoles with 1-benzyl-5-amino-1H-indoles together.Obtain yellow solid (compound IV b5), yield 63.4%.Fusing point: 175-177 ℃.
1H?NMR(δ，CDCl
3)：5.28(s，2H，CH
2)，5.35(s，2H，CH
2)，6.44-6.45(d，1H，J＝3.6?Hz，indole?H)，6.60-6.61(d，1H，J＝3.6Hz，indole?H)，6.86-6.92(m，1H，aromatic?H)，6.96-6.99(m，2H，aromatic?H)，7.05-7.08(m，3H，aromatic?H)，7.15-7.19(m，5H，aromatic?H)，7.21-7.25(m，2H，aromatic?H)，7.27-7.34(m，5H，imidazolin-2-one?H，indole?H×4)，7.41-7.43(d，1H，J＝8.8Hz，indole?H)，7.68-7.69(d，1H，J＝2.0Hz，indole?H)，7.82(s，1H，indole?H)，7.95-8.01(m，1H，indole?H)，10.91(s，1H，-O＝C-N-H-).
Embodiment 7:N, the preparation of 3-two (1-benzyl-1H-indoles-5-yl)-4-(4-chloro-phenyl-)-4-tetrahydroglyoxaline-2-ketone-1-methane amide (compound IV b6)
Operating process and embodiment 2 just replace 5-amino-1H-indoles with 1-benzyl-5-amino-1H-indoles together, and 4-chloro-alpha-aminoacetophenone hydrochloride replaces 2,4-two fluoro-alpha-aminoacetophenone hydrochlorides.Obtain yellow solid (compound IV b6), yield 65.3%.Fusing point: 177-179 ℃.
1H?NMR(δ，CDCl
3)：5.22-5.24(d，4H，J＝7.6Hz，CH
2×2)，6.45-6.47(dd，2H，J＝2.8Hz，6.8Hz，indole?H)，6.87-6.89(d，1H，J＝8.8Hz，indole?H)，6.96-7.08(m，10H，aromatic?H，indole?H)，7.11-7.25(m，10H，aromatic?H，indole?H)，7.48(s，1H，imidazolin-2-one?H)，7.89(s，1H，indole?H)，10.78(s，1H，-O＝C-N-H-).
Embodiment 8:N, the preparation of 3-two (1-benzyl-1H-indoles-5-yl)-4-(4-bromophenyl)-4-tetrahydroglyoxaline-2-ketone-1-methane amide (compound IV b7)
Operating process and embodiment 2 just replace 5-amino-1H-indoles with 1-benzyl-5-amino-1H-indoles together, and 4-bromo-alpha-aminoacetophenone hydrochloride replaces 2,4-two fluoro-alpha-aminoacetophenone hydrochlorides.Obtain yellow solid (compound IV b7), yield 59.8%.Fusing point: 197-199 ℃.
1H?NMR(δ，CDCl
3)：5.30-5.33(d，4H，J＝8.8Hz，CH
2×2)，6.53-6.56(dd，2H，J＝3.2?Hz，8.8?Hz，indole?H)，6.95-7.00(m，3H，aromatic?H)，7.08-7.14(m，3H，aromatic?H)，7.19-7.20(d，1H，J＝3.6Hz，indole?H)，7.23-7.25(m，2H，aromatic?H)，7.26-7.27(m，3H，aromatic?H)，7.29-7.34(m，8H，aromatic?H，indole?H)，7.35(s，1H，imidazolin-2-one?H)，7.54-7.55(d，1H，J＝1.6Hz，indole?H)，7.96-7.97(d，1H，J＝1.6Hz，indole?H)，10.85(s，1H，-O＝C-N-H-).
The preparation of embodiment 9:1-ethanoyl-3-(1H-indoles-5-yl)-4-(2,4 difluorobenzene base)-4-tetrahydroglyoxaline-2-ketone (compound IV c1)
Operating process and embodiment 2 are with 2 together, and 4-two fluoro-alpha-acetamido-methyl phenyl ketones replace 2,4-two fluoro-alpha-aminoacetophenone hydrochlorides.Obtain yellow solid (compound IV c1), yield 53.2%.Fusing point: 198-200 ℃.
1H?NMR(δ，CDCl
3)：2.75(s，3H，O＝C-CH
3)，6.48-6.49(s，1H，indole?H)，6.65-6.77(m，2H，aromatic?H)，6.91-6.94(dd，1H，J＝2.0Hz，8.0?Hz，indole?H)，6.98-7.04(m，1H，indole?H)，7.19-7.21(m，1H，indole?H)，7.25-7.26(m，1H，indoleH)，7.28(s，1H，imidazoline?H)，7.44-7.45(d，1H，J＝1.2Hz，aromatic?H)，8.41(s，1H，indole?N-H).
The preparation of embodiment 10:1-ethanoyl-3-(1H-indoles-5-yl)-4-(4-chloro-phenyl-)-4-tetrahydroglyoxaline-2-ketone (compound IV c2)
Operating process and embodiment 2 just replace 2 with 4-chloro-alpha-acetamido-methyl phenyl ketone, 4-two fluoro-alpha-aminoacetophenone hydrochlorides together.Obtain yellow solid (compound IV c2), yield 43.2%.Fusing point: 222-224 ℃.
1H?NMR(δ，CDCl
3)：2.74(s，3H，O＝C-CH
3)，6.50(s，1H，indole?H)，6.89-6.90(d，1H，J＝1.6?Hz，indole?H)，7.02-7.04(d，2H，J＝8.0Hz，aromatic?H)，7.13-7.15(d，2H，J＝8.0Hz，aromatic?H)，7.21(s，2H，indole?H)，7.27-7.29(d，1H，J＝8.8?Hz，indole?H)，7.49(s，1H，imidazolin-2-one?H)，8.46(s，1H，indole?N-H).
The preparation of embodiment 11:1-ethanoyl-3-(1H-indoles-5-yl)-4-(4-bromophenyl)-4-tetrahydroglyoxaline-2-ketone (compound IV c3)
Operating process and embodiment 2 just replace 2 with 4-bromo-alpha-acetamido-methyl phenyl ketone, 4-two fluoro-alpha-aminoacetophenone hydrochlorides together.Obtain yellow solid (compound IV c3), yield 48.2%.Fusing point: 188-190 ℃.
1H?NMR(δ，CDCl
3)：2.73(s，3H，O＝C-CH
3)，6.53(s，1H，indole?H)，6.91-6.94(dd，1H，J＝2.0Hz，8.4Hz，indole?H)，6.96-6.98(d，2H，J＝8.8Hz，aromatic?H)，7.22(s，2H，indole?H)，7.29-7.32(d，2H，J＝8.8Hz，aromatic?H)，7.32(s，1H，indoleH)，7.50(s，1H，imidazolin-2-one?H)，8.38(s，1H，indole?N-H).
The preparation of embodiment 12:1-ethanoyl-3-(1H-indoles-5-yl)-4-(3, the 4-Dimethoxyphenyl)-4-tetrahydroglyoxaline-2-ketone (compound IV c4)
Operating process and embodiment 2 are with 3 together, and 4-dimethoxy-alpha-acetamido-methyl phenyl ketone replaces 2,4-two fluoro-alpha-aminoacetophenone hydrochlorides.Obtain yellow solid (compound IV c4), yield 5 1.2%.Fusing point: 117-119 ℃.
1H?NMR(δ，CDCl
3)：2.74(s，3H，O＝C-CH
3)，3.47(s，3H，OCH
3)，3.80(s，3H，OCH
3)，6.5?1-6.53(dd，2H，J＝2.0Hz，6.0Hz，indole?H)，6.67-6.75(m，2H，aromatic?H)，6.96-6.99(dd，1H，J＝2.0Hz，8.8Hz，indole?H)，7.16(s，1H，aromaticH)，7.23-7.24(m，1H，indole?H)，7.34-7.35(d，1H，J＝8.8Hz，indole?H)，7.52(s，1H，imidazolin-2-one?H)，8.35(s，1H，indole?N-H).
The preparation of embodiment 13:1-ethanoyl-3-(1H-indoles-5-yl)-4-(4-p-methoxy-phenyl)-4-tetrahydroglyoxaline-2-ketone (compound IV c5)
Operating process and embodiment 2 just replace 2 with 4-methoxyl group-alpha-acetamido-methyl phenyl ketone, 4-two fluoro-alpha-aminoacetophenone hydrochlorides together.Obtain yellow solid (compound IV c5), yield 43.2%.Fusing point: 155-157 ℃.
1H?NMR(δ，CDCl
3)：2.73(s，3H，O＝C-CH
3)，3.80(s，3H，OCH
3)，6.51(s，1H，indole?H)，6.69-6.71(d，2H，J＝8.8Hz，aromatic?H)，6.92-6.96(m，2H，indole?H)，7.02-7.05(d，2H，J＝8.8Hz，aromatic?H)，7.13(s，1H，indole?H)，7.22-7.23(m，1H，indole?H)，7.51(s，1H，imidazolin-2-one?H)，8.38(s，1H，indole?N-H).
The preparation of embodiment 14:1-ethanoyl-3-(1-Methyl-1H-indole-5-yl)-4-(4-chloro-phenyl-)-4-tetrahydroglyoxaline-2-ketone (compound IV c6)
Operating process and embodiment 2 just replace 5-amino-1H-indoles with 1-methyl 5-amino-1H-indoles together, and 4-chloro-alpha-acetamido-methyl phenyl ketone replaces 2,4-two fluoro-alpha-aminoacetophenone hydrochlorides.Obtain yellow solid (compound IV c6), yield 51.4%.Fusing point: 159-161 ℃.
1H?NMR(δ，CDCl
3)：2.73(s，3H，O＝C-CH
3)，3.81(s，3H，N-CH
3)，6.46-6.47(d，1H，J＝2.8Hz，indole?H)，6.47-6.96(dd，1H，J＝2.0Hz，8.0Hz，indole?H)，6.96-6.98(d，2H，J＝8.8Hz，aromatic?H)，7.04-7.05(d，1H，J＝2.4Hz，indole?H)，7.13-7.15(d，2H，J＝8.8Hz，aromatic?H)，7.21(s，1H，imidazolin-2-one?H)，7.28-7.30(d，1H，J＝8.0Hz，indole?H)，7.38-7.39(d，1H，J＝1.6Hz，indole?H).
The preparation of embodiment 15:1-ethanoyl-3-(1-Methyl-1H-indole-5-yl)-4-(4-bromophenyl)-4-tetrahydroglyoxaline-2-ketone (compound IV c7)
Operating process and embodiment 2 just replace 5-amino-1H-indoles with 1-methyl 5-amino-1H-indoles together, and 4-bromo-alpha-acetamido-methyl phenyl ketone replaces 2,4-two fluoro-alpha-aminoacetophenone hydrochlorides.Obtain yellow solid (compound IV c7), yield 49.5%.Fusing point: 192-194 ℃.
1H?NMR(δ，CDCl
3)：2.73(s，3H，O＝C-CH
3)，3.80(s，3H，N-CH
3)，6.46-6.47(d，1H，J＝2.8Hz，indole?H)，6.96-6.98(m，3H，aromatic?H，indole?H)，7.10-7.11(d，1H，J＝2.8Hz，indole?H)，7.21(s，1H，indole?H)，7.29-7.31(m，3H，aromatic?H，imidazolin-2-one?H)，7.47-7.48(d，1H，J＝8.8Hz，indole?H).
The preparation of embodiment 16:1-ethanoyl-3-(1-Methyl-1H-indole-5-yl)-4-(3, the 4-Dimethoxyphenyl)-4-tetrahydroglyoxaline-2-ketone (compound IV c8)
Operating process and embodiment 2 just replace 5-amino-1H-indoles with 1-methyl 5-amino-1H-indoles together, and 3,4-dimethoxy-alpha-acetamido-methyl phenyl ketone replaces 2,4-two fluoro-alpha-aminoacetophenone hydrochlorides.Obtain yellow solid (compound IV c8), yield 45.6%.Fusing point: 135-137 ℃.
1H?NMR(δ，CDCl
3)：2.75(s，3H，O＝C-CH
3)，3.51(s，3H，OCH
3)，3.81(s，6H，OCH
3，N-CH
3)，6.45-6.46(d，1H，J＝2.0Hz，indole?H)，6.58(s，1H，indole?H)，6.67-6.71(m，2H，aromatic?H)，7.01-7.03(d，1H，J＝8.8Hz，indole?H)，7.10-7.11(d，1H，J＝2.8Hz，indole?H)，7.17(s，1H，aromatic?H)，7.29-7.32(d，1H，J＝8.8Hz，indole?H)，7.52(s，1H，imidazolin-2-one?H).
The preparation of embodiment 17:1-ethanoyl-3-(1-benzyl-1H-indoles-5-yl)-4-(2,4 difluorobenzene base)-4-tetrahydroglyoxaline-2-ketone (compound IV c9)
Operating process and embodiment 2 just replace 5-amino-1H-indoles with 1-benzyl-5-amino-1H-indoles together.Obtain yellow solid (compound IV c9), yield 38.6%.Fusing point: 192-194 ℃.
1H?NMR(δ，CDCl
3)：2.72(s，3H，O＝C-CH
3)，5.28(s，2H，CH
2)，6.49-6.50(d，1H，J＝2.8Hz，indole?H)，6.91-6.92(dd，1H，J＝2.4Hz，8.8Hz，indole?H)，6.99-7.03(m，1H，indole?H)，7.09-7.10(m，3H，aromatic?H)，7.14-7.15(d，1H，J＝3.2Hz，indole?H)，7.20-7.24(m，3H，aromatic?H)，7.27-7.29(m，3H，aromatic?H×2，imidazolin-2-one?H)，7.45-7.46(d，1H，J＝2.0Hz，indole?H).
The preparation of embodiment 18:1-ethanoyl-3-(1-benzyl-1H-indoles-5-yl)-4-(4-chloro-phenyl-)-4-tetrahydroglyoxaline-2-ketone (compound IV c10)
Operating process and embodiment 2 just replace 5-amino-1H-indoles with 1-benzyl-5-amino-1H-indoles together, and 4-chloro-alpha-acetamido-methyl phenyl ketone replaces 2,4-two fluoro-alpha-aminoacetophenone hydrochlorides.Obtain yellow solid (compound IV c10), yield 45.2%.Fusing point: 163-165 ℃.
1H?NMR(δ，CDCl
3)：2.72(s，3H，O＝C-CH
3)，5.31(s，2H，CH
2)，6.52-6.53(d，1H，J＝2.8Hz，indole?H)，6.90-6.92(dd，1H，J＝2.4Hz，8.0Hz，indole?H)，7.02-7.04(m，2H，aromatic?H)，7.09-7.24(m，7H，aromatic?H×5，indole?H×2)，7.29-7.33(m，3H，aromatic?H×2，imidazolin-2-one?H)，7.49-7.50(d，1H，J＝8.8?Hz，indole?H).
Embodiment 19: indole-substituteing imidazoline-2-ketones derivant is to the vitro inhibition effect of different tumour cells
1. experiment material
Cell strain: human leukemia cell K562, people's cancer of the stomach SGC-7901, people's small cell carcinoma of lung A549, Human Prostate Cancer Cells PC-3.
Substratum: RPMI 1640 substratum contain 10% calf serum.
Medicine and preparation: medicine is the above-mentioned synthetic compound IV of institute, and medicine is dissolved in DMSO.
2. experimental technique
With the above-mentioned tumour cell that is in logarithmic phase, with 2 * 10
4Individual/ml is inoculated in 96 well culture plates, and every hole adds cell suspension 200 μ l, after cultivating 24 h, adds indole-substituteing imidazoline-2-ketones compound (0.08-50 μ g/ml) the 2 μ l of 5 kinds of concentration respectively, and each concentration is established 3 multiple holes.Cell is at 37 ℃, 5%CO
2After hatching 72 hours in the incubator, adding concentration is the MTT solution 10 μ l of 5mg/ml, continues to cultivate 4 hours.Supernatant is removed in suction, adds 100 μ l DMSO and shakes up, and with the OD value in ELIASA each hole of mensuration under the 570nm wavelength, the calculation formula of cell inhibitory rate is:
Cell inhibitory rate %=(control group OD value-medication group OD value)/control cells OD value * 100% usefulness Bliss method is obtained IC
50
3. experimental result
After the indole-substituteing imidazoline-2-ketones derivant effect 48 hours, measure IC respectively
50Value.The result shows that most compounds all have vitro inhibition effect in various degree, wherein IC to various tumour cells
50Value has less than 10 μ M: compound IV c1, IVc2, IVc3, IVc7 are to the K562 human leukemia cell; Compound IV c2 is to the A549 non-small cell lung cancer cell; Compound IV c2 is to SGC-7901 people's cancer of the stomach; Compound IV c1, IVc2 are to Human Prostate Cancer Cells PC-3.Wherein compound IV a, IVc2, IVc3, IVc7 are to the IC of SGC-7901 people's cancer of the stomach effect
50Value is less than positive control medicine NSC-757. and Docetaxel; Compound IV c1, IVc2 are to the IC of Human Prostate Cancer Cells PC-3 effect
50Value is less than positive control medicine NSC-757..They to the body outer suppressioning experiment result of tumour cell (being the MV of three tests) referring to table 1.
This compounds of integration test is to the vitro inhibition effect of different tumour cells, and compound IV c1 and IVc2 are more remarkable to the restraining effect of various tumor cell lines, and antitumor spectra is wider.
Table 13-indyl-4-aryl-4-imidazoline-2-ketones compound effect in 48 hours is to the vitro inhibition effect of tumour cell
| Compound | IC 50(μG/ml) | |||
| K562 | SGC-7901 | A549 | PC-3 | |
| IVa1IVc1IVc2IVc3IVc4IVc7IVc8 NSC-757. Docetaxel | 22.28 0.76 7.16 5.37 ＞50 1.69 11.19 ＜0.08 ＜0.08 | 38.26 11.33 7.99 13.35 ＞50 17.90 ＞50 41.23 43.79 | - a 19.49 6.17 - - - - - - | ＞50 5.64 4.47 - - - - 36.19 - |
a"-" expression undetermined IC
50Value.
Claims (6)
1. the salt accepted of indole-substituteing imidazoline-2-ketones derivant or its physiology is characterized in that having following general structure:
Wherein
R
1Be H, 2 or 3 or 4-F, 2 or 3 or 4-Cl, 2 or 3 or 4-Br, 2 or 3 or 4-NO
2, 2 or 3 or 4-OC
2H
5, 2 or 3 or 4-OCH
3, 2 or 3 or 4-CH
3, 2 or 3 or 4-OH, 2 or 3 or 4-N (CH
3)
2, 3,4-(OCH
3)
2, 3-NO
2-4-OCH
3, 3-NH
2-4-OCH
3, 3-NH
3 +Cl
--4-OCH
3, 3-OH-4-OCH
3, 3-OCH
3-4-OH, 4-OH-3,5-(OCH
3)
2Or 3,4,5-(OCH
3)
3
R
2Be H, CHO, COCH
3, CONH-(1H-indoles-5-yl), CONH-(1-Methyl-1H-indole-5-yl) or CONH-(1-benzyl-1H-indoles-5-yl);
R
3Be H, CH
3Or Bn.
2. the preparation method of the salt that indole-substituteing imidazoline-2-ketones derivant according to claim 1 or its physiology are accepted; It is characterized in that: the cyclization dehydration reaction takes place and obtains target compound IVa and target compound IVb in compound I and compound I I in the inert solvent under nitrogen protection; Solvent for use is a benzene, toluene or YLENE, and temperature of reaction is between 80-140 ℃; Gained target compound IVa and IVb get pure products through column chromatography
Reaction formula:
3. the preparation method of the salt that indole-substituteing imidazoline-2-ketones derivant according to claim 2 or its physiology are accepted is characterized in that: gained target compound IVa and IVb process the salt that physiology is accepted.
4. the preparation method of the salt that indole-substituteing imidazoline-2-ketones derivant according to claim 1 or its physiology are accepted; It is characterized in that: the cyclization dehydration reaction takes place and obtains target compound IVc under nitrogen protection in compound I I and compound III in inert solvent, solvent for use is a benzene; Toluene or YLENE; Temperature of reaction is between 80-140 ℃, and gained target compound IVc gets pure products through column chromatography
Reaction formula:
5. the preparation method of the salt that indole-substituteing imidazoline-2-ketones derivant according to claim 4 or its physiology are accepted is characterized in that: gained target compound IVc processes the salt that physiology is accepted.
6. the application of the salt that indole-substituteing imidazoline-2-ketones derivant according to claim 1 or its physiology are accepted in the preparation antitumor drug.
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| WO2003095452A1 (en) * | 2002-05-08 | 2003-11-20 | Janssen Pharmaceutica N.V. | Substituted pyrroline kinase inhibitors |
| CN1571781A (en) * | 2001-10-22 | 2005-01-26 | 田边制药株式会社 | 4-imidazolin-2-one compounds |
| WO2005047266A1 (en) * | 2003-11-14 | 2005-05-26 | Lorus Therapeutics Inc. | Aryl imidazoles and their use as anti-cancer agents |
| CN1832939A (en) * | 2003-05-30 | 2006-09-13 | 杰明X生物技术公司 | Triheterocyclic compounds, compositions, and methods for treating cancer or viral diseases |
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| CN1571781A (en) * | 2001-10-22 | 2005-01-26 | 田边制药株式会社 | 4-imidazolin-2-one compounds |
| WO2003095452A1 (en) * | 2002-05-08 | 2003-11-20 | Janssen Pharmaceutica N.V. | Substituted pyrroline kinase inhibitors |
| CN1832939A (en) * | 2003-05-30 | 2006-09-13 | 杰明X生物技术公司 | Triheterocyclic compounds, compositions, and methods for treating cancer or viral diseases |
| WO2005047266A1 (en) * | 2003-11-14 | 2005-05-26 | Lorus Therapeutics Inc. | Aryl imidazoles and their use as anti-cancer agents |
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