CN101514192A - Quinoxalinone derivative with activity for reversing tumor cell multidrug resistance and preparation method thereof - Google Patents
Quinoxalinone derivative with activity for reversing tumor cell multidrug resistance and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a quinoxalinone derivative with activity for reversing tumor cell multidrug resistance and a preparation method thereof, belonging to the technical field of pharmaceutical chemistry. The quinoxalinone derivative has a structure shown in the general formula (I), wherein, R1 and R2 are same or different and are respectively selected from C<1-4> linear chain or branched alkyl, halogen, cyano-group, alkoxy group containing 1 to 4 carbon atoms and haloalkyl containing 1 to 4 carbon atoms; and R3 is selected from hydroxyl, methoxy, ethoxy, carboxyl methyl or ethyl substituted natural L-amino acid residue, optionally substituted other primary amine and optionally substituted secondary amine. A compound of the invention can increase the cell toxicant efficacy of K562/A02 multidrug resistance cell strain expressed by adriamycin towards P-glycosidoprotein in the experiment for screening the invitro pharmacological activity for reversing multidrug resistance cell strain K562/A02, and the quinoxalinone derivative is effective multidrug resistance reversal agent and is probable to be developed into novel chemotherapeutic drug sensitizing agent.
Description
Technical field
The present invention relates to Quinoxalinone derivative that has activity for reversing tumor cell multidrug resistance and preparation method thereof, belong to the pharmaceutical chemistry technical field.
Background technology
At present, chemotherapy remains the most important means of oncotherapy, yet the multidrug resistance phenomenon that occurs in the chemotherapy becomes stubborn problem day by day, becomes the most important reason of chemotherapy failure, has also become a great problem that oncotherapy has to face.Carried out many years for the research that reverses multidrug resistance, the tumour cell that studies show that most of multidrug resistance is all followed the overexpression of P-glycoprotein, P-glycoprotein relies on its special structure initiatively chemotherapeutics to be transported to the extracellular in born of the same parents, causes multidrug resistance to produce thereby make the continuous reduction of the interior drug level of born of the same parents cause tumour cell effectively not killed.Therefore designing the P-glycoprotein inhibitors is considered to an approach that effectively overcomes the multidrug resistance phenomenon.Present bibliographical information to have an active compound of the multidrug resistance of reverse most because activity is not high, toxicity is too strong or influence the dynamic process of chemotherapeutic and can't move towards clinical use, still do not have to apply to clinical multidrug-resistance reversal agent listing up to now, seeking safely and effectively multidrug-resistance reversal agent and lead compound thereof still is the important topic of antitumor drug research and development.
Summary of the invention
The object of the present invention is to provide a class to have the Quinoxalinone derivative of activity for reversing tumor cell multidrug resistance, this compounds has the pharmacologically active of reversing multiple medicine resistance of tumor cells, is expected to be used for the sensitizer of tumor chemical therapy.
Another object of the present invention is to provide such to have the preparation method of the Quinoxalinone derivative of activity for reversing tumor cell multidrug resistance.
Technical scheme of the present invention is: have the Quinoxalinone derivative of activity for reversing tumor cell multidrug resistance, it is characterized in that its structure just like general formula (I):
In the formula: R
1And R
2Identical or different, be selected from hydrogen, C independently of one another
1～4Straight or branched alkyl, halogen, cyano group, contain 1～4 carbon atom alkoxyl group, contain the haloalkyl of 1～4 carbon atom;
R
3Be selected from the secondary amine that hydroxyl or methoxy or ethoxy or carboxyl become methyl esters or ethyl substituted natural L-amino acid residue, other primary amine groups that replace arbitrarily, replace arbitrarily; Wherein said natural L-amino acid residue is selected from L-Serine, L-arginine, L-Threonine, L-glycine, L-aspartic acid, L-L-Ala, L-glutaminate, L-Xie Ansuan, L-tyrosine, L-leucine, L-Isoleucine, L-halfcystine, altheine, L-phenylalanine, L-L-glutamic acid, L-methionine(Met), L-Histidine, L-proline(Pro), L-oxyproline, L-Methionin, L-tryptophane; Other primary amine groups of described any replacement are selected from phenyl amines, the C of replacement
1～4Alkylamino, pentamethylene base amino, hexanaphthene amino, γ-An Jidingsuan methyl esters, 6-aminocaprolc acid methyl esters; The secondary amine of described any replacement is selected from the two C of replacement of N-
1～4Alkylamino, morpholinyl, piperazinyl, substituted piperazinyl.
Described Quinoxalinone derivative with activity for reversing tumor cell multidrug resistance comprises following compounds:
2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate;
2-(6,7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate;
2-(6,7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-ethyl acetate;
2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-ethyl acetate;
2-(2-(6,7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-ethyl acetate;
2-(2-(6,7-dimethoxy-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-ethyl acetate;
(2S, 4R)-4-hydroxyl-1-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-pyrryl-2-carboxylate methyl ester;
(S)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-3-phenylalanine methyl ester;
(S)-2-(2-(6,7-two chloro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-3-phenylalanine methyl ester;
(S)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-1,5-Methyl glutarate;
(S)-2-(2-(6,7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-1,5-Methyl glutarate;
(S)-2-(2-(6,7-dimethoxy-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-1,5-Methyl glutarate;
(S)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-4-(methylthio group)-methyl-butyrate;
(S)-2-(2-(6,7-dimethoxy-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-4-(methylthio group)-methyl-butyrate;
(S)-2-(2-(6,7-two chloro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-4-(methylthio group)-methyl-butyrate;
(S)-3-hydroxyl-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-methyl propionate;
N-cyclohexyl-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-ethanamide;
N-cyclohexyl-2-(6,7-dimethoxy-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-ethanamide;
N-cyclohexyl-2-(6,7-two chloro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-ethanamide;
6-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-hexyl methyl esters;
6-(2-(6,7-dimethoxy-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-hexyl methyl esters;
6-(2-(6,7-two chloro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-hexyl methyl esters;
4-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-butyl methyl esters;
(E)-3-methyl isophthalic acid-(2-oxygen-2-(4-(3-hydrocinnamyl-1-thiazolinyl)-piperazine-1-yl)-ethyl)-quinoxaline-2-(2H)-ketone.
Preparation method with Quinoxalinone derivative of activity for reversing tumor cell multidrug resistance is characterized in that it mainly realizes by following steps: a) with 4, the 5-position is by R
1, R
2Dibasic O-Phenylene Diamine and Pyruvic Acid Methyl ester heating reflux reaction in certain solvent prepares quinazolinone parent nucleus compound (II); B) compound (II) and bromo or chloracetic acid ethyl ester under the weak base catalyst effect in ethanol or acetone solvent heating reflux reaction, hydrolysis obtains compound (III) then; C) compound (III) obtains compound (I) with amino substitution compound condensation in reaction solvent under the effect of condensing agent.
Described preparation method with Quinoxalinone derivative of activity for reversing tumor cell multidrug resistance, wherein the solvent described in the step a) is ethanol or tetrahydrofuran (THF) or methylene dichloride or 1, the 4-dioxane; The consumption of described solvent be every mmole 4, the 5-position is by R
1, R
2Dibasic O-Phenylene Diamine is with 4～5ml solvent; Described 4,5-position is by R
1, R
2The mol ratio of dibasic O-Phenylene Diamine and Pyruvic Acid Methyl ester consumption is 1: 1.1～1.2.
Described preparation method with Quinoxalinone derivative of activity for reversing tumor cell multidrug resistance, wherein the weak base catalyst described in the step b) is weak mineral alkali, preferred yellow soda ash or salt of wormwood; Described compound (II) is 1: 1.2: 1.2 with the mol ratio of ethyl acetate bromo or chloro and weak base catalyst consumption; The consumption of described ethanol or acetone solvent is that the compound (II) of every mmole is with 8～10ml solvent; Described hydrolysis is to be to stir 4 hours in the alcoholic solution of 0.4mol/L～2mol/L potassium hydroxide in concentration, adds water then and finishes with hcl acidifying to pH=1～3.
Described preparation method with Quinoxalinone derivative of activity for reversing tumor cell multidrug resistance, in the step c), described amino substitution compound is the L-amino acid derivatives, the preferred 1-ethyl of condensing agent-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl) adds I-hydroxybenzotriazole (HOBt), preferred anhydrous methylene chloride of reaction solvent or N, dinethylformamide, compound (III) is 1: 1: 1.1～1.2: 1.1～1.2 with the mol ratio of amino substitution compound and condensing agent EDCHCl and condensing agent HOBt consumption, the consumption of reaction solvent be the compound (III) of every mmole with 2.5～5ml solvent, temperature of reaction is below 10 ℃.
Described preparation method with Quinoxalinone derivative of activity for reversing tumor cell multidrug resistance, in the step c), described amino substitution compound is other primary amine or the secondary amine class beyond the L-amino acid derivatives, the preferred N of condensing agent, N '-carbonyl dimidazoles, the preferred anhydrous methylene chloride of reaction solvent or tetrahydrofuran (THF) or N, dinethylformamide, compound (III) is 1: 1: 2 with the mol ratio of amino substitution compound and condensing agent consumption, the consumption of reaction solvent be the compound (III) of every mmole with 5～10ml solvent, temperature of reaction is 0～30 ℃.
Quinoxalinone derivative with activity for reversing tumor cell multidrug resistance of the present invention, the preparation route of target compound is as shown in table 1:
Table 1
The invention has the beneficial effects as follows: on cell levels, made the external pharmacologically active screening that reverses multidrug resistance cell strain K562/A02 of the Quinoxalinone derivative with activity for reversing tumor cell multidrug resistance of the present invention.Experimental result shows that described compound can strengthen Zorubicin greatly the cell toxicant of the K562/A02 multidrug resistance cell strain of P-glycoprotein high expression level is renderd a service (the pharmacology test result such as the table 2 of part of compounds), be effective multidrug-resistance reversal agent, being expected to develop becomes novel chemotherapeutics sensitizer.
Reverse the external pharmacologically active screening of multidrug resistance cell strain K562/A02, concrete principle and program brief introduction are as follows:
With the restraining effect of tetramethyl-azo azoles salt colorimetry (mtt assay) assessing compound on cell proliferation ability, if testing compound can reverse multidrug resistance cell K562/A02, then Zorubicin (Adriamycin) can strengthen greatly to its lethal effect.Finite concentration (is used its IC usually
10) testing compound respectively with the Zorubicin drug combination of a series of concentration, acted on the K562/A02 cell respectively 24,48,72,96,120 hours, use the MTT experimental technique to calculate the cell number that lives, calculate IC
50Value; Use the IC of Zorubicin separately
50Value is also in kind calculated, and the two is compared and obtains reversing multiple (ReversalFactor, RF) value.Obviously, RF value Gao Ze more represents the reversing drug resistance ability of testing compound strong more, and RF equals 1 expression does not have the multidrug resistance of reverse activity.The parallel laboratory test triplicate, verapamil (Verapamil, Ver, 4 μ g/ml) is done positive control.Non-drug-resistant cell strain K562 to the K562/A02 correspondence has also done same pharmacology test simultaneously, its RF=1, prove that this compounds can not strengthen the lethality of Zorubicin to non-drug-resistant cell strain, also can illustrate this compounds really by reversion MDR but not cytotoxicity has strengthened the susceptibility of mdr cell to Zorubicin.
Table 2
Embodiment
The compound that use table 3 of the present invention is listed is furthermore bright, but does not limit the present invention.
Table 3
Further specify the present invention below in conjunction with embodiment.
Embodiment 1
(S)-2-(2-(6,7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-1, the preparation of 5-Methyl glutarate (compound N is O.1 in the table 3)
3,4-difluoroaniline 32.1g (0.25mol) is with 1, and 4-dioxane 180ml dissolves, ice bath drips acetic anhydride 30.46g (0.30mol) after stirring 10min down, and ice bath stirs 1h down, after transfer to room temperature, after the TLC detection reaction finishes, be spin-dried for solvent, add 100ml water again, filter, filter cake washes 4 times with water and gets white solid 3,4-two fluoroacetanilides, productive rate: 97.5%, m.p.=96～98 ℃; Get 3,4-two fluoroacetanilide 5g (0.03mol) the dense H of 40ml
2SO
4After dissolving, ice bath are stirred 20min down, ground KNO
33.54g (0.035mol) add, after the TLC detection reaction finished, reaction solution was poured into and is separated out yellow solid in the trash ice in batches, filtered, and got 2-nitro-4 with ethyl alcohol recrystallization, 5-two fluoroacetanilides, and productive rate: 82%, m.p.=104～105 ℃; Get 2-nitro-4,5-two fluoroacetanilide 2g are dissolved in the H that concentration is 70% (massfraction)
2SO
4In, reflux 3hr, reaction solution pour in the trash ice, filter, and the filter cake ethyl alcohol recrystallization gets yellow solid 4,5-two fluoro-2-N-methyl-p-nitroanilines, productive rate: 70%, m.p.=109-111 ℃; Get SnCl
22H
2O7.77g (0.034mol) is dissolved in (the about 1h of stirring at normal temperature) in the 20ml concentrated hydrochloric acid, 4,5-two fluoro-2-N-methyl-p-nitroaniline 2g (0.011mol) add in batches, and normal temperature is reaction down, after the TLC detection reaction finishes, adjust pH approximately to about 13, is used ethyl acetate extraction under the condition of ice bath, ethyl acetate be spin-dried for solid, get 4 with re-crystallizing in ethyl acetate, 5-difluoro O-Phenylene Diamine, productive rate: 75%, m.p.=130-133 ℃; 4,5-difluoro O-Phenylene Diamine 1g (0.007mol) and Pyruvic Acid Methyl ester 0.85g (0.008mol) are dissolved in the 30ml ethanol, reflux 3hr, be spin-dried for solvent, add 20ml water and 60ml ethyl acetate extraction three times, be spin-dried for, re-crystallizing in ethyl acetate obtains 6,7-two fluoro-3-methyl-quinoxaline-2-(1H)-ketone, productive rate: 62%, m.p.=286～287 ℃; Take by weighing 6,7-two fluoro-3-methyl-quinoxaline 2-(1H)-ketone 1g (0.005mol), chloracetic acid ethyl ester 0.75g (0.006mol) and K
2CO
30.84g (0.006mol) put into 100ml single port bottle, add acetone 50ml, reflux, the TLC detection reaction finishes, and is spin-dried for solvent and gets solid, add 30ml water and 50ml ethyl acetate extraction three times, ethyl acetate be spin-dried for solid, with ethyl alcohol recrystallization get 2-(6,7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-ethyl acetate, productive rate: 69%, m.p.=168～169 ℃; Claim 2-(6,7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-ethyl acetate 0.5g (0.002mol) uses dissolve with ethanol, adds the KOH solution 9ml of 0.4mol/L, 40 ℃ of reaction 4hr, be spin-dried for solvent, add 10ml water, transfer pH=3, filter with hydrochloric acid, filter cake wash with water 2-(6,7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate, productive rate: 81.2%, m.p.=228～230 ℃; Get 2-(6,7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate 2g (0.008mol) is dissolved in the 20ml dry DMF, add EDCl 1.8g (0.009mol) after stirring half an hour under 0 ℃, HOBt1.21g (0.009mol) continues to keep 0 ℃ of reaction to add L-phenylalanine methyl ester hydrochloride 1.53g (0.008mol) and triethylamine 0.91g (0.009mol) after 2 hours, system temperature keeps below 5 ℃, after the TLC detection reaction finishes, decompression is removed DMF and is got oily matter, dissolve with ether 100ml, use saturated sodium bicarbonate solution 50ml respectively, 5% (massfraction) citric acid solution 50ml, water 50ml, saturated sodium-chloride 50ml washing, use anhydrous sodium sulfate drying, be spin-dried for solvent, (2-(6 to get (S)-2-with recrystallizing methanol, 7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-1, the 5-Methyl glutarate, productive rate: 55%, m.p.=183～184 ℃; H
1-NMR:(CDCl
3) δ: 2.56 (3H, s), 2.97 (1H, dd, J=5.4,13.8Hz), 3.17 (1H, dd, J=5.4,14.1Hz), 3.75 (3H, s), 4.54 (1H, d, J=15.0Hz), 4.88 (2H, m), 6.65 (1H, br), 6.91-7.65 (7H, m); ESI-MS 416.5[M+H].
Embodiment 2
The preparation of N-cyclohexyl-2-(6,7-dimethoxy-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-ethanamide (compound N O.16 in the table 3)
2-(6, the preparation of 7-dimethoxy-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate and the 2-(6 among the embodiment 1, the preparation method of-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate is similar, 2-(6,7-dimethoxy-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate 2.78g (10mmol) is dissolved in the 50ml dry DMF, add EDCHCl 2.4g (12mmol), system keeps 0 ℃ to stir 1 hour, add cyclo-hexylamine 1.0g (10mmol) then, under the nitrogen protection, be warmed up to room temperature and continue to stir about 5 hours, detecting reaction up to TLC finishes, add entry 100ml, 50ml ethyl acetate extraction three times is with 50ml washing three times, again with 50ml saturated sodium-chloride washing three times, anhydrous sodium sulfate drying 24 hours, decompression is spin-dried for solvent, obtains deep yellow oily thing, rapid column chromatography (eluent: ethyl acetate/petroleum ether=1/4), obtain yellow solid, productive rate: 73%, m.p.=251～252 ℃;
1H-NMR:(DMSO-d
6) δ: 1.121-1.264 (5H, m), 1.532-1.553 (1H, m), 1.668-1.745 (4H, m), 2.502 (3H, s), 3.549-3.605 (1H, m), 3.825-3.892 (6H, m), 4.839-4.899 (2H, m), 6.742 (1H, s), 7.281 (1H, s), 8.220 (1H, d, J=7.8Hz); ESI-MS:360.4[M+H].
Embodiment 3
2-(6, the preparation of 7-two chloro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-N-(3, the 4-Dimethoxyphenyl)-ethanamide (compound N is O.20 in the table 3)
2-(6,7-two chloro-3-methyl-preparation of 2-oxygen-quinoxaline-1-(2H)-yl)-acetate and the 2-(6 among the embodiment 1, the preparation method of 7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate is similar, 2-(6,7-two chloro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate 2.78g (10mmol) is dissolved in the 30ml thionyl chloride, reflux 3 hours, the evaporated under reduced pressure solvent gets light yellow oil, be dissolved in the 100ml anhydrous methylene chloride, 0 ℃ was stirred 30 minutes down, slowly add 3,4-dimethoxyaniline 1.53g (10mmol) keeps system temperature to continue for 0 ℃ to stir about 1 hour, detecting raw material reaction up to TLC finishes, solvent evaporated obtains white solid, and ethyl alcohol recrystallization obtains white crystal 2-(6,7-two chloro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-N-(3, the 4-Dimethoxyphenyl)-and ethanamide 1.95g, yield 52%, m.p.=219～220 ℃;
1H-NMR:(CDCl
3) δ: 2.65 (3H, s), 3.83 (6H, d, J=0.92Hz), 4.99 (2H, s), 6.74-7.87 (7H, m), 8.49 (1H, s); ESI-MS:354.4[M+H].
Embodiment 4
(E)-preparation of 3-methyl isophthalic acid-(2-oxygen-2-(4-(3-hydrocinnamyl-1-thiazolinyl)-piperazine-1-yl) ethyl)-quinoxaline-2-(2H)-ketone (compound N is O.22 in the table 3)
O-Phenylene Diamine 1.08g (10mmol) is dissolved among the dehydrated alcohol 50ml, after treating to dissolve fully, disposable adding Pyruvic Acid Methyl ester 1.05g (12mmol), kept reflux 2 hours, cooling is left standstill and yellow mercury oxide occurred, filters collecting precipitation, and ethyl alcohol recrystallization obtains needle-like yellow crystals 3-methyl-quinoxaline-2-(1H)-ketone 1.41g, yield 88%, m.p.=241～243 ℃; Take by weighing 3-methyl-quinoxaline-2-(1H)-ketone 1.0g (6.25mmol), ethyl bromoacetate 1.04g (6.25mmol) is dissolved among the acetone 50ml, adds 6g Na
2CO
3Make catalyzer, kept reflux 6 hours, the evaporated under reduced pressure solvent obtains yellow solid, the 100ml washing, solid collected by filtration, ethyl alcohol recrystallization obtains yellow crystals 2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-ethyl acetate 1.08g, yield 74%, m.p.=121～123 ℃; (3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-ethyl acetate 1g (4.07mmol) is dissolved in the methanol solution (KOH concentration is 2mol/L) of 30mlKOH 2-, stirring at normal temperature 4 hours, add concentrated hydrochloric acid and be acidified to pH=1, separate out white precipitate, obtain white crystal 2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate 0.81g with methyl alcohol or water recrystallization, yield 92%, m.p.=225～227 ℃; (3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate 2.18g (10mmol) is dissolved in the 100ml anhydrous methylene chloride 2-, treat to dissolve fully the back and add CDL3.24g (20mmol), vigorous stirring is 1 hour under the normal temperature, disposable adding cinnamyl piperazine 2.02g (10mmol), continue to stir 6 hours, the low pressure solvent evaporated gets solid, massive laundering, get orange solid (E)-3-methyl isophthalic acid-(2-oxygen-2-(4-(3-hydrocinnamyl-1-thiazolinyl)-piperazine-1-yl)-ethyl)-quinoxaline-2-(2H)-ketone 1.98g with ether/acetone recrystallization, yield 49%, m.p.=275～276 ℃;
1H-NMR:(DMSO-d
6) δ: 2.455-2.502 (3H, m), 3.045-3.152 (1H, m), 3.219-3.233 (2H, m), 3.588-3.703 (2H, m), 3.708 (1H, s), 3.987 (2H, s), 3.519-3.703 (2H, m), 4.287-4.402 (2H, m), 6.443 (1H, t, J=7.2Hz), 6.873 (1H, d, J=15.0Hz), 7.354-7.529 (8H, m), 7.778 (1H, d, J=7.8Hz); ESI-MS:404.5[M+H].
Embodiment 5
6-(the preparation of 2-(6,7-two chloro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-hexyl methyl esters (compound N O.27 in the table 3)
2-(6,7-two chloro-3-methyl-preparation of 2-oxygen-quinoxaline-1-(2H)-yl)-acetate and the 2-(6 among the embodiment 1, the preparation method of 7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate is similar, 2-(6,7-two chloro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate 2.23g (0.008mol) is dissolved in the 100ml anhydrous methylene chloride, treat to dissolve fully the back and add 2.6g CDL (0.016mol), 6-aminocaprolc acid methyl ester hydrochloride 1.45g (0.008mol), triethylamine 0.91g (0.009mol), 30 ℃ of down reactions 5 hours, be spin-dried for behind the solvent solid.Massive laundering, recrystallizing methanol get 6-(2-(6,7-dimethoxy-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-hexyl methyl esters, productive rate 79%, m.p.=152-153 ℃;
1H-NMR (DMSO-d
6) δ: 1.204-1.255 (2H, m), 1.368-1.418 (2H, m), 1.479-1.529 (2H, m), 2.270 (2H, t, J=7.2Hz), 2.452 (3H, s), 3.062 (2H, q, J=6.0Hz), 3.577 (3H, s), 5.086 (2H, s), 7.664 (1H, s), 7.994-8.057 (1H, m), 8.217 (1H, sH, t, J=5.4Hz); ESI-MS:414.7[M+H].
Claims (10)
1, the Quinoxalinone derivative that has activity for reversing tumor cell multidrug resistance is characterized in that its structure just like general formula (I):
In the formula: R
1And R
2Identical or different, be selected from hydrogen, C independently of one another
1～4Straight or branched alkyl, halogen, cyano group, contain 1～4 carbon atom alkoxyl group, contain the haloalkyl of 1～4 carbon atom;
R
3Be selected from the secondary amine that hydroxyl or methoxy or ethoxy or carboxyl become methyl esters or ethyl substituted natural L-amino acid residue, other primary amine groups that replace arbitrarily, replace arbitrarily.
2, according to the described Quinoxalinone derivative of claim 1 with activity for reversing tumor cell multidrug resistance, it is characterized in that described natural L-amino acid residue is selected from L-Serine, L-arginine, L-Threonine, L-glycine, L-aspartic acid, L-L-Ala, L-glutaminate, L-Xie Ansuan, L-tyrosine, L-leucine, L-Isoleucine, L-halfcystine, altheine, L-phenylalanine, L-L-glutamic acid, L-methionine(Met), L-Histidine, L-proline(Pro), L-oxyproline, L-Methionin, L-tryptophane.
According to the described Quinoxalinone derivative of claim 1, it is characterized in that 3, other primary amine groups of described any replacement are selected from phenyl amines, the C of replacement with activity for reversing tumor cell multidrug resistance
1-4Alkylamino, pentamethylene base amino, hexanaphthene amino, γ-An Jidingsuan methyl esters, 6-aminocaprolc acid methyl esters.
According to the described Quinoxalinone derivative of claim 1, it is characterized in that 4, the secondary amine of described any replacement is selected from the two C of replacement of N-with activity for reversing tumor cell multidrug resistance
1-4Alkylamino, morpholinyl, piperazinyl, substituted piperazinyl.
5, according to the described Quinoxalinone derivative of claim 1, it is characterized in that, comprise following compounds with activity for reversing tumor cell multidrug resistance:
2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate;
2-(6,7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetate;
2-(6,7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-ethyl acetate;
2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-ethyl acetate;
2-(2-(6,7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-ethyl acetate;
2-(2-(6,7-dimethoxy-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-ethyl acetate;
(2S, 4R)-4-hydroxyl-1-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-pyrryl-2-carboxylate methyl ester;
(S)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-3-phenylalanine methyl ester;
(S)-2-(2-(6,7-two chloro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-3-phenylalanine methyl ester;
(S)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-1,5-Methyl glutarate;
(S)-2-(2-(6,7-two fluoro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-1,5-Methyl glutarate;
(S)-2-(2-(6,7-dimethoxy-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-1,5-Methyl glutarate;
(S)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-4-(methylthio group)-methyl-butyrate;
(S)-2-(2-(6,7-dimethoxy-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-4-(methylthio group)-methyl-butyrate;
(S)-2-(2-(6,7-two chloro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-4-(methylthio group)-methyl-butyrate;
(S)-3-hydroxyl-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-methyl propionate;
N-cyclohexyl-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-ethanamide;
N-cyclohexyl-2-(6,7-dimethoxy-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-ethanamide;
N-cyclohexyl-2-(6,7-two chloro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-ethanamide;
6-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-hexyl methyl esters;
6-(2-(6,7-dimethoxy-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-hexyl methyl esters;
6-(2-(6,7-two chloro-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-hexyl methyl esters;
4-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-acetamido)-butyl methyl esters;
(E)-3-methyl isophthalic acid-(2-oxygen-2-(4-(3-hydrocinnamyl-1-thiazolinyl)-piperazine-1-yl)-ethyl)-quinoxaline-2-(2H)-ketone.
6, the preparation method who has the Quinoxalinone derivative of activity for reversing tumor cell multidrug resistance is characterized in that it mainly realizes by following steps: a) with 4, the 5-position is by R
1, R
2Dibasic O-Phenylene Diamine and Pyruvic Acid Methyl ester heating reflux reaction in certain solvent prepares quinazolinone parent nucleus compound (II); B) compound (II) and ethyl acetate bromo or chloro under the weak base catalyst effect in ethanol or acetone solvent heating reflux reaction, hydrolysis obtains compound (III) then; C) compound (III) obtains compound (I) with amino substitution compound condensation in reaction solvent under the effect of condensing agent.
According to the described preparation method of claim 6, it is characterized in that 7, the solvent described in the step a) is ethanol or tetrahydrofuran (THF) or methylene dichloride or 1, the 4-dioxane with Quinoxalinone derivative of activity for reversing tumor cell multidrug resistance; The consumption of described solvent be every mmole 4, the 5-position is by R
1, R
2Dibasic O-Phenylene Diamine is with 4～5ml solvent; Described 4,5-position is by R
1, R
2The mol ratio of dibasic O-Phenylene Diamine and Pyruvic Acid Methyl ester consumption is 1: 1.1～1.2.
According to the described preparation method of claim 6, it is characterized in that 8, the weak base catalyst described in the step b) is weak mineral alkali, preferred yellow soda ash or salt of wormwood with Quinoxalinone derivative of activity for reversing tumor cell multidrug resistance; Described compound (II) is 1: 1.2: 1.2 with the mol ratio of bromo or chloracetic acid ethyl ester and weak base catalyst consumption; The consumption of described ethanol or acetone solvent is that the compound (II) of every mmole is with 8～10ml solvent; Described hydrolysis is to be to stir 4 hours in the alcoholic solution of 0.4mol/L～2mol/L potassium hydroxide in concentration, adds water then and finishes with hcl acidifying to pH=1～3.
9, according to the described preparation method of claim 6 with Quinoxalinone derivative of activity for reversing tumor cell multidrug resistance, it is characterized in that, in the step c), described amino substitution compound is the L-amino acid derivatives, the preferred 1-ethyl of condensing agent-(3-dimethylaminopropyl) carbodiimide hydrochloride adds I-hydroxybenzotriazole, preferred anhydrous methylene chloride of reaction solvent or N, dinethylformamide, compound (III) is 1: 1: 1.1～1.2: 1.1～1.2 with the mol ratio of amino substitution compound and condensing agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and condensing agent I-hydroxybenzotriazole consumption, the consumption of reaction solvent be the compound (III) of every mmole with 2.5～5mL solvent, temperature of reaction is below 10 ℃.
10, according to the described preparation method of claim 6 with Quinoxalinone derivative of activity for reversing tumor cell multidrug resistance, it is characterized in that, in the step c), described amino substitution compound is other primary amine or the secondary amine class beyond the L-amino acid derivatives, the preferred N of condensing agent, N '-carbonyl dimidazoles, the preferred anhydrous methylene chloride of reaction solvent or tetrahydrofuran (THF) or N, dinethylformamide, compound (III) is 1: 1: 2 with the mol ratio of amino substitution compound and condensing agent consumption, the consumption of reaction solvent be the compound (III) of every mmole with 5～10mL solvent, temperature of reaction is 0～30 ℃.
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