CN100404514C - 2-substituted phenyl-4,4,5,5-tetramethyl-1,3,-dioxy imidazolines, their preparation and pharmaceutical use - Google Patents

2-substituted phenyl-4,4,5,5-tetramethyl-1,3,-dioxy imidazolines, their preparation and pharmaceutical use Download PDF

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CN100404514C
CN100404514C CNB2004100742101A CN200410074210A CN100404514C CN 100404514 C CN100404514 C CN 100404514C CN B2004100742101 A CNB2004100742101 A CN B2004100742101A CN 200410074210 A CN200410074210 A CN 200410074210A CN 100404514 C CN100404514 C CN 100404514C
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CN1743316A (en
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彭师奇
赵明
王超
吴一卉
李铮
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Capital Medical University
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Abstract

The present invention relates to novel 2-substituted phenyl-4, 4, 5, 5-tetramethyl-1, 3-dioxyimidazoline which is represented by the general formula I, relates to the preparation of an imidazole nitrous oxides free radical by using 2-nitropropane as a raw material through alkylation, reduction, condensation, oxidation, etc., and further relates to the application of the 2-substituted phenyl-4, 4, 5, 5-tetramethyl-1, 3-dioxyimidazoline to be used as an active oxygen scavenging agent of nitric oxide, O2, OH, H2O2, etc.

Description

2-substituted-phenyl-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline, their preparation and the application in medication preparation
Technical field
The present invention relates to the novel 2-substituted-phenyl-4,4,5 of a class, 5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline, its preparation method, and the purposes in medicine.
Background technology
NO is important informational molecule and effector molecule, participate in the various physiological functions of body, for example participate in the transmission of the nerve signal in blood pressure regulation, anticoagulant, immune response, the adjusting brain, and as (the Moncada such as courier of peripheral nervous system, S.Palmer, R.M.J.Higgs, E.A.Nitric oxidephysiology, pathophysiolgy, and pharmacology.Pharmacol.Rev.199143:109-142).Keep the normal level of body intracellular nitric oxide, normal vital movement is most important for keeping.Certainly, the body intracellular nitric oxide discharges the too much or very few dysfunction that all can cause body, causes a lot of diseases.
When the body intracellular nitric oxide discharges when too much, nitrogen protoxide meeting and superoxide anion react, generation has the peroxide nitroso-group of reactive behavior, produces cytotoxicity, causes nerve injury, Parkinson's disease (Gross, S.S.Volin, M.S.Nitric oxide:Pathological mechanisms.Ann.Rev.Physiol, 1995,57:737-769), degenerative brain disorder (Akama KT, Albanese C, Pestell RGand Van Eldik LJ; Amyloid beta-peptide stimulates nitric oxide production inastrocytes through an NFkB-dependent mechanism.Proc Natl Acad Sci USA 199895:5795-5800) nerve degenerative diseases such as.The body intracellular nitric oxide can cause invalid reparation circulation to the destruction of dna single chain with to the activation of gathering (ADP-ribose) synthetic enzyme, causes depleted of energy, and pair cell causes damage.The peroxide nitroso-group can oxidized protein, lipid, carbohydrate and nucleic acid, hydroxylation and nitration reaction, initiation inflammatory reaction can take place, cause arteriosclerosis, sacroiliitis, endotoxin shock disease, ischemical reperfusion injury, or respiratory distress syndrome (Demiry ü rek AT, Cakici I, Kanzik I.Peroxynitrite:A putative cytotoxin.Pharmacol.Toxicol.1998,82:113-117).Nitric oxide inhibitor more and more receives publicity in above-mentioned a series of treatment of diseases.
Though nitric oxide synthase inhibitor activity also has clear and definite prospect in the relevant disease of treatment nitrogen protoxide, but nitric oxide synthetase divides two kinds of induction type and composing types, nitric oxide synthase inhibitor activity often all has restraining effect to two kinds of synthetic enzyme, thereby have influence on nitric oxide production normal physiological function, the damage body.In addition, the slow onset of nitric oxide synthase inhibitor activity can not be removed a large amount of nitrogen protoxides of cerebral ischemia reperfusion moment generation, a little less than the neural cell injury protective capability to cerebral ischemia reperfusion at once.2-substituted-phenyl-4 of the present invention, 4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is an imidazole class nitroxyl free radical, can remove intravital nitrogen protoxide (Joseph rapidly, J.Kalyanaraman, B.Hyde, J.S.Trapping of nitricoxide by nitronyl nitroxides:an electron spin resonance investigation BiochemBiophys Res Commun 1993,192,926-34).Nitronylnitroxide can suppress the blood pressure reduction and improve renal function (Yoshida in pathological models such as septic shock disease, M.Akaike, T.Wada, Y.Sato, K.Ikeda, K.Ueda, S.Maeda, H.Therapeutic effects of imidazolineoxylN-oxide against endotoxin shock through its direct nitric oxide-scavenging activityBiochem Biophys Res Commun 1994,202,923-30; Mitaka, C.Hirata, Y.Yokoyama, K.Nagura, T.Tsunoda, Y.Amaha, K.Beneficial effect ofcarboxy-PTIO on hemodynamic and blood gas changes in septic shock dogs; CritCare 1997,1:45-50; Ayana, A.M.Sherief, H.T.Erisksson S.Zeriehun L.Effectof nitric oxide scavengers, carboxy-PTIO on endotoxin induced shock in sheep, Ethiop.J.Health Dev.2000; 14 (1): 85-89).The imidazoles nitroxyl free radical not only can be removed nitrogen protoxide, can also with O 2 .-, OH, H 2O 2Isoreactivity oxygen (the Haseloff that reacts, R.F.Zollner, S.Kirilyuk, I.A.Grigor ' ev, I.A.Reszka, R.Bernhardt, R.Mertsch, K.Roloff, B.Blasig, I.E.Superoxide-mediated reduction of the nitroxide group can preventdetection of nitric oxide by nitronyl nitroxides; Free Radic Res 1997,26 7-17), has the function of removing oxyradical, and the cell of oxygen free radical injury is had very strong provide protection.The synergy of free radical and the damage of pair cell are the important steps in a lot of disease pathologic processes.Except that producing nitrogen protoxide, also produce O when for example ischemic is irritated again simultaneously 2 .-, nitrogen protoxide and O 2 .-React, generate ONOOH, resolve into NO again 2And OH.NO 2All can cause damage with OH to neurocyte.Especially OH, neurocyte toxicity is stronger.The imidazoles nitroxyl free radical can be removed this two kinds of free radicals simultaneously, more helps the state of an illness and alleviates.
Though the imidazoles nitroxyl free radical can be removed nitrogen protoxide and oxyradical simultaneously, reaction rate constants is also inequality.Imidazoles nitroxyl free radical and OH reaction rate constants are 10 9M -1s -1(Blasig, I.E.Superoxide-mediated reduction of the nitroxide group can prevent detection ofnitric oxide by nitronyl nitroxides; Free Radic Res 1997,26,7-17) and the NO reaction rate constants be 10 4M -1s -1(Akaike, T.Yoshida, M.Miyamoto, Y.Sato, K.Kohno, M.Sasamoto, K.Miyazaki, K.Ueda, S.Maeda, H.Antagonistic action ofimidazolineoxyl N-oxides against endothelium-derived relaxing factor/.NO througha radical reaction; Biochemistry 1993,32,827-32), with the reaction of oxyradical also will be hurry up.In the disease relevant with most oxidative stresss, a large amount of releases of active oxygen are extremely harmful.Be attended by the link that nitrogen protoxide produces, adopting the treatment of imidazoles nitroxyl free radical not only can play the effect of a stone two birds, and can be controlled at and remove the nitrogen protoxide level limitedly and make and do not have influence on nitric oxide production physiological function.
Summary of the invention
The present invention relates to the 2-substituted-phenyl-4,4,5 of general formula I representative, 5-tetramethyl--1,3-dioxy base imidazolines, its isomer or derivative:
Figure C20041007421000061
Wherein
Each R represents hydrogen independently of one another; halogen; nitro, hydroxyl replaces or the unsubstituted alkoxyl group that contains 1-12 carbon atom; replace or unsubstituted linearity or the branched-alkyl that contains 1-12 carbon atom; replace or unsubstituted linearity or the branching thiazolinyl that contains 1-12 carbon atom, replace or unsubstituted C3-C12 cycloalkyl, replace or unsubstituted C3-C12 heterocyclic radical; replace or unsubstituted C3-C12 heteroaryl; replace or unsubstituted primary of 1-20 the carbon atom that contain; the second month in a season or tertiary amine groups replace or unsubstituted C1-12 acidic group, replace or unsubstituted C1-12 ester group; the alkoxyl group carboxyl; alkylsulfonyl, cyano group, imino-; alkylthio
Above-mentioned substituent carbochain can be chosen wantonly and insert 1-3 heteroatoms that is selected among S, O and the N in the end of the chain or chain,
Wherein two R can connect together and form the optional heteroatomic ring that is selected among O, N or the S that contains;
N is the integer of 1-5.
In I, more preferably R=H, 4 '-Br, 4 '-Cl, 4 '-CH 3, 4 '-OCH 3, 4 '-OH, 4 '-NO 2, 3 '-NO 2, 3 '-OH, 2 '-OH, 4 '-(2-bromo-oxyethyl group), 4 '-methoxy carboxyl, 2 '-F, 2 '-NO 2, 4 '-N (CH 3) 2N is preferably the integer of 1-3, more preferably the integer of 1-2; Or (R) nBe 2 ', 4 '-two-Cl, 3 '-OCH 3-4 '-OH, 3 ', 4 '-two-OCH 3, 2 ', 4 '-two-OCH 3, 3 ', 4 '-methylene-dioxy, 3 '-OH-4 '-OCH 3
The invention still further relates to the intermediate general formula I I of preparation general formula I (2-substituted-phenyl-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline):
Figure C20041007421000071
Wherein
R 1And R 2Independent separately expression hydrogen or protecting group;
R independently represents hydrogen separately; halogen; nitro, hydroxyl replaces or the unsubstituted alkoxyl group that contains 1-12 carbon atom; replace or unsubstituted linearity or the branched-alkyl that contains 1-12 carbon atom; replace or unsubstituted linearity or the branching thiazolinyl that contains 1-12 carbon atom, replace or unsubstituted C3-C12 cycloalkyl, replace or unsubstituted C3-C12 heterocyclic radical; replace or unsubstituted C3-C12 heteroaryl; replace or unsubstituted primary of 1-20 the carbon atom that contain; the second month in a season or tertiary amine groups replace or unsubstituted C1-12 acidic group, replace or unsubstituted C1-12 ester group; the alkoxyl group carboxyl; alkylsulfonyl, cyano group, imino-; alkylthio
Above-mentioned substituent carbochain can be chosen wantonly and insert 1-3 heteroatoms that is selected among S, O and the N in the end of the chain or chain,
Wherein two R can connect together and form the optional heteroatomic ring that is selected among O, N or the S that contains;
N is the integer of 1-5.
In formula II, preferred R=H, 4 '-Br, 4 '-Cl, 4 '-CH 3, 4 '-OCH 3, 4 '-OH, 4 '-NO 2, 3 '-NO 2, 3 '-OH, 2 '-OH, 4 '-(2-bromo-oxyethyl group), 4 '-methoxy carboxyl, 2 '-F, 2 '-NO 2, 4 '-N (CH 3) 2N is preferably the integer of 1-3, more preferably the integer of 1-2; Or (R) nBe 2 ', 4 '-two-Cl, 3 '-OCH 3-4 '-OH, 3 ', 4 '-two-OCH 3, 2 ', 4 '-two-OCH 3, 3 ', 4 '-methylene-dioxy, 3 '-OH-4 '-OCH 3
The invention still further relates to the preparation method of the compound of general formula I I, comprising:
A, reductive agent for example lithium aluminium hydride, sodium borohydride, iron powder and hydrochloric acid or zinc powder and ammonium chloride in the presence of, allow 2,3-two-methyl-2,3-two-nitrobutane:
Figure C20041007421000072
Optionally be reduced to 2,3-two-methyl-2,3-two-azanol base butane:
Figure C20041007421000081
B, again with the substituted benzaldehyde condensation of following formula:
Figure C20041007421000082
Wherein R independently represents hydrogen separately; halogen; nitro, hydroxyl replaces or the unsubstituted alkoxyl group that contains 1-12 carbon atom; replace or unsubstituted linearity or the branched-alkyl that contains 1-12 carbon atom; replace or unsubstituted linearity or the branching thiazolinyl that contains 1-12 carbon atom, replace or unsubstituted C3-C12 cycloalkyl, replace or unsubstituted C3-C12 heterocyclic radical; replace or unsubstituted C3-C12 heteroaryl; replace or unsubstituted primary of 1-20 the carbon atom that contain; the second month in a season or tertiary amine groups replace or unsubstituted C1-12 acidic group, replace or unsubstituted C1-12 ester group; the alkoxyl group carboxyl; alkylsulfonyl, cyano group, imino-; alkylthio
Above-mentioned substituent carbochain can be chosen wantonly and insert 1-3 heteroatoms that is selected among S, O and the N in the end of the chain or chain,
Wherein two R can connect together and form the optional heteroatomic ring that is selected among O, N or the S that contains,
N is the integer of 1-5;
Form the compound of general formula I I:
Figure C20041007421000083
Wherein R and n as defined above, R 1And R 2Independent separately expression hydrogen or protecting group.
The invention further relates to the novel 2-substituted-phenyl-4,4,5 of a class of general formula I representative, 5-tetramethyl--1, the preparation method of 3-dioxy base tetrahydroglyoxaline comprises that be the compound of general formula I with oxygenant (for example PbO) with the compound oxidation of general formula I I:
Figure C20041007421000091
Wherein R as defined above.
Starting raw material 2 of the present invention, 3-two-methyl-2,3-two-nitrobutane are raw material with the nitropropane, condensation is 2 in the presence of bromine, 3-two-methyl-2,3-two-nitrobutane.
In the preparation of compound of the present invention, the condensation reaction of 2-nitropropane in the presence of bromine is at Ca (OH) 2, KOH, NaOH one class alkali the aqueous solution in carry out, preferably in the NaOH aqueous solution, carry out, the concentration of alkali aqueous solution is 2mol/l to 10mol/l, is preferably 6mol/l.The temperature of dripping bromine is 4 ℃ to-4 ℃, is preferably 0 ℃.The temperature of condensation reaction is 64 ℃ to 94 ℃, is preferably 84 ℃, and the reaction times is 1 to 5 hour, is preferably 3 hours.
In the preparation of compound of the present invention, 2,3-two-methyl-2,3-two-nitrobutane is reduced to 2,3-two-methyl-2, the reductive agent of 3-two-azanol base butane is the reductive agent of lithium aluminium hydride, sodium borohydride, iron powder and hydrochloric acid and zinc powder and ammonium chloride one class, is preferably zinc powder and ammonium chloride.The temperature that adds zinc powder is 4 ℃ to-4 ℃, is preferably 0 ℃.The temperature of reaction is 10 ℃ to 30 ℃, is preferably 25 ℃, and the reaction times is 1 to 5 hour, is preferably 3 hours.
In the preparation of compound of the present invention, 2,3-dimethyl-2, the reaction solvent of 3-two-azanol base butane and substituted benzaldehyde is an alcohols, is preferably methyl alcohol.The reaction room temperature is 10 ℃ to 30 ℃, is preferably 25 ℃.Reaction times is 10 to 25 hours, is preferably 16 hours.
In the preparation of compound of the present invention, dihydroxyl-tetramethyl-imidazolidine is oxidized to 2-substituted-phenyl-4,4,5,5-tetramethyl--1, and the oxygenant of 3-dioxy base tetrahydroglyoxaline is H 2O 2, KMnO 4, PbO 2One class oxygenant is preferably PbO 2Reaction solvent is an alcohols, is preferably methyl alcohol.The reaction room temperature is 10 ℃ to 30 ℃, is preferably 25 ℃.Reaction times is 0.5 to 2 hour, is preferably 0.5 hour.
The invention further relates to the 2-substituted-phenyl-4,4,5 of general formula I representative, 5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is as nitrogen protoxide, O 2 -, OH, H 2O 2The application of isoreactivity oxygen scavenqer.The present invention adopts the PC12 cell strain to measure the 2-substituted-phenyl-4,4,5 of general formula I, and 5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are removed nitric oxide production activity, removed the activity of the active of hydrogen peroxide and removing hydroxy radical qiao.Find the 2-substituted-phenyl-4,4,5 of general formula I, 5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is the outstanding scavenging agent of nitrogen protoxide, hydrogen peroxide and hydroxy radical qiao.
Table 1. 2-substituted-phenyl-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is removed the activity by base
Compd NO/EC 50 uM H 2O 2/EC 50 uM ·OH/EC 50 uM
I-1 63.10 144.54 47.86
I-2 41.69 229.09 57.54
I-3 47.86 263.03 56.23
I-4 33.11 128.82 33.88
I-5 30.90 85.11 40.74
I-6 44.67 83.18 38.02
I-7 263.03 467.74 104.71
I-8 61.66 363.08 69.18
I-9 56.23 129.84 53.70
I-10 13.49 128.82 33.11
I-11 25.70 97.72 37.15
I-12 13.49 54.95 15.14
I-13 30.20 245.47 35.48
I-14 33.88 64.57 38.02
I-15 20.89 112.20 34.67
I-16 13.18 125.89 33.11
I-17 61.66 100.00 30.20
I-18 44.67 138.04 44.67
I-19 47.86 154.88 29.51
I-20 27.54 109.65 33.11
I-21 19.05 45.71 20.89
The invention still further relates to 2-substituted-phenyl-4,4,5,5-tetramethyl--1,3-dioxy base imidazolines is at preparation treatment nerve injury, Parkinson's disease, nerve degenerative diseases such as degenerative brain disorder, inflammation, arteriosclerosis, sacroiliitis, all kinds of shocks, endotoxin shock disease especially is with the ischemical reperfusion injury diseases associated, especially coronary heart disease (as myocardial infarction), cerebral thrombosis, cerebral infarction, cerebral embolism, pulmonary embolism, or the purposes in the medicine of disease such as respiratory distress syndrome.
The invention still further relates to the 2-substituted-phenyl-4,4,5 that contains general formula I, 5-tetramethyl--1, the pharmaceutical composition of 3-dioxy base imidazolines and the pharmaceutically acceptable carrier of choosing wantonly.In described pharmaceutical composition, the amount of active compound of the present invention can be 1-99wt%.
Compound as herein described can utilize various route of administration or mode to be released into the patient.The route of administration that is fit to includes but not limited to suction, transdermal, oral, rectum, in mucous membrane, intestines and administered parenterally, administered parenterally comprises intramuscular, subcutaneous and intravenous injection.
Term used herein " administration " comprises that all directly arrive the means at its predictive role position with indirect release compound.
Compound as herein described or its pharmaceutically acceptable derivates can be individually dosed or with other The compounds of this invention Combined Preparation, and/or with the form administration of other known drugs associatings.
Active compound of the present invention can form administration own, perhaps with the pharmaceutical compositions administration, and wherein active compound and one or more pharmaceutically acceptable carriers, vehicle or mixing diluents.Pharmaceutical composition is normally prepared in the usual way used according to the present invention, uses acceptable carrier on one or more physiology, comprises vehicle and auxiliary agent, and they help active compound is processed into can be at the preparation that pharmaceutically uses.Appropriate formulations depends on selected route of administration, can make according to general knowledge well known in the art.
The compounds of this invention also can be prepared and be used for administered parenterally or transdermal administration or mucosal.Perhaps adopt the mode administration of suppository or implants.
It will be understood by those skilled in the art that on the basis of The compounds of this invention, can adopt suitable drug delivery system (DDS), to obtain more favourable effect.
Preferably, composition is a unit dosage, for example tablet or capsule.
The selection of administering mode and effective dose will be especially according to the disease of being treated and different.In the limit of power that is chosen in those skilled in the art of administering mode and dosage.
The unit dosage of The compounds of this invention will contain 0.1 to 99 weight % active substance usually, be more typically 5 to 75 weight % active substances.For instance, unit dosage can contain 10mg to 0.5g compound, is more typically 50mg to 500mg.
Each dose unit or each oral administration preferably contain 50 to 1000mg structural formula I compounds or its pharmaceutically acceptable derivates, administration every day 3 times or determine according to the dining number of times.
Compound of the present invention will be according to the amount administration that required result of treatment effectively is provided.Provide the necessary concentration of required result of treatment will be especially according to clear and definite character, patient's age, body weight and the severity of disease of disease and different.
Usually, The compounds of this invention day dosage will be in the scope of 0.05mg/kg to 40mg/kg body weight, more preferably 2mg/kg to 30mg/kg body weight, particularly 5mg/kg to 25mg/kg body weight.
For the general population of body weight 60kg, typical every day of the dosage of The compounds of this invention can be 0.01-1.2g/d, can divide 2-3 administration, and children's consumption cuts down according to the circumstance.Compound of the present invention is salify according to a conventional method, for example makes hydrochloride.
But, the frequency of the size of dosage and administration is decided by the doctor who treats this patient the most at last and judges.
Embodiment
In order to explain the present invention, provide a series of examples of executing below.These examples are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
Illustrate: intermediate and degree of purity of production confirm that with TLC EI-MS measures with the Trace MS System mass spectrograph of U.S. Thermo Finnigan company.Infrared spectrum (IR) adopts Avatar 360 Fourier transformation infrared spectrometers of U.S. Nicolet company to measure.Nuclear-magnetism spectrum (NMR) adopts NEC AL-300 FTNMR System to measure.The micro-fusing point instrument of the X75 that fusing point adopts Beijing instrument electric light instrument plant of section to produce is measured, and thermometer is not proofreaied and correct.Silica gel for chromatography is produced by Haiyang Chemical Plant, Qingdao.
The preparation of The compounds of this invention intermediate
One, 2,3-dimethyl-2, the preparation of 3-dinitrobenzene butane
34.5g (0.39mol, 35ml) the 2-nitropropane is added in 65ml NaOH (6mol/l) aqueous solution.Bathe under the agitation condition at cryosel, drip 10ml (0.19mol) Br 2, drip in the 1hr.Add 128ml ethanol then.Reaction mixture refluxes in 84 ℃ and stirs 3hr, the sheet insolubles occurs.Take advantage of heat to pour in the 400ml frozen water reaction mixture.Suction filtration gets white plates crystallization 25g (73%), mp 110-112 ℃.
Two, 2,3-dimethyl-2, the preparation of 3-dihydroxy amido butane
With 7.0g (40mmol) 2,3-dimethyl-2,3-dinitrobenzene butane and 4.0g NH 4Cl is suspended in 80ml ethanol (50%) solution.Ice bath stirs down.In 3hr, add the 16.0g zinc powder.After zinc powder adds, remove ice bath, continue stirring at room reaction 3hr, then with the reaction solution suction filtration.Filter cake is with 50% aqueous ethanolic solution repetitive scrubbing.The filtrate and the washings that merge are regulated pH=2 with concentrated hydrochloric acid, are evaporated to muddy.Add an amount of salt of wormwood in slurry, after mixing thoroughly, use apparatus,Soxhlet's, chloroform is an extraction agent, extracting 6hr.Extracting solution is evaporated on a small quantity, separates out white crystals 2.60g (44%), mp 157-159 ℃ behind the adding sherwood oil.
Three, 1,3-dihydroxyl-2-phenyl-4,4,5, the preparation of 5-tetramethyl-imidazolidine
212mg (2mmol) phenyl aldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 3ml methyl alcohol, and behind the stirring at room 16hr, TLC shows that raw material point disappears.Leach white solid 401mg (85%) and be directly used in next step reaction.Sample behind the TLC purifying, EI-MS:236.3[M] +R f0.64 (CHCl 3/ CH 3OH, 10: 1), mp:168-169; IR (KBr) 3340 (OH); 1600,1450 (phenyl ring); NMR (CDCl 3) δ 1.14 (s, 4-CH 3), 4.78 (s, CH), 7.31-7.51 (m, 5-ArH), 7.71 (2-OH).Ultimate analysis: C 13H 20N 2O 2Calculated value is: C, 66.07; H, 8.53; N, 11.85; Measured value is: C, 66.12; H, 8.61; N, 11.93.
Embodiment 1. 2-phenyl-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
95mg (0.4mmol) 1,3-dihydroxyl-2-phenyl-4,4,5,5-tetramethyl-glyoxalidine quinoline is dissolved in the 5ml methyl alcohol.In the solution that obtains, add 0.5g PbO 2, behind the stirring at room 0.5hr, TLC shows that raw material point disappears.Suction filtration is removed solid.Be evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets black-and-blue crystal 74mg (80%).R f0.54 (CHCl 3/ CH 3OH, 20: 1); Mp 84-85 ℃; EI-MS 233[M] +, 201[M-32] +, 145[M-88] +IR (KBr) 1610,1450 (phenyl ring).Ultimate analysis: C 13H 17N 2O 2Calculated value is: C, 66.93; H, 7.34; N, 12.01; Measured value is: C, 67.02; H, 7.41; N, 12.09.
Embodiment 2. 2-(4 '-bromophenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(4 '-bromophenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
370mg (2mmol) p-bromobenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 2ml methyl alcohol.Behind the reaction solution stirring at room 16hr, TLC shows that raw material point disappears.Leach white solid 320mg (51%), be directly used in next step reaction.Sample obtains white crystals behind the TLC purifying, EI-MS:314[M] +R f0.69 (CHCl 3/ CH 3OH, 10: 1); IR (KBr): 3310 (OH); 1590,1450 (phenyl ring); 1075 (Br); 830 (=C-H) (1, the 4-di-substituted-phenyl); NMR (CDCl 3) δ 1.14 (s, 4-CH 3), 4.77 (s, CH), 7.37 (d, 2-ArH), 7.47 (d, 2-ArH), 7.73 (2-OH).Ultimate analysis: C 13H 19N 2O 2The Br calculated value is: C, 49.54; H, 6.08; N, 8.89; Measured value is: C, 49.62; H, 6.14; N, 8.93.
(2.2-4 '-bromophenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
250mg (0.8mmol) 1,3-dihydroxyl-2-(4 '-bromophenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 30ml methyl alcohol.In this solution, add 0.5g PbO 2After stirring 10min, suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets blue tiny needle-like crystal 230mg (93%).R f0.85 (CHCl 3/ CH 3OH, 20: 1); Mp 89-91 ℃, EI-MS:311[M] +, 279[M-32] +IR (KBr): 1600,1450 (phenyl ring); 1070 (Br); 825 (=C-H) (1, the 4-di-substituted-phenyl).Ultimate analysis: C 13H 16N 2O 2The Br calculated value is: C, 50.02; H, 5.17; N, 8.97; Measured value is: C, 50.12; H, 5.23; N, 9.05.
Embodiment 3.2-(4 '-chloro-phenyl-)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(4 '-chloro-phenyl-)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
281mg (2mmol) 4-chloro-benzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 2ml methyl alcohol, and behind the stirring at room 12hr, TLC shows that raw material point disappears.Suction filtration obtains white crystals 330mg (61%), R f0.73 (CHCl 3/ CH 3OH, 10: 1), be directly used in next step reaction.EI-MS:270[M] +NMR (CDCl 3) δ 1.05 (s, 4-CH 3), 4.50 (s, CH), 7.38 (d, 2-ArH), 7.48 (d, 2-ArH) 7.80 (2-OH); IR (KBr): 3325 (OH); 1600,1500 (phenyl ring); 1085 (Cl); 825 (=C-H) (1 ', 4 '-di-substituted-phenyls).Ultimate analysis: C 13H 16N 2O 2The Cl calculated value is: C, 57.67; H, 7.07; N, 10.35; Measured value is: C, 57.72; H, 7.12; N, 10.43.
(2.2-4 '-chloro-phenyl-)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
250mg (0.92mmol) 1,3-dihydroxyl-2-(4 '-chloro-phenyl-)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 30ml methyl alcohol.In this solution, add 0.5g PbO 2Behind the stirring at room 10min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets blue tiny needle-like crystal 240mg (97%).R f0.67 (CHCl 3/ CH 3OH, 20: 1); Mp 103-105 ℃; EI-MS:267[M] +, 179[M-88] +IR (KBr): 1590,1500 (phenyl ring); 1090 (Cl); 820 (=C-H) (1, the 4-di-substituted-phenyl).Ultimate analysis: C 13H 13N 2O 2The Cl calculated value is: C, 58.32; H, 6.02; N, 10.46; Measured value is: C, 58.41; H, 6.14; N, 10.54.
Embodiment 4.2-(4 '-aminomethyl phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(4 '-aminomethyl phenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
240mg (2mmol, 0.236ml) 4-tolyl aldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 2ml methyl alcohol, and behind the stirring at room 12hr, TLC shows that raw material point disappears.Suction filtration gets white crystals 350mg (60%), R f0.61 (CHCl 3/ CH 3OH, 10: 1), be directly used in next step reaction.EI-MS:250[M] +NMR (CDCl 3) δ 1.29 (s, 4-CH 3), 1.37 (s, 1-CH 3), 4.90 (s, CH), 7.68 (d, 2-ArH), 8.22 (d, 2-ArH), 8.35 (2-OH); IR (KBr): 3335 (OH); 2985 (CH 3); 1600,1500 (phenyl ring); 815 (=C-H) (1 ', 4 '-di-substituted-phenyls).Ultimate analysis: C 14H 22N 2O 2Calculated value is: C, 67.17; H, 8.86; N, 11.19; Measured value is: C, 67.23; H, 8.81; N, 11.25.
(2.2-4 '-aminomethyl phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
250mg (1mmol) 1,3-dihydroxyl-2-(4 '-aminomethyl phenyl)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 60ml methyl alcohol.In this solution, add 0.5g PbO 2, behind the stirring at room 30min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) obtains blue solid 197mg (80%).R f0.88 (CHCl 3/ CH 3OH, 20: 1); Mp 86-88 ℃; EI-MS:247[M] +, 215[M-32] +IR (KBr): 2980 (CH 3); 1610,1500,1450 (phenyl ring); 810 (=C-H) (1 ', 4 '-di-substituted-phenyls).Ultimate analysis: C 14H 19N 2O 2Calculated value is: C, 67.99; H, 7.74; N, 11.33; Measured value is: C, 67.92; H, 7.83; N, 11.38.
Embodiment 5.2-(4 '-p-methoxy-phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(4 '-p-methoxy-phenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
273mg (2mmol) 4-methoxybenzaldehyde (p-anisaldehyde) and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 2ml methyl alcohol, and behind the stirring at room 16hr, TLC shows that raw material point disappears.Suction filtration gets white crystals 372mg (70%), R f0.52 (CHCl 3/ CH 3OH, 10: 1), be directly used in next step reaction.EI-MS:266[M] +NMR (DMSO) δ 1.06 (s, 4-CH 3), 3.73 (s, 1-OCH 3), 4.56 (s, CH), 6.88 (d, 2-ArH), 7.38 (d, 2-ArH), 7.77 (2-OH); IR (KBr): 3340 (OH); 2835 (OCH 3); 1600,1500 (phenyl ring); 825 (=C-H) (1 ', 4 '-di-substituted-phenyls).Ultimate analysis: C 14H 22N 2O 3Calculated value is: C, 63.14; H, 8.33; N, 10.52; Measured value is: C, 63.19; H, 8.38; N, 10.49.
(2.2-4 '-p-methoxy-phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
266mg (1mmol) 1,3-dihydroxyl-2-(4 '-p-methoxy-phenyl)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 60ml methyl alcohol.In this solution, add 0.6g PbO 2, behind the stirring at room 30min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) obtains blue solid 258mg (97%), R f0.54 (CHCl 3/ CH 3OH, 20: 1); Mp89-92 ℃; EI-MS:263[M] +, 231[M-32] +IR (KBr): 2830 (OCH 3); 1600 (phenyl ring); 835 (=C-H) (1 ', 4 '-di-substituted-phenyls).Ultimate analysis: C 14H 19N 2O 3Calculated value is: C, 63.86; H, 7.27; N, 10.64; Measured value is: C, 63.92; H, 7.35; N, 10.59.
Embodiment 6.2-(4 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(4 '-hydroxy phenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
244mg (2mmol) p-Hydroxybenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 3ml methyl alcohol, and behind the stirring at room 8hr, TLC shows that raw material point disappears.Suction filtration gets white crystals 257mg (51%), R f0.67 (CHCl 3/ CH 3OH, 6: 1), be directly used in next step reaction.EI-MS:252[M] +NMR (DMSO) δ 1.03 (s, 4-CH 3), 4.39 (s, CH), 6.70 (d, 2-ArH), 7.23 (d, 2-ArH), 7.63 (s, OH), 7.85 (2-OH); IR (KBr): 3310 (OH); 1610,1500,1450 (phenyl ring); 830 (=C-H) (1 ', 4 '-di-substituted-phenyls).Ultimate analysis: C 13H 20N 2O 3Calculated value is: C, 61.88; H, 7.99; N, 11.10; Measured value is: C, 61.92; H, 8.04; N, 11.17.
(2.2-4 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
126mg (0.5mmol) 1,3-dihydroxyl-2-(4 '-hydroxy phenyl)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 30ml methyl alcohol.In this solution, add 300mg PbO 2, behind the stirring at room 40min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent), De Lanse solid 65mg (52%).R f0.13 (CHCl 3/ CH 3OH, 20: 1); Mp 134-135 ℃, EI-MS:249[M] +, 218[M-31] +IR (KBr): 3250 (OH); 1500,1490 (phenyl ring); 840 (=C-H) (1 ', 4 '-di-substituted-phenyls).Ultimate analysis: C 13H 17N 2O 3Calculated value is: C, 62.64; H, 6.87; N, 11.24; Measured value is: C, 62.75; H, 6.93; N, 11.21.
Embodiment 7.2-(4 '-nitrophenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(4 '-nitrophenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
302mg (2mmol) paranitrobenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 6ml methyl alcohol, and behind the stirring at room 12hr, TLC shows that raw material point disappears.Leach white crystals 355mg (63%), R f0.59 (CHCl 3/ CH 3OH, 10: 1), be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:281[M] +NMR (DMSO) δ 1.09 (s, 4-CH 3), 4.71 (s, CH), 7.70 (d, 2-ArH), 8.21 (d, 2-ArH), 8.40 (2-OH).IR (KBr): 3325 (OH); 1365 (NO 2); 1590,1500,1450 (phenyl ring); 835 (=C-H) (1 ', 4 '-di-substituted-phenyls).Ultimate analysis: C 13H 19N 3O 4Calculated value is: C, 55.51; H, 6.81; N, 14.94; Measured value is: C, 55.64; H, 6.93; N, 14.89.
(2.2-4 '-nitrophenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
281mg (1mmol) 1,3-dihydroxyl-2-(4 '-nitrophenyl)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol.In this solution, add 0.7g PbO 2, behind the stirring at room 40min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets yellow-green colour crystal 2 03mg (73%).R f0.65 (CHCl 3/ CH 3OH, 20: 1); Mp175-176 ℃; EI-MS:278[M] +, 246[M-32] +IR (KBr): 1360 (NO 2); 1600,1500,1450 (phenyl ring); 830 (=C-H) (1 ', 4 '-di-substituted-phenyls).Ultimate analysis: C 13H 16N 3O 4Calculated value is: C, 56.11; H, 5.79; N, 15.10; Measured value is: C, 56.15; H, 5.82; N, 15.18.
Embodiment 8.2-(3 '-nitrophenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(3 '-nitrophenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
302mg (2mmol) 3-nitrobenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 4ml methyl alcohol, and behind the stirring at room 20hr, TLC shows that raw material point disappears, and leaches white powder 421mg (75%), R f0.51 (CHCl 3/ CH 3OH, 10: 1), be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:281[M] +NMR (DMSO) δ 0.52 (s, 4-CH 3), 4.19 (s, CH), 7.04 (dd, ArH), 7.34 (t, ArH), 7.57 (t, ArH), 7.77 (s, ArH) 8.03 (2-OH); IR (KBr): 3315 (OH); 1530,1360 (NO 2); 1600,1500 (phenyl ring); 875,790,685 (=C-H) (1 ', 3 '-di-substituted-phenyls).Ultimate analysis: C 13H 19N 3O 4Calculated value is: C, 55.51; H, 6.81; N, 14.94; Measured value is: C, 55.61; H, 6.90; N, 14.87.
(2.2-3 '-nitrophenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
281mg (1mmol) 1,3-dihydroxyl-2-(3 '-nitrophenyl)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol.In this solution, add 0.7g PbO 2, behind the stirring at room 20min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets dark blue-green solid 216mg (78%).R f0.69 (CHCl 3/ CH 3OH, 20: 1); 162 ℃ of mp; EI-MS:278[M] +, 247[M-31] +IR (KBr): 1530,1350 (NO 2); 1600,1450 (phenyl ring); 880,790,680 (=C-H) (1 ', 3 '-di-substituted-phenyls).Ultimate analysis: C 13H 16N 3O 4Calculated value is: C, 56.11; H, 5.79; N, 15.10; Measured value is: C, 56.19; H, 5.84; N, 15.16.
Embodiment 9.2-(3 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(3 '-hydroxy phenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
245mg (2mmol) 3-hydroxy benzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 2ml methyl alcohol, and behind the stirring at room 24hr, TLC shows that raw material point disappears, and leaches white powder 304mg (60.3%), R f0.56 (CHCl 3/ CH 3OH, 6: 1), be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:252[M] +NMR (DMSO) δ 1.05 (s, 4-CH 3), 4.51 (s, CH), 6.89 (m, 4-ArH), 7.71 (s, OH), 7.95 (2-OH); IR (KBr): 3320 (OH); 1600,1500, (phenyl ring); 880,795,695 (=C-H) (1 ', 3 '-di-substituted-phenyls).Ultimate analysis: C 13H 20N 2O 3Calculated value is: C, 61.88; H, 7.99; N, 11.10; Measured value is: C, 61.85; H, 8.05; N, 11.18.
(2.2-3 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
252mg (1mmol) 1,3-dihydroxyl-2-(3 '-hydroxy phenyl)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 40ml methyl alcohol.In this solution, add 0.7g PbO 2, behind the stirring at room 10min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets blue rhomboidan 192mg (76%).R f0.33 (CHCl 3/ CH 3OH, 20: 1); Mp137-139 ℃; EI-MS:249[M] +, 218[M-31] +IR (KBr): 3340 (OH); 1590,1500,1450 (phenyl ring); 880,800,690 (=C-H) (1 ', 3 '-di-substituted-phenyls).Ultimate analysis: C 13H 17N 2O 3Calculated value is: C, 62.64; H, 6.87; N, 11.24; Measured value is: C, 62.71; H, 6.94; N, 11.18.
Embodiment 10.2-(3 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(3 ', 4 '-dimethoxy phenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
677mg (4mmol) 3,4-dimethoxy benzaldehyde and 292mg (4mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 4ml methyl alcohol, and behind the stirring at room 20hr, TLC shows that raw material point disappears, and leaches white powder 390mg (33%), R f0.52 (CHCl 3/ CH 3OH, 6: 1), be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:296[M] +NMR (DMSO) δ 1.05 (s, 4-CH 3), 3.74 (s, 2-OCH 3), 4.53 (s, CH), 6.73 (d, ArH), 6.85 (d, ArH), 7.08 (d, ArH), 7.85 (2-OH); IR (KBr): 3310 (OH); 2825 (OCH 3); 1610,1500 (phenyl ring); 815,865 (=C-H) (1 ', 2 ', 4 '-tri-substituted phenyl).Ultimate analysis: C 15H 24N 2O 4Calculated value is: C, 60.79; H, 8.16; N, 9.45; Measured value is: C, 60.82; H, 8.23; N, 9.54.
(2.2-3 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
296mg (1mmol) 1,3-dihydroxyl-2-(3 ', 4 '-dimethoxy phenyl)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 100ml methyl alcohol.In this solution, add 1.0g PbO 2, behind the stirring at room 20min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets blue square crystal 246mg (83%).R f0.34 (CHCl 3/ CH 3OH, 20: 1); Mp 95-97 ℃; EI-MS:293[M] +IR (KBr): 2830 (OCH 3); 1600,1450 (phenyl ring); 820,870 (=C-H) (1 ', 2 ', 4 '-tri-substituted phenyl).Ultimate analysis: C 15H 21N 2O 4Calculated value is: C, 61.42; H, 7.22; N, 9.55; Measured value is: C, 61.56; H, 7.29; N, 9.61.
Embodiment 11.2-(3 '-methoxy-4 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(3 '-methoxy-4 '-hydroxy phenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
304mg (2mmol) 3-methoxyl group, 4-hydroxy benzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 2ml methyl alcohol, and behind the stirring at room 20hr, TLC shows that raw material point disappears, and leaches white powder 186mg (33%), R f0.47 (CHCl 3/ CH 3OH, 6: 1).Be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:282[M] +NMR (DMSO) δ 1.04 (s, 4-CH 3), 3.74 (s, OCH 3), 4.41 (s, CH), 6.70 (d, ArH), 6.85 (d, ArH), 7.02 (s, ArH), 7.68 (s, OH), 8.05 (2-OH); IR (KBr): 3310 (OH); 2840 (OCH 3); 1600,1500,1450 (phenyl ring); 815,870 (=C-H) (1 ', 2 ', 4 '-tri-substituted phenyl).Ultimate analysis: C 14H 22N 2O 4Calculated value is: C, 59.56; H, 7.85; N, 9.92; Measured value is: C, 59.61; H, 7.92; N, 9.85.
(2.2-3 '-methoxy-4 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
141mg (0.5mmol) 1,3-dihydroxyl-2-(3 '-methoxy-4 '-hydroxy phenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol, adds 0.5g PbO in this solution 2, behind the stirring at room 15min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets blue solid 100mg (71%); R f0.38 (CHCl 3/ CH 3OH, 20: 1); Mp 83-85 ℃; EI-MS:279[M] +, 247[M-32] +IR (KBr): 3340 (OH); 2830 (OCH 3); 1590,1490,1450 (phenyl ring); 820,875 (=C-H) (1 ', 2 ', 4 '-tri-substituted phenyl).Ultimate analysis: C 14H 19N 2O 4Calculated value is: C, 60.20; H, 6.86; N, 10.03; Measured value is: C, 60.23; H, 6.91; N, 10.08.
Embodiment 12.2-(2 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(2 ', 4 '-dimethoxy phenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
332mg (2mmol) 2,4-dimethoxy benzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 5ml methyl alcohol, and behind the stirring at room 20hr, TLC shows that raw material point disappears, and leaches white powder 349mg (59%), R f0.49 (CHCl 3/ CH 3OH, 10: 1).Be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:296[M] +NMR (DMSO) δ 1.03 (s, 4-CH 3), 3.72 (s, 2-OCH 3), 4.99 (s, CH), 7.45 (m, 3-ArH), 7.79 (2-OH); IR (KBr): 3295 (OH); 2825 (OCH 3); 1600,1500,1450 (phenyl ring); 810,865 (=C-H) (1 ', 2 ', 4 '-tri-substituted phenyl).Ultimate analysis: C 15H 24N 2O 4Calculated value is: C, 60.79; H, 8.16; N, 9.45; Measured value is: C, 60.82; H, 8.21; N, 9.51.
(2.2-2 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
296mg (1mmol) 1,3-dihydroxyl-2-(2 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol, adds 0.5g PbO in this solution 2, behind the stirring at room 15min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets purple solid 249mg (85%); R f0.37 (CHCl 3/ CH 3OH, 20: 1); Mp75-77 ℃; EI-MS:293[M] +, 261[M-32] +IR (KBr): 2830 (OCH 3); 1610,1590,1450 (phenyl ring); 805,870 (=C-H) (1 ', 2 ', 4 '-tri-substituted phenyl).Ultimate analysis: C 15H 21N 2O 4Calculated value is: C, 61.42; H, 7.22; N, 9.55; Measured value is: C, 61.49; H, 7.31; N, 9.62.
Embodiment 13.2-(2 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(2 ', 4 '-dichlorophenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
350mg (2mmol) 2,4-chlorobenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 3ml methyl alcohol, and behind the stirring at room 20hr, TLC shows that raw material point disappears, and leaches white powder 427mg (70%), R f0.69 (CHCl 3/ CH 3OH, 10: 1).Be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:305[M] +NMR (DMSO) δ 1.11 (s, 4-CH 3), 5.01 (s, CH), 7.45 (m, 2-ArH), 7.74 (d, ArH); 8.13 (2-OH); IR (KBr): 3315 (OH); 1590,1450 (phenyl ring); 995 (Cl); 820,865 (=C-H) (1 ', 2 ', 4 '-tri-substituted phenyl).Ultimate analysis: C 13H 18N 2O 2Cl 2Calculated value is: C, 51.16; H, 5.94; N, 9.18; Measured value is: C, 51.24; H, 5.99; N, 9.23.
(2.2-2 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
305mg (1mmol) 1,3-dihydroxyl-2-(2 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 80ml methyl alcohol, adds 1.0g PbO in this solution 2, behind the stirring at room 40min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets purple solid 265mg (88%); R f0.54 (CHCl 3/ CH 3OH, 20: 1); Mp123-125 ℃; EI-MS:302[M] +, 270[M-32] +IR (KBr): 1590,1450 (phenyl ring); 1000 (Cl); 825,870 (=C-H) (1 ', 2 ', 4 '-tri-substituted phenyl).Ultimate analysis: C 13H 15N 2O 2Cl 2Calculated value is: C, 51.67; H, 5.00; N, 9.27; Measured value is: C, 51.73; H, 5.08; N, 9.35.
Embodiment 14.2-(2 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(2 '-hydroxy phenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
244mg (2mmol) salicylic aldehyde (2-hydroxy benzaldehyde) and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 1.5ml methyl alcohol, and behind the stirring at room 20hr, TLC shows that raw material point disappears, and leaches white powder 287mg (57%), R f0.73 (CHCl 3/ CH 3OH, 6: 1).Be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:252[M] +NMR (DMSO) δ 1.08 (s, 4-CH 3), 4.63 (s, CH), 6.70 (m, 2-ArH), 7.14 (m, 2-ArH), 8.12 (s, ArH), 8.35 (2-OH); IR (KBr): 3325 (OH), 1600,1500, (phenyl ring); 765 (=C-H) (1 ', 2 '-di-substituted-phenyls).Ultimate analysis: C 13H 20N 2O 3Calculated value is: C, 61.88; H, 7.99; N, 11.10; Measured value is: C, 61.93; H, 8.05; N, 11.16.
(2.2-2 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
160mg (0.63mmol) 1,3-dihydroxyl-2-(2 '-hydroxy phenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 40ml methyl alcohol, adds 0.5g PbO in this solution 2, behind the stirring at room 60min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets blue solid 100mg (64%); R f0.75 (CHCl 3/ CH 3OH, 20: 1); Mp83-85 ℃; EI-MS:249[M] +, 217[M-32] +IR (KBr): 3345 (OH), 1610,1500,1450 (phenyl ring); 760 (=C-H) (1 ', 2 '-di-substituted-phenyls).Ultimate analysis: C 13H 17N 2O 3Calculated value is: C, 62.64; H, 6.87; N, 11.24; Measured value is: C, 62.58; H, 6.93; N, 11.35.
Embodiment 15.2-(3 ', 4 '-methylene dioxy phenyl group)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(3 ', 4 '-methylene dioxy phenyl group)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
300mg (2mmol) piperonylaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 4ml methyl alcohol, and behind the stirring at room 24hr, TLC shows that raw material point disappears, and leaches white powder 240mg (43%), R f0.47 (CHCl 3/ CH 3OH, 10: 1).Be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:280[M] +NMR (DMSO) δ 1.11 (s, 4-CH 3), 4.66 (s, CH), 5.99 (s, CH 2), 6.90 (m, 3-ArH), 7.83 (2-OH); IR (KBr): 1600 (phenyl ring); 910 (C-O); 1240,1100 (Ar-O-R).IR (KBr): 3315 (OH); 1600 (phenyl ring); 915 (C-O); 1235,1105 (Ar-O-R).Ultimate analysis: C 14H 20N 2O 4Calculated value is: C, 59.99; H, 7.19; N, 9.99; Measured value is: C, 60.04; H, 7.25; N, 10.09.
(2.2-3 ', 4 '-methylene dioxy phenyl group)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
200mg (0.71mmol) 1,3-dihydroxyl-2-(3 ', 4 '-methylene dioxy phenyl group)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 60ml methyl alcohol, adds 0.8g PbO in this solution 2, behind the stirring at room 15min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets blue solid 162mg (64%).R f0.75 (CHCl 3/ CH 3OH, 20: 1); Mp 97-99 ℃; EI-MS:277[M] +, 246[M-32] +IR (KBr): 1600 (phenyl ring); 910 (C-O); 1240,1100 (Ar-O-R).Ultimate analysis: C 14H 17N 2O 4Calculated value is: C, 60.64; H, 6.18; N, 10.10; Measured value is: C, 60.72; H, 6.24; N, 10.15.
Embodiment 16.1,3-dihydroxyl-2-(4 '-bromo ethoxyl phenenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
250mg (1mmol) 2-(4 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline, 0.5ml1,2-ethylene dibromide and 150mg sodium ethylate are dissolved among the anhydrous THF of 5ml, and behind 60 ℃ of stirring 8hr, TLC shows that raw material point disappears.Be evaporated to dried under the reaction mixture room temperature.The residue column chromatography for separation (chloroform: methyl alcohol=50: 1), get target compound 25mg (10%), mp117-118 ℃, EI-MS:356[M] +IR (KBr): 1600,1500,1450 (phenyl ring); 840 (=C-H) (1 ', 4 '-di-substituted-phenyls); 1250 (Ar-O-R).Ultimate analysis: C 15H 20N 2O 2The Br calculated value is: C, 50.57; H, 5.66; N, 7.86; Measured value is: C, 50.52; H, 5.71; N, 7.93.
Embodiment 17.1,3-dihydroxyl-2-(4 '-methoxy carboxyl phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1,2-(4 '-ethoxy carboxylic acid, ethyl ester base) phenyl-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
250mg (1mmol) 2-(4 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline, 0.32ml bromoethyl acetate and 100mg sodium ethylate are dissolved among the anhydrous THF of 5ml, and behind 60 ℃ of stirring 5hr, TLC shows that raw material point disappears.Be evaporated to dried under the reaction mixture room temperature.Residue column chromatography for separation (chloroform is an eluent) gets target compound 300mg (90%), mp107-109 ℃.
2,2-(4 '-methoxy carboxyl) phenyl-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
33mg (0.1mmol) 2-(4 '-ethoxy carboxylic acid, ethyl ester base) phenyl-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is dissolved in the 3ml methyl alcohol, adds 7 2N NaOH, and behind the stirring at room 30min, TLC shows that raw material point disappears.Reaction solution is at room temperature reduced pressure steaming to a small amount of, add the 2ml saturated common salt aqueous solution, with 2N HCl accent pH=5-6, with chloroform (3ml * 3) extraction solution repeatedly, the combined chloroform layer is used anhydrous sodium sulfate drying, and evaporated under reduced pressure gets blue needle crystal 30mg (100%) under the room temperature; Mp155-157 ℃, EI-MS:307[M] +, 276[M-31] +IR (KBr): 1760 (carboxylic carbonyls); 1605,1490,1450 (phenyl ring); 830 (=C-H) (1 ', 4 '-di-substituted-phenyls); 1260 (Ar-O-R).Ultimate analysis: C 15H 19N 2O 5Calculated value is: C, 68.62; H, 6.23; N, 9.12; Measured value is: C, 68.69; H, 6.31; N, 9.08.
Embodiment 18.2-(2 '-fluorophenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(2 '-fluorophenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
248mg (2mmol) 2-fluorobenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 3ml methyl alcohol, and behind the stirring at room 24hr, TLC shows that raw material point disappears, and leaches white crystals 366mg (72%).R f0.69 (CHCl 3/ CH 3OH, 6: 1), be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:254[M] +NMR (DMSO) δ 1.07 (m, 4-CH 3), 4.95 (s, CH), 7.18 (m, 3-ArH), 7.68 (dd, 2-ArH), 8.14 (2-OH); IR (KBr): 3310 (OH), 1600,1500 (phenyl ring); 1130,1235 (F); 775 (=C-H) (1 ', 2 '-di-substituted-phenyls).Ultimate analysis: C 13H 19N 2O 4The F calculated value is: C, 61.40; H, 7.53; N, 11.02; Measured value is: C, 61.49; H, 7.61; N, 11.09.
(2.2-2 '-fluorophenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
254mg (1mmol) 1,3-dihydroxyl-2-(2 '-fluorophenyl)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol, adds 0.5g PbO in this solution 2, behind the stirring at room 30min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets blue colored crystal 218mg (87%); R f0.52 (CHCl 3/ CH 3OH, 20: 1); Mp 112-114 ℃; EI-MS:251[M] +, 219[M-32] +IR (KBr): 1610,1450 (phenyl ring); 1135,1230 (F); 770 (=C-H) (1 ', 2 '-di-substituted-phenyls).Ultimate analysis: C 13H 16N 2O 4The F calculated value is: C, 62.14; H, 6.42; N, 11.15; Measured value is: C, 62.23; H, 6.58; N, 11.09.
Embodiment 19.2-(2 '-nitrophenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(2 '-nitrophenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
302mg (2mmol) 2-nitrobenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 5ml methyl alcohol, and behind the stirring at room 18hr, TLC shows that raw material point disappears, and leaches white crystals 410mg (73%), R f0.54 (CHCl 3/ CH 3OH, 10: 1), be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:281[M] +NMR (DMSO) δ 1.08 (m, 4-CH 3), 5.37 (s, CH), 7.52 (t, ArH), 7.69 (t, ArH), 7.80 (dd, ArH), 8.05 (d, ArH), 8.23 (2-OH); IR (KBr): 3325 (OH); 1535,1365 (NO 2); 1600,1450 (phenyl ring); 750 (=C-H) (1 ', 2 '-di-substituted-phenyls).Ultimate analysis: C 13H 19N 3O 4Calculated value is: C, 55.51; H, 6.81; N, 14.94; Measured value is: C, 55.46; H, 6.90; N, 14.86.
(2.2-2 '-nitrophenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
281mg (1mmol) 1,3-dihydroxyl-2-(2 '-nitrophenyl)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol, adds 0.5g PbO in this solution 2, behind the stirring at room 40min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets blue colored crystal 208mg (75%); R f0.49 (CHCl 3/ CH 3OH, 20: 1); Mp 145-147 ℃; EI-MS:278[M] +, 246[M-32] +IR (KBr): 1530,1360 (NO 2); 1450 (phenyl ring); 740 (=C-H) (1 ', 2 '-di-substituted-phenyls).Ultimate analysis: C 13H 16N 3O 4Calculated value is: C, 56.11; H, 5.79; N, 15.10; Measured value is: C, 56.21; H, 5.85; N, 15.04.
Embodiment 20.2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
304mg (2mmol) 3-hydroxyl, 4-methoxybenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 4ml methyl alcohol, and behind the stirring at room 20hr, TLC shows that raw material point disappears, and leaches white powder 276mg (49%), R f0.52 (CHCl 3/ CH 3OH, 6: 1), be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:282[M] +NMR (DMSO) δ 1.03 (s, 4-CH 3), 3.72 (s, OCH 3), 4.53 (s, CH), 6.19 (s, 2-ArH), 6.94 (s, ArH), 7.65 (s, OH), 8.04 (2-OH); IR (KBr): 3340 (OH); 2825 (OCH 3); 1600,1500,1450 (phenyl ring); 825 (=C-H) (1 ', 2 ', 4 '-tri-substituted phenyl).Ultimate analysis: C 14H 22N 2O 4Calculated value is: C, 59.56; H, 7.85; N, 9.92; Measured value is: C, 59.65; H, 7.93; N, 9.89.
(2.2-3 '-hydroxyl-4 '-p-methoxy-phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
141mg (0.5mmol) 1,3-dihydroxyl-2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol, adds 0.5g PbO in this solution 2, behind the stirring at room 20min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets blue colored crystal 95mg (68%); R f0.34 (CHCl 3/ CH 3OH, 20: 1); Mp 117-119 ℃; EI-MS:279[M] +, 247[M-32] +IR (KBr): 3320 (OH); 2830 (OCH 3); 1590,1500,1460 (phenyl ring); 820 (=C-H) (1 ', 2 ', 4 '-tri-substituted phenyl).Ultimate analysis: C 14H 19N 2O 4Calculated value is: C, 60.20; H, 6.86; N, 10.03; Measured value is: C, 60.31; H, 6.79; N, 10.15.
Embodiment 21.2-(4 '-dimethylamino phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
1.1,3-dihydroxyl-2-(4 '-dimethylamino phenyl)-4,4,5, the preparation of 5-tetramethyl-imidazolidine
298mg (2mmol) 4-N, N-dimethylbenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 4ml methyl alcohol, and behind the stirring at room 20hr, TLC shows that raw material point disappears, and leaches white powder 173mg (31%), R f0.53 (CHCl 3/ CH 3OH, 6: 1), be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:279[M] +NMR (DMSO) δ 1.04 (s, 4-CH 3), 2.85 (s, 2-CH 3), 4.01 (s, CH), 6.68 (d, 2-ArH), 7.25 (d, 2-ArH), 8.07 (2-OH); IR (KBr): 3345 (OH); 2840 (CH 3); 1595,1450, (phenyl ring); 840 (=C-H) (1 ', 4 '-di-substituted-phenyls).Ultimate analysis: C 15H 25N 3O 2Calculated value is: C, 64.49; H, 9.02; N, 15.04; Measured value is: C, 64.58; H, 9.12; N, 15.17.
(2.2-4 '-dimethylamino phenyl)-4,4,5,5-tetramethyl--1, the preparation of 3-dioxy base tetrahydroglyoxaline
140mg (0.5mmol) 1,3-dihydroxyl-2-(4 '-dimethylamino phenyl)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol, adds 0.5g PbO in this solution 2, behind the stirring at room 40min, TLC shows that raw material point disappears.Suction filtration is removed solid, is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets blue colored crystal 92mg (66%); R f0.51 (CHCl 3/ CH 3OH, 20: 1); Mp151-154 ℃; EI-MS:276[M] +, 244[M-32] +IR (KBr): 2850 (CH 3); 1595,1500, (phenyl ring); 845 (=C-H) (1 ', 4 '-di-substituted-phenyls).Ultimate analysis: C 15H 22N 3O 2Calculated value is: C, 65.19; H, 8.02; N, 15.21; Measured value is: C, 65.25; H, 8.13; N, 15.16
The preparation of embodiment 40 drug combination injections of the present invention
The compound that the embodiment of the invention of 2ml water for injection and 0.1g is prepared is made injection according to a conventional method.
The preparation of embodiment 41 pharmaceutical composition tablets of the present invention
After compound 50mg and lactose 180mg that the embodiment of the invention is prepared, starch 260mg and Magnesium Stearate 10mg mixed evenly, technology was made tablet routinely.
Test routine 1.2-substituted-phenyl-4,4,5,5-tetramethyl--1, the cytoactive of 3-dioxy base tetrahydroglyoxaline
One, medicine and reagent
1, for test agent: the concentrated solution of the compound that the embodiment of the invention is prepared, through the degerming of φ 0.22um filtering with microporous membrane, is distributed into small packages-80 ℃ refrigerator and preserves in the DMEM serum-free medium with DMSO (DMSO content is lower than 0.5%) hydrotropy.Thaw during experiment, be diluted to different concns with serum-free medium.
2, reagent: Sodium Nitroprusside (Sodium Nitroprusside, SNP), MTT (tetramethyl-azo azoles salt), poly-l-lysine; Sodium.alpha.-ketopropionate is available from Sigma company; High sugared Dulbecco ' s modified Eagle ' smedium (DMEM) substratum, foetal calf serum is available from Gibco BRL company; Horse serum is available from HyClone company; Ferrous sulfate, hydrogen peroxide is available from Beijing reagent company.
3, cell: the PC12 cell, rat suprarenal gland pheochromocytoma clone strain, medical university provides by consonance.
4, cell culture fluid
Complete culture solution: high sugared DMEM nutrient solution includes 10% horse serum, 5% foetal calf serum, 1.0mM Sodium.alpha.-ketopropionate, 100UmL -1Penicillin, 100gmL -1Streptomycin sulphate, pH are about 7.2.
Serum-free medium: high sugared DMEM nutrient solution contains the 1.0mM Sodium.alpha.-ketopropionate, 100UmL -1Penicillin, 100gmL -1Streptomycin sulphate, pH are about 7.2, do not contain serum.
The pastille nutrient solution: respectively with different compounds with the 0.5%DMSO hydrotropy, be made into concentration and be respectively 12.5uM, 25uM, 50uM, 100uM, 200uM, the high sugared DMEM nutrient solution of 500uM contains the 1.0mM Sodium.alpha.-ketopropionate, 100UmL -1Penicillin, 100gmL -1Streptomycin sulphate, pH are about 7.2, do not contain serum.
5, cell cultures
The PC12 cell is at 37 ℃, relative humidity 100%, 5%CO 2Under-95% air conditions, cultivate in the sugared DMEM complete culture solution of height, changed a not good liquor in 2～3 days, passed a generation in 5～6 days.Digest 1min with 0.02%EDTA when going down to posterity, the piping and druming cell dispersion becomes single cell suspension, and centrifugal (800rpm 5min), through the PBS washing once, again with the complete culture solution suspension cell, is inoculated in bag by the culturing bottle of poly-l-lysine.
Get be in logarithmic phase cell with 2 * 10 5The density in/hole goes down to posterity to be inoculated in and wraps in advance by in 96 well culture plates of poly-l-lysine, cultivates and implements experiment in 24 hours later on.
Two, remove nitric oxide production determination of activity
Cell inoculation is in 96 orifice plates after 24 hours, and the reject original fluid adds the pastille nutrient solution that contains different sorts and different concns compound, is placed on 37 ℃, relative humidity 100%, 5%CO 2-95% air conditions is cultivated 1 hour down to adapt to pharmaceutical environment, adds the serum-free medium 10ul that contains SNP then, makes final concentration reach 2mM, act on after 2 hours, the exhaustion nutrient solution changes serum-free medium into and continues to cultivate 14 hours, carries out cytoactive and measures.Experiment is provided with and does not add the blank group of damage, singly add the model group of damage, and has not only added medicine but also added the experimental group of damage, establishes 4 multiple holes for every group and makes parallel sample.Singly add the medicine contrast of medicine and the blank of DMSO and the experiment proved that with the normal blank of cultivating there is not significant difference, so medicine and DMSO ignore to the influence of experiment.
Three, remove the determination of activity of hydrogen peroxide
Consistent with the method for removing nitric oxide production determination of activity, the damage condition is 1mM H 2O 2Act on 1 hour.
Four, remove the determination of activity of hydroxy radical qiao
Consistent with the method for removing nitric oxide production determination of activity, the damage condition is 1mM H 2O 2/ 30uMFe (II) acts on 1 hour.
Five, mtt assay is measured cell activity
Cell to be measured is added 10ulMTT, make final concentration reach 0.5mg/mL, put into incubator and hatched 4 hours, absorb nutrient solution, add the formazan particle that 100uL DMSO dissolving generates, shaking table shakes up 20min, detects the absorbancy (OD of wavelength 570/630nm with full-automatic microplate reader 570/630).
Six, the calculating of cell protective effect
The protective effect of medicine pair cell is according to formula Effect%=(OD Drug-OD Model)/(OD Control-OD ModelCalculate) * 100, adopts biparametric Hill model to carry out nonlinear fitting by drug concentrations and protection efficient and do the measuring effect curve, obtain the EC50 value of every kind of compound.
Seven, test-results
Test-results sees Table 1.The result shows that The compounds of this invention is outstanding activity in vivo oxygen scavenqer.
Table 1.2-substituted-phenyl-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is removed the activity by base
Compd NO/EC 50 uM H 2O 2/EC 50 uM ·OH/EC 50 uM
I-1 63.10 144.54 47.86
I-2 41.69 229.09 57.54
I-3 47.86 263.03 56.23
I-4 33.11 128.82 33.88
I-5 30.90 85.11 40.74
I-6 44.67 83.18 38.02
I-7 263.03 467.74 104.71
I-8 61.66 363.08 69.18
I-9 56.23 129.84 53.70
I-10 13.49 128.82 33.11
I-11 25.70 97.72 37.15
I-12 13.49 54.95 15.14
I-13 30.20 245.47 35.48
I-14 33.88 64.57 38.02
I-15 20.89 112.20 34.67
I-16 13.18 125.89 33.11
I-17 61.66 100.00 30.20
I-18 44.67 138.04 44.67
I-19 47.86 154.88 29.51
I-20 27.54 109.65 33.11
I-21 19.05 45.71 20.89

Claims (6)

1. the 2-substituted-phenyl-4,4,5 of general formula I representative, 5-tetramethyl--1,3-dioxy base imidazolinium compounds:
Figure C2004100742100002C1
In general formula I, n=0-2; When n=0, the compound of general formula I is a 2-phenyl-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline; R is selected from 4-Br, 4-Cl, 4-CH when n=1 3, 4-OCH 3, 4-OH, 4-NO 2, 3-NO 2, 3-OH, 2-OH, 4-(2-bromo-oxyethyl group), 4-methoxy carboxyl, 2-F, 2-NO 2Or 4-N (CH 3) 2When n=2, R is selected from 3,4-two-OCH 3, 3-OCH 3-4-OH, 2,4-two-OCH 3, 2,4-two-Cl, 3 ', 4 '-(methylenedioxy) or 3-OH-4-OCH 3
2. method for preparing claim 1 compound of Formula I, this method comprises:
(1) 2-nitropropane and bromine are carried out condensation reaction in the aqueous solution of alkali, prepare 2,3-two-methyl-2,3-two-nitrobutane;
(2) with 2,3-two-methyl-2,3-two-nitrobutane is reduced to 2,3-two-methyl-2,3-two-azanol base butane;
(3) 2,3-dimethyl-2, the substituted benzaldehyde shown in 3-two-azanol base butane and the formula II carries out condensation reaction in alcoholic solvent, prepare dihydroxyl-tetramethyl-imidazolidine;
Figure C2004100742100003C1
N=0-2; Wherein, when n=1, R is selected from 4-Br, 4-Cl, 4-CH 3, 4-OCH 3, 4-OH, 4-NO 2, 3-NO 2, 3-OH, 2-OH, 4-(2-bromo-oxyethyl group), 4-methoxy carboxyl, 2-F, 2-NO 2Or 4-N (CH 3) 2When n=2, R is selected from 3,4-two-OCH 3, 3-OCH 3-4-OH, 2,4-two-OCH 3, 2,4-two-Cl, 3 ', 4 '-(methylenedioxy) or 3-OH-4-OCH 3
(4) with dihydroxyl-tetramethyl-imidazolidine oxidation, promptly.
3. the 2-substituted-phenyl-4,4,5 of the general formula I of claim 1 representative, 5-tetramethyl--1,3-dioxy base imidazolinium compounds in preparation as the application in the medicine of active oxygen scavenger.
4. according to the application of claim 3, wherein active oxygen is selected from nitrogen protoxide, O - 2, OH or H 2O 2
5. the 2-substituted-phenyl-4 of the general formula I of claim 1 representative, 4,5,5-tetramethyl--1, the purposes of 3-dioxy base imidazolinium compounds in preparation treatment nerve injury, nerve degenerative diseases, inflammation, arteriosclerosis, sacroiliitis, endotoxin shock, coronary heart disease, cerebral thrombosis, myocardial infarction and pulmonary embolism disease medicament.
6. a pharmaceutical composition is characterized in that: the 2-substituted-phenyl-4,4,5,5-tetramethyl--1,3-dioxy base imidazolinium compounds and the acceptable common carrier of pharmacy that contain the general formula I representative of claim 1.
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CN102898507B (en) * 2012-09-05 2015-05-27 上海晟顺生物科技有限公司 Thrombolysis oligopeptide-imidazolidine binary conjugate, preparation method and uses thereof
CN103396368B (en) * 2013-07-29 2016-01-13 中国人民解放军第四军医大学 The application of nitroxyl free radical in treatment ischemical reperfusion injury
CN103351383B (en) * 2013-07-29 2015-03-25 中国人民解放军第四军医大学 5-fluorouracil nitroxyl-free-radical anti-tumor drug
CN104844516B (en) * 2015-03-31 2017-12-19 西安工业大学 Containing the difunctional radiation injury protection medicine of phenols and its synthesis and application
CN105001261B (en) * 2015-07-16 2017-04-12 中国人民解放军第四军医大学 Mitochondrial function protecting agent, preparation method therefor and application thereof
CN107235908A (en) * 2017-06-22 2017-10-10 西安工业大学 A kind of methyl orange degradation agent and preparation method thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Trapping of nitric oxide bty nitronyl nitroxides:an electron spinresonance investigation. Joy hoseph etc.Biochemical and biophysical research communications,Vol.192 No.2. 1993
Trapping of nitric oxide bty nitronyl nitroxides:an electron spinresonance investigation. Joy hoseph etc.Biochemical and biophysical research communications,Vol.192 No.2. 1993 *

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