CN101701032A - Quinoxalinone low molecular weight peptide derivative with matrix metalloproteinases inhibition function and preparation method and application thereof - Google Patents
Quinoxalinone low molecular weight peptide derivative with matrix metalloproteinases inhibition function and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a quinoxalinone low molecular weight peptide derivative with matrix metalloproteinases inhibition function and a preparation method and application thereof, belonging to the technical field of medicinal chemistry. The quinoxalinone low molecular weight peptide derivative has a structure shown as a general formula (I), wherein R, R2, R3, R4, R5 and R6 are defined in a specification. The quinoxalinone low molecular weight peptide derivative has definite MMP-2 inhibition activity proved in in-vitro enzyme inhibition activity experiments, is an effective matrix metalloproteinases inhibitor and is expected to be developed into a novel anti-cancer medicine.
Description
Technical field
The present invention relates to quinazolinone small molecules class peptide matrix inhibitors of metalloproteinase and its production and application, belong to the pharmaceutical chemistry technical field.
Background technology
Malignant tumour is to cause one of human dead principal disease, and the cancer therapy drug that the selectivity of searching high-efficiency low-toxicity is high is extremely urgent.Matrix metalloproteinase (Matrix metalloproteinases, MMPs) be the endopeptidase that a class activity depends on zine ion, its main physiological function is degraded and reconstituted cell epimatrix, has been proved to be and is bringing into play crucial effect in tumor growth, invasion and attack, transfer and cancerous tissue angiogenic growth.Found 28 kinds of mammiferous MMP hypotypes at present, the MMPs family member who so classifies numerous, and because of the high expression level of MMPs has participated in the numerous physiological processs of human body, it obviously is inappropriate therefore suppressing all MMPs family members.People recognize the importance of exploitation specificity MMPs inhibitor thus.Present research to the MMP inhibitor concentrates on and designs and synthesizes the high specific inhibitor of a certain MMPs family member selectivity, thereby reduces toxic side effect, raising effect selectivity.
The poor prognosis that has confirmed the malignant phenotype of MMP-2 (gelatin enzyme A) and invasive tumor and cancer patients is closely related, and it has participated in tumour cell to the invasion and attack of basilar membrane, matrix and the transfer of cancer cells.Do not express MMP-2 in the healthy tissues, and in the tumor tissues extensively high expression level [referring to Skiles, J.W.; Gonnella, N.C.; Jeng, A.Y.Curr.Med.Chem.2004,11,2911-77.Ramnath, N.; Creaven, P.J.Curr.Oncol.Rep.2004,6,96-102.].MMP-2 has become the attractive target spot of tumor research and developing anti-tumor medicaments, with this target spot design and searching specificity and the high inhibitor of selectivity, is a class very promising in the current anti-tumor angiogenesis drug.
Summary of the invention
The object of the present invention is to provide a class to have the quinazolinone small molecules class peptide derivant of matrix metalloproteinase inhibitory activity, this compounds can be used as specificity MMP-2 inhibitor, so might become therapeutic index higher can be used for clinical medicine.
Another object of the present invention provides the preparation method and the application of this analog derivative.
The technical scheme that the present invention takes is:
Have the quinazolinone small molecules class peptide derivant of matrix metalloproteinase inhibitory activity, it has the structure of following general formula (I):
In the formula: (1) R
1, R
2, R
3And R
4Identical or different, be hydrogen, C independently of one another
1～8Straight or branched alkyl, C
2-8Straight or branched thiazolinyl, C
2-8Straight or branched alkynyl, assorted alkyl, C
3-12Cycloalkyl, following substituting group, and at least one is following substituting group: halogen, nitro, aryl, heteroaryl, hydroxyl, aryloxy, heteroaryl oxygen base, assorted alkoxyl group, amino, C
1～8Straight or branched amino, dialkyl amido, arylamino, heteroaryl amino, C
1～8Alkyl aryl amino, assorted alkylamino, sulfydryl, C
1～8Alkyl thiol, aryl sulfydryl, heteroaryl sulfydryl, assorted alkyl thiol, C
1～8Alkyl sulphonyl, aryl sulfonyl, heteroarylsulfonyl, C
1～8Alkane sulfoxide group, aryl sulfoxide group, heteroaryl sulfoxide group, cyano group, C
1～8Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, C
1～8Alkoxyl group or C
1～8Haloalkyl;
(2) R
5For carboxyl becomes methyl esters/ethyl substituted natural L-amino acid residue, other primary amine groups that replace arbitrarily or any other secondary amine that replace; Wherein natural L-amino acid residue comprises 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 and L-tryptophane; Other primary amine groups that replace comprise arylamino, heteroaryl amino, C arbitrarily
1～8Alkyl aryl amino, assorted alkylamino, C
1-8Straight or branched alkylamino, pentamethylene base amino, hexanaphthene amino, γ-An Jidingsuan methyl esters and 6-aminocaprolc acid methyl esters; Other secondary amine that replace comprise the two C of replacement of N-arbitrarily
1-4Alkylamino, morpholinyl, piperazinyl and substituted piperazinyl;
(3) R
6Be pharmaceutically acceptable mineral acid or organic acid, preferred hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, heavy sulfuric acid, phosphoric acid, carbonic acid, stable hydrocarbon acid is (as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, tetradecanoic acid, palmitinic acid, the pearly-lustre resin acid, stearic acid, eicosanoic acid docosoic, cerinic acid, myricyl acid), unsaturated hydrocarbons acid (as loses resin acid, the Ba Dousuan butenoic acid, eleostearic acid, oleic acid, linolic acid, Sorbic Acid), polyacid (oxalic acid, maleic acid, succsinic acid, adipic acid, jambulol, cork acid, sebacic acid, brassylic acid, thapsic acid, toxilic acid, fumaric acid), various replacement organic carboxyl acids are (as lactic acid, oxysuccinic acid, tartrate, citric acid, styracin, Whitfield's ointment, gallic acid, M-nitro benzoic acid, urobenzoic acid, creatine, phenylic acid, picric acid, oxyacetic acid, 2 hydroxy propanoic acid, 2-oxo propionic acid, 2-hydroxyl-1,2,3-the third three acid, fumaric acid, gluconic acid, saccharic acid, phenylformic acid, toluylic acid, 2 hydroxybenzoic acid, the 4-amino-2-hydroxybenzoic acid, methylsulfonic acid, ethyl sulfonic acid, the cyclohexyl-sulfinic acid, Phenylsulfonic acid, tosic acid, coffic acid, crust is acid not, oxysuccinic acid, citric acid, xitix, pseudolaricis acid, chlorogenic acid etc.).
Above-mentioned term implication is as follows among the present invention:
Assorted alkyl refers to saturated or undersaturated, side chain or straight chain, substituted or unsubstitutedly contain a heteroatomic alkyl at least.
Aryl is meant the aromatic carbocyclic group, and preferred aromatic ring contains 6～18 carbon atoms.
Halogen or halogen comprise fluorine, chlorine, bromine, iodine.
Cycloalkyl is saturated or unsaturated, and cyclic group replacement or unsubstituted, this ring can be monocycle or condensed ring, bridged ring or volution or contain heteroatomic ring system.Preferred 3～9 atoms of monocycle encircle preferred 7～13 atoms more, and heteroatoms is meant nitrogen, sulphur, phosphorus, oxygen etc.
Heteroaryl is an aromatic heterocycle, can be monocycle or many rings, preferred heteroaryl comprises: thienyl, pyrryl, furyl, pyridyl, pyrazine, thiazolyl, quinolyl, isoquinoline 99.9, pyrimidyl, tetrazole base, benzofuryl, benzothiazolyl, indyl, piperazinyl, tetrahydrochysene piperazinyl or the like.
The described preferred following compounds of quinazolinone small molecules class peptide derivant with matrix metalloproteinase inhibitory activity:
(R)-methyl 4-methyl-2-((S)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-Phenylpropionamide) methyl valerate,
(S)-methyl 3-(4-oxybenzene)-2-((S)-2-(2-(3-methyl-2-oxygen-quinoline beautiful jade-1-(2H)-yl) acetamido)-3-Phenylpropionamide) methyl propionate,
(S)-methyl 4-(2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-Phenylpropionamide) methyl-butyrate,
(S)-methyl 6-(2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-Phenylpropionamide) methyl caproate,
(R)-methyl 4-((S)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-Phenylpropionamide)-4-methylmercapto butyric acid methyl esters,
(S)-N-(3, the 4-dichlorophenyl)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide,
(S)-N-(4-chloro-phenyl-)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide,
(S)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-p-toluene propionic acid amide,
(S)-N-(3-chloro-4-fluorophenyl)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide,
(S)-N-(4-bromophenyl)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide,
(S)-N-(3, the 4-difluorophenyl)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide,
(S)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-N, 3-diphenylprop acid amides,
(S)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-o-toluene propionic acid amide,
(S)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-m-toluene propionic acid amide,
(S)-N-sec.-propyl-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide,
(S, E)-N-(1-(4-cinnamyl piperazine-1-yl)-1-oxygen-3 hydrocinnamyl-2-yl)-2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) ethanamide,
(R)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-propyl group propionic acid amide,
(R)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-propyl group propionic acid amide,
(R)-N-butyl-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide,
(S)-and N, N-diethyl-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide.
Have the preparation method of the quinazolinone small molecules class peptide derivant of matrix metalloproteinase inhibitory activity, may further comprise the steps:
(1) use 2-, 3-, 4-, 5-position respectively by R
1, R
2, R
3, R
4O-Phenylene Diamine that replaces and Pyruvic Acid Methyl ester be heating reflux reaction Cheng Huan in certain solvent, resulting product again with ethyl chloroacetate or ethyl bromoacetate under the weak base catalyst effect, heating reflux reaction prepares compound (II) in ethanol or acetone solvent;
(2) compound (II) under the basic catalyst effect in certain solvent, obtain compound (III) 60～100 ℃ of following hydrolysis;
(3) compound (III) is under the effect of alkali, condensing agent CDI or condensing agent EDCHCl+HOBt (EDCHCl and HOBt mol ratio 1: 1) or condensing agent DCC or condensing agent IBCF, in reaction solvent with the phenylalanine methyl ester hydrochloride condensation, obtain compound (IV), then compound (IV) under the basic catalyst effect in aqueous ethanolic solution or methanol aqueous solution or THF 60～100 ℃ of following hydrolysis obtain compound (V);
(4) compound (V) obtains target product (I) with the condensation of various amino acid methyl ester hydrochloride in reaction solvent under the effect of alkali, condensing agent CDI or condensing agent EDCHCl+HOBt (EDCHCl and HOBt mol ratio 1: 1) or condensing agent DCC or condensing agent IBCF; Perhaps earlier in reaction solvent, with SOCl
2Or PCl
3Reaction obtains compound (VI), and compound (VI) obtains (I) with various amino-complex condensation reactions under the basic catalyst effect then.
Solvent described in the above-mentioned steps (1) is dehydrated alcohol, anhydrous tetrahydro furan, anhydrous methylene chloride or anhydrous 1, the 4-dioxane; The consumption of described solvent is that 2-, 3-, 4-, the 5-position of every mmole is respectively by R
1, R
2, R
3, R
4The O-Phenylene Diamine that replaces is with 6～7mL solvent; Described 2-, 3-, 4-, 5-position are respectively by R
1, R
2, R
3, R
4The O-Phenylene Diamine that replaces and the mol ratio of Pyruvic Acid Methyl ester consumption are 1: 1.1～1.2; Described weak base catalyst is weak mineral alkali, preferred yellow soda ash or salt of wormwood; The mol ratio of described annulation product and bromo or chloracetic acid ethyl ester and weak base catalyst consumption is 1: 1.1～1.2: 1.1～1.2; The consumption of described ethanol or acetone solvent is that the annulation product of every mmole is with 8～10mL solvent.
Solvent described in the step (2) is preferentially selected aqueous ethanolic solution (V
Water: V
Ethanol1～5) or methanol aqueous solution (V=1:
Water: V
Methyl alcohol1～5) or THF=1:, consumption is that the compound (II) of every mmole is with 8～10mL solvent, used basic catalyst is potassium hydroxide, sodium hydroxide or lithium hydroxide, and described compound (II) is 1: 1.2～2 with the mol ratio of basic catalyst consumption.
Solvent described in the step (3) is anhydrous DCM, THF or DMF, and consumption is that the compound (III) of every mmole is with 8～15mL solvent; Used alkali is triethylamine, N-methylmorpholine, salt of wormwood or yellow soda ash; Described compound (III) is 1: 1.2～1.5: 1.2～1.5: 1.2～1.5 with the mol ratio of the consumption of phenylalanine methyl ester hydrochloride and condensing agent and alkali; Described aqueous ethanolic solution is V
Water: V
Ethanol=1: 1～5, methanol aqueous solution is V
Water: V
Methyl alcohol=1: 1～5, described aqueous ethanolic solution or methanol aqueous solution or THF consumption are that the compound (IV) of every mmole is with 8～10mL, used basic catalyst is potassium hydroxide, sodium hydroxide or lithium hydroxide, and compound (IV) is 1: 1.2～2 with the mol ratio of basic catalyst consumption.
Alkali described in the step (4) is triethylamine, N-methylmorpholine, salt of wormwood or yellow soda ash, described compound (V) is 1: 1.2～1.5: 1.2～1.5: 1.2～1.5 with the mol ratio of the consumption of various amino acid methyl ester hydrochlorides and condensing agent and alkali, described basic catalyst is t-BuOK, potassium hydroxide, sodium hydroxide or lithium hydroxide, described compound (VI) is 1: 1.2～1.5 with the mol ratio of basic catalyst consumption, described compound (VI) and various amino-complexs and SOCl
2(or PCl
3) the mol ratio of consumption be 1: 1.2～1.5: 1.2～1.5, described reaction solvent is anhydrous DCM, anhydrous THF, dry DMF or anhydrous dioxane, the compound (V) that consumption is every mmole is with 8～10mL solvent.
Quinazolinone small molecules class peptide derivant with matrix metalloproteinase inhibitory activity of the present invention, the preparation route of target compound is as follows:
Quinoxalinone derivative of the present invention can free form or is existed with salt form.Pharmacy acceptable salt comprises conventional avirulent salt, comprises Quinoxalinone derivative alkali and quaternary ammonium salt inorganic or that organic acid forms.
The quinazolinone small molecules class peptide derivant that the present invention has matrix metalloproteinase inhibitory activity is preparing the especially medicine of human diseases of prevention or the treatment Mammals relevant with the matrix metal proteinase activity unconventionality expression, the particularly application in the medicine of preparation prevention or treatment cancer, inflammation, multiple sclerosis disease, various tissue ulcer, various tissue ulcers venereal disease disease and periodontopathy.These compounds of the present invention can suppress at least a mammiferous matrix metalloproteinase, preferred MMP-2.Therefore, to contain formula (I) structural compounds be the pharmaceutically acceptable pharmaceutical composition of main active ingredient for the present invention design.
A kind of pharmaceutical composition except that containing one or more pharmaceutically acceptable carriers or vehicle, also comprises the quinazolinone small molecules class peptide derivant that a kind of the present invention who contains therapeutic dose has matrix metalloproteinase inhibitory activity at least.
This kind composition can be made into oral preparations and parenteral formulations, can be tablet, pill, capsule or injection.
The present invention comprises the medicine of the The compounds of this invention that contains therapeutic dose and the pharmaceutical composition of one or more pharmaceutically acceptable carriers and/or vehicle.The pharmaceutical carrier that uses can be solid or liquid.
The typical solid carrier comprises lactose, terra alba, sucrose, talcum, gel, agar, pectin, gum arabic, Magnesium Stearate, stearic acid or the like.Solid carrier can comprise that also one or more may be simultaneously as sweetener, lubricant, solubilizing agent, suspension agent, filler, glidant, compression aid, the material of tackiness agent or tablet-disintegrating agent; It can also be an encapsulating material.In powder, carrier is pulverizing solid, and it mixes with pulverizing activeconstituents.In tablet, activeconstituents and the carrier with necessary compression property are with suitable mixed, with the shape and the size compression of needs.Powder and tablet preferably comprise 99% activeconstituents at the most.Suitable solid carrier comprises, for example, and calcium phosphate, Magnesium Stearate, talcum, sugar, hole sugar, dextrin, starch, gelled fibre element, methylcellulose gum, sodium carboxymethyl-cellulose, polyvinylpyrrolidone, low melt wax and ion exchange resin.
Exemplary of liquid carriers comprises syrup, peanut oil, sweet oil, water or the like.Liquid vehicle is used to prepare solution, suspension, emulsion, syrup.Activeconstituents can dissolve or be suspended in pharmaceutically acceptable liquid vehicle, as water, and organic solvent, the mixture of the two or pharmaceutically acceptable oils or fat.Liquid vehicle can comprise other suitable medicated premix such as solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweetener, sweetener, suspension agent, thickening material, pigment, viscosity modifier or osmotic pressure regulator.The suitable example that is used for the liquid vehicle of oral and administered parenterally comprises that water (partly comprises as above-mentioned additive, derivatived cellulose for example, the preferably carboxymethyl cellulose sodium salt solution), alcohol (comprises monohydroxy-alcohol and polyvalent alcohol, and oils (for example fractionated coconut oil and peanut oil) ethylene glycol for example) and their derivative.The carrier that is used for administered parenterally can also be grease such as ethyl oleate and sec.-propyl myristate.Aseptic liquid vehicle is used for the aseptic fluid composition of parenteral admin.The liquid vehicle that is used for pressurized compositions can be halohydrocarbon or other acceptable propelling agent pharmaceutically.Sterile solution or suspension composition of liquid medicine can be used for, for example intravenously, muscle, intraperitoneal or subcutaneous injection.But single pushes or injection gradually during injection, goes into 30 minutes intravenously perfusion.This compound can also be with the form oral administration of liquid or solids composition.
Carrier or vehicle can comprise time lag material known in the art, as glyceryl monostearate or glycerol disterate acid, can also comprise wax, ethyl cellulose, Vltra tears, methyl methacrylate or the like.When preparation is used for when oral, generally acknowledge PHOSALPG-50 (phospholipid and 1, the 2-propylene glycol is concentrated, A.Nattermann ﹠amp; Cie.GmbH) 0.01% tween 80 in is used for the preparation of the acceptable oral preparation of other compounds, can be adapted to the preparation of all cpds of the present invention.
Can use medicament forms miscellaneous when giving The compounds of this invention.If the use solid carrier, preparation can be tablet, is placed into powder or piller form or lozenge or lozenge form in the hard capsule.The amount of solid carrier changes to a great extent, but preferably from about 25mg to about 1g.If the use liquid vehicle, preparation can be syrup, emulsion, soft gelatin capsule, aseptic injectable solution in the liquid suspension of ampoule or non-water or suspension.
In order to obtain stable water miscible formulation, compound or its pharmacy acceptable salt can be dissolved in the organic or inorganic aqueous acid, 0.3M succsinic acid or citric acid solution.Optionally, the tart derivative can be dissolved in suitable basic solution.If can not get soluble form, compound can be dissolved in suitable cosolvent or their combination.The example of suitable cosolvent like this includes but are not limited to, and concentration range is from the ethanol of 0-60% cumulative volume, propylene glycol, Liquid Macrogol, polysorbate 80, glycerine, polyoxyethylene fatty acid ester, Fatty Alcohol(C12-C14 and C12-C18) or the strong fatty acid ester of glycerine or the like.
Various release systems are known and can be used for compound or the administration of its various preparations that these preparations comprise tablet, capsule, injectable solution, the capsule in the liposome, particulate, microcapsule or the like.The method of introducing includes, but are not limited to skin, intracutaneous, muscle, endoperitoneal, intravenous, subcutaneous, nasal cavity, lung, peridural, eyes and (preferred usually) oral route.Compound can be by administration easily any or that other is suitable, for example by injecting or bolus injection, by epithelium or mucous membrane circuit (for example, oral mucosa, rectum and intestinal mucosa or the like) absorbs or support by carrying medicament and can be with its biologically active agent administration.Can whole body or topical.Be used for nose, when the treatment of segmental bronchus or lung disease or prevention, preferred route of administration is oral, nasal administration or segmental bronchus smoke substance or atomizer.
Description of drawings
Fig. 1 is the free amino canonical plotting of measuring in the gelatin for Fig. 1.
Embodiment
The compound that use table 1 of the present invention is listed is furthermore bright, but does not limit the present invention.
Table 1
Further specify the present invention below in conjunction with embodiment.
(R)-methyl 4-methyl-2-(preparation method of (S)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-hydrocinnamamide) methyl valerate (compound 1 in the table 1)
(10.81g 0.10mol), adds in the 250ml dehydrated alcohol, and stirring at normal temperature 15min is to dissolving, and (12.77g 0.11mol), has yellow solid to generate, and continues to stir 4h, and reaction finishes to add Pyruvic Acid Ethyl ester to take by weighing O-Phenylene Diamine.Suction filtration gets light yellow solid, and ethyl alcohol recrystallization obtains 3-methyl-quinoxaline-2 (1H)-ketone, and productive rate is 92.7%, m.p.=241-243 ℃; Take by weighing 3-methyl-quinoxaline-2 (1H)-ketone (8.01g, 0.05mol), Anhydrous potassium carbonate (8.29g, 0.06mol) and ethyl chloroacetate (7.353g, 0.06mol), add 200ml acetone, be suspension, add Tetrabutyl amonium bromide (0.5g, cat.), reflux under the oil bath condition, the TLC detection reaction finishes, remove solvent under reduced pressure, add 100ml water and 200ml ethyl acetate extraction three times, ethyl acetate be spin-dried for solid, get 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-ethyl acetate with ethyl alcohol recrystallization, productive rate is 73.2%, m.p.=120-122 ℃; (2.24g 0.04mol), adds 40ml distilled water, and stirring and dissolving is standby to take by weighing the potassium hydroxide solid.((4.93g 0.02mol), adds the 80ml dehydrated alcohol to 3-methyl-2-oxo quinoxaline-1 (2H)-yl)-ethyl acetate to take by weighing 2-, be suspension, stirring at normal temperature 10min adds the potassium hydroxide aqueous solution of preparation in advance, 40 ℃ of reaction 4h are spin-dried for solvent, add 20ml water, transfer pH=2 with 4N hydrochloric acid, filter, filter cake washes with water, gets 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-acetate with the tetrahydrofuran (THF) recrystallization, productive rate: 87.3%, m.p.=225～227 ℃; Take by weighing 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-acetate (2.18g, 0.01mol), HOBT (1.62g, 0.012mol), be suspended in the 60ml anhydrous methylene chloride, adding L-phenylalanine methyl ester hydrochloride behind the stirring at normal temperature 1h (2.37g, 0.011mol), EDCI (2.3g, 0.012mol), (2.53g 0.025mol), continues to stir 10h to anhydrous triethylamine, after the TLC detection reaction finishes, methylene dichloride is removed in decompression, uses the 100ml acetic acid ethyl dissolution, use successively the 1mol/L citric acid solution (2 * 50ml), saturated NaHCO
3Solution extraction (2 * 50ml), saturated NaCl solution (2 * 50ml) washing, organic layer removes solvent under reduced pressure after with anhydrous magnesium sulfate drying, get (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-methyl phenylpropionate with recrystallizing methanol, yield is 72.3%, m.p.=209-210 ℃.(2.24g 0.04mol), adds 50ml distilled water, and stirring and dissolving is standby to take by weighing the potassium hydroxide solid.(7.59g 0.02mol), adds dehydrated alcohol (100ml) to take by weighing compound (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-methyl phenylpropionate, stirring at normal temperature 10min, add the potassium hydroxide solution of preparation in advance, continue to stir 4h, reaction finishes.Remove solvent under reduced pressure, add 50ml distilled water, regulate about pH=2 with 4N hydrochloric acid, filter, filter cake washes with water, gets (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-phenylpropionic acid with the tetrahydrofuran (THF) recrystallization, yield is 85.2%, m.p.=225-227 ℃.Take by weighing (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-phenylpropionic acid (3.654g, 0.01mol), HOBT (1.485g, 0.011mol) be suspended in the 150ml anhydrous methylene chloride, add (R)-methyl 2-amino-4-methylvaleric acid methyl ester hydrochloride (1.998 behind the stirring at normal temperature 1h, 0.011mol), EDCI (2.108g, 0.011mol), anhydrous triethylamine (2.53g, 0.025mol), continue to stir 10h, after the TLC detection reaction finished, methylene dichloride was removed in decompression, use the 150ml acetic acid ethyl dissolution, use 1mol/L citric acid solution (2 * 50ml) successively, saturated NaHCO
3Solution extraction (2 * 50ml), saturated NaCl solution (2 * 50ml) washing, organic layer removes solvent under reduced pressure after with anhydrous magnesium sulfate drying, column chromatography (eluent: ethyl acetate/petroleum ether=1/6), yellow solid, productive rate: 53.1%, m.p.=241-242 ℃; ESI-MS 492.6 (M+H),
1H-NMR:(DMSO-d
6, ppm) δ: 0.8335 (d, J=6.6Hz, 3H, CH
3), 0.882 (d, J=6Hz, 3H, CH
3), 1.504-1.608 (m, 3H, CH, CH
2), 2.435 (s, 3H, CH
3), 2.762 (dd, J=10.8,13.8Hz, 2H, CH
2), 3.064 (dd, J=4.2,14.4Hz, 1H, NCH), 3.628 (s, 3H, CH
3), 4.299-4.337 (m, 1H, CHCO), 4.587-4.625 (m, 1H, CHCO), 4.695 (d, J=16.8Hz, 1H, NCHCO), 4.984 (d, J=16.8Hz, 1H, NCHCO), 6.829 (d, J=8.4Hz, 1H, ArH), 7.247-7.325 (m, 6H, ArH), 7.379 (t, J=7.2Hz, 1H, ArH), 7.730 (d, J=7.8Hz, 1H, ArH), 8.489 (d, J=7.8Hz, 1H, CONH), 8.712 (d, J=9Hz, 1H, CONH).
(S)-2-(preparation method of 2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-p-toluene propionic acid amide (compound 10 in the table 1)
(10.81g 0.10mol), adds the 250ml dehydrated alcohol to take by weighing O-Phenylene Diamine, stirring at normal temperature 15min is to dissolving, (12.77g 0.11mol), has yellow solid to generate to add Pyruvic Acid Ethyl ester, continue to stir 4h, the TLC detection reaction finishes, and suction filtration, ethyl alcohol recrystallization get light yellow solid 3-methyl-quinoxaline-2 (1H)-ketone, productive rate is 92.7%, m.p.=241-243 ℃; Take by weighing 3-methyl-quinoxaline-2 (1H)-ketone (8.01g, 0.05mol), Anhydrous potassium carbonate (8.29g, 0.06mol) and ethyl chloroacetate (7.353g, 0.06mol), add 200ml acetone, be suspension, add Tetrabutyl amonium bromide (0.5g, cat.), reflux under the oil bath condition, the TLC detection reaction finishes, remove solvent under reduced pressure, add 100ml water and 200ml ethyl acetate extraction three times, ethyl acetate be spin-dried for solid, get 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-ethyl acetate with ethyl alcohol recrystallization, productive rate is 73.2%, m.p.=120-122 ℃; (2.24g 0.04mol), adds 40ml distilled water, and stirring and dissolving is standby to take by weighing the potassium hydroxide solid.((4.93g 0.02mol), adds the 80ml dehydrated alcohol to 3-methyl-2-oxo quinoxaline-1 (2H)-yl)-ethyl acetate to take by weighing 2-, be suspension, stirring at normal temperature 10min adds the potassium hydroxide aqueous solution of preparation in advance, 40 ℃ of reaction 4h are spin-dried for solvent, add 20ml water, transfer pH=2 with 4N hydrochloric acid, filter, filter cake washes with water, gets 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-acetate with the tetrahydrofuran (THF) recrystallization, productive rate: 87.3%, m.p.=225-227 ℃; Take by weighing 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-acetate (2.18g, 0.01mol), HOBT (1.62g, 0.012mol), be suspended in the 60ml anhydrous methylene chloride, adding L-phenylalanine methyl ester hydrochloride behind the stirring at normal temperature 1h (2.37g, 0.011mol), EDCI (2.3g, 0.012mol), (2.53g 0.025mol), continues to stir 10h to anhydrous triethylamine, after the TLC detection reaction finishes, methylene dichloride is removed in decompression, uses the 100ml acetic acid ethyl dissolution, use successively the 1mol/L citric acid solution (2 * 50ml), saturated NaHCO
3Solution extraction (2 * 50ml), saturated NaCl solution (2 * 50ml) washing, organic layer removes solvent under reduced pressure after with anhydrous magnesium sulfate drying, get (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-methyl phenylpropionate with recrystallizing methanol, yield is 72.3%, m.p.=209-210 ℃.(2.24g 0.04mol), adds 50ml distilled water, and stirring and dissolving is standby to take by weighing the potassium hydroxide solid.(7.59g 0.02mol), adds dehydrated alcohol (100ml) to take by weighing compound (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-methyl phenylpropionate, stirring at normal temperature 10min, add the potassium hydroxide solution of preparation in advance, continue to stir 4h, reaction finishes.Remove solvent under reduced pressure, add 50ml distilled water, regulate about pH=2 with 4N hydrochloric acid, filter, filter cake washes with water, gets (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-phenylpropionic acid with the tetrahydrofuran (THF) recrystallization, yield is 85.2%, m.p.=225-227 ℃.Take by weighing (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-phenylpropionic acid (0.73g, 0.002mol), add the 20ml anhydrous methylene chloride, slowly be added dropwise to the 10ml sulfur oxychloride with constant pressure funnel then, stirring at normal temperature 0.5h, the TLC detection reaction finishes.Remove solvent under reduced pressure, (2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-phenylpropyl alcohol acyl chlorides, productive rate is 88.7% to get yellow-green colour solid (R)-2-.(0.11g 1mmol) is dissolved in the 20ml anhydrous methylene chloride, adds potassium tert.-butoxide (0.11g in batches to take by weighing para-totuidine, 1.02mmol), stirring at normal temperature 10min takes by weighing (R)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-phenylpropyl alcohol acyl chlorides (0.38g, 1mmol), add in batches, continue to stir 10h, after the TLC detection reaction finishes, remove solvent under reduced pressure, (eluent: petrol ether/ethyl acetate=3/1), get white solid, productive rate is 32.2% to column chromatography.m.p.＝277-278℃，ESI-MS?455.3(M+H)，
1H-NMR：(DMSO-d
6，ppm)δ：2.25(s，3H，CH
3)，2.44(s，3H，CH
3)，2.89(dd，J＝9.6，13.2Hz，1H，CH
2)，3.09(dd，J＝5.4，13.8Hz，1H，CH
2)，4.75(m，2H，NCH
2CO)，5.01(d，J＝16.2Hz，1H，CH)，6.96(d，J＝8.4Hz，1H，ArH)，7.12-7.47(m，12H，ArH)，7.74(d，J＝7.8Hz，1H，ArH)，8.86(d，J＝7.8Hz，1H，ArH)，10.03(s，1H，CONH).
(S)-N-(3-chloro-4-fluorophenyl)-2-(preparation method of 2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-hydrocinnamamide (compound 11 in the table 1)
(S)-(embodiment 2 is seen in the preparation of 2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-phenylpropyl alcohol acyl chlorides to 2-, take by weighing 3-chloro-4-fluoroaniline (0.15g, 1mmol) be dissolved in the 20ml anhydrous methylene chloride, add potassium tert.-butoxide (0.11g in batches, 1.02mmol) potassium tert.-butoxide, stirring at normal temperature 10min, add (R)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-phenylpropyl alcohol acyl chlorides (0.38g that has prepared in batches, 1mmol), continue to stir 10h, after the TLC detection reaction finishes, remove solvent under reduced pressure, add the 30ml ethyl acetate and make dissolving, with the saturated NaCl extraction of 20ml 2 times, organic layer with anhydrous magnesium sulfate drying after, remove solvent under reduced pressure, (eluent: petrol ether/ethyl acetate=5/1), (2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-hydrocinnamamide, yield is 47.1% to column chromatography to get white solid (R)-N-(3-chloro-4-fluorophenyl)-2-.m.p.＝251～253℃，ESI-MS?493.9(M+H)，
1H-NMR：(DMSO-d
6，ppm)δ：2.45(s，3H，CH
3)，2.91(dd，J＝9.6，13.2Hz，1H，CH
2)，3.10(dd，J＝5.4，13.8Hz，1H，CH
2)，4.66(m，2H，NCH
2CO)，5.00(d，J＝16.8Hz，1H，CH)，6.99(d，J＝8.4Hz，1H，ArH)，7.24-7.47(m，9H，ArH)，7.74((d，J＝7.8Hz，1H，ArH)，7.88(dd，J＝2.4，6.6Hz，1H，ArH)，8.92((d，J＝7.8Hz，1H，ArH)，10.33(s，1H，CONH).
Embodiment 4
2-(6, the preparation method of 7-two chloro-3-methyl-2-oxo quinoxaline-1 (2H)-yl)-N-(3, the 4-Dimethoxyphenyl) ethanamides (compound 15 in the table 1)
(S)-(embodiment 2 is seen in the preparation of 2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-phenylpropyl alcohol acyl chlorides to 2-.Take by weighing o-toluidine (0.107g, 1mmol) be dissolved in the 20ml anhydrous methylene chloride, add salt of wormwood (0.14g in batches, 1.02mmol), stirring at normal temperature 10min, add (R)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-phenylpropyl alcohol acyl chlorides (0.38g that has prepared in batches, 1mmol), continue to stir 10h, after the TLC detection reaction finishes, remove solvent under reduced pressure, add the 30ml ethyl acetate and make dissolving, with the saturated NaCl extraction of 20ml 2 times, organic layer with anhydrous magnesium sulfate drying after, remove solvent under reduced pressure, column chromatography (eluent: petrol ether/ethyl acetate=4/1), (2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-phenyl-N-O-toluene propionic acid amide, productive rate is 51.8% to get white solid (R)-2-.m.p.＝239～242℃，ESI-MS?454.7(M+H)，
1H-NMR：(DMSO-d
6，ppm)δ：2.07(s，3H，CH
3)，2.45(s?3H，CH
3)，2.94(dd，J＝9.6，13.8Hz，1H，CH)，3.15(dd，J＝5.4，13.8Hz，1H，CH)，4.79(m，2H，NCH
2CO)，5.05(d，J＝16.8Hz，1H，CHCO)，6.96(d，J＝8.4Hz，1H，ArH)，7.08-7.42(m，11H，ArH)，7.74(1H，d，J＝7.8Hz，ArH)，8.88(d，J＝8.4Hz，1H，ArH)，9.513(s，1H，CONH).
(R)-2-(preparation method of 2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-propyl group propionic acid amide (compound 23 in the table 1)
(S)-preparation of 2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-phenylpropionic acid sees embodiment 1, take by weighing (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-phenylpropionic acid (3.654g, 0.01mol), HOBT (1.485g, 0.011mol) be suspended in the 150ml anhydrous methylene chloride, add behind the stirring at normal temperature 1h propylamine (0.65g, 0.011mol), EDCI (2.108g, 0.011mol), (2.53g 0.025mol), continues to stir 10h to anhydrous triethylamine, after the TLC detection reaction finishes, methylene dichloride is removed in decompression, uses the 150ml acetic acid ethyl dissolution, uses 1mol/L citric acid solution (2 * 50ml) successively, saturated NaHCO
3Solution extraction (2 * 50ml), saturated NaCl solution (2 * 50ml) washing, organic layer removes solvent under reduced pressure after with anhydrous magnesium sulfate drying, column chromatography (eluent: ethyl acetate/petroleum ether=1/6 is to 1/3), white solid, productive rate: 49.8%, m.p.=241-242 ℃; ESI-MS 407.4 (M+H),
1H-NMR:(DMSO-d
6, ppm) δ: 0.790 (t, J=7.2Hz, 3H, CH
3), 1.355-1.391 (m, 2H, CH
2), 2.438 (s, 3H, CH
3), 2.785 (dd, J=9.6,13.8Hz, 1H, CH), 2.969-3.059 (m, 3H, CH
2, CH), and 4.469-4.507 (m, 1H, CH), 4.721 (d, J=16.8Hz, 1H, NCHCO), 5.023 (d, J=16.8Hz, 1H, NCHCO), 6.904 (d, J=8.4Hz, 1H, ArH), 7.230-7.327 (m, 6H, ArH), 7.732-7.410 (m, 1H, ArH), 7.724-7.740 (m, 1H, ArH), 8.022 (t, J=6Hz, 1H, CONH), 8.693 (d, J=9Hz, 1H, CONH).
6.1 target compound suppresses gelatinase activity test (In vitro)
6.1.1 principle: succinyl gelatin has been proved to be can be by the MMP-2 hydrolysis, and the height of the free amine group concentration that peptide bond hydrolysis produces is proportionate with enzymic activity.Free amine group in the succinyl oxide protection gelatin, the uncle's ammonia and 2,4 that exposes after the hydrolysis; 6-trinitro-benzene-sulfonic acid (TNBS) reaction solution; determine amino content by the optical density that detects 450nm wavelength place, thereby determine the activity of MMP-2, reflect the inhibition situation of compound indirectly MMP-2.
6.1.2 materials and methods:
Through biotech company of section, TNBS, gelatin are available from sigma company available from glad for MMP-2
6.1.2.1 free amino mensuration in the gelatin:
Glycine be dissolved in 50mmol/L sodium borate buffer liquid (5ml, pH8.5) in, be mixed with 0.007mol/L solution, get different volumes glycine solution and TNBS the reaction 30min, specimen sees Table 2, makes typical curve as shown in Figure 1.
Table 2
Typical curve is: A=0.13485C-0.10038
Gelatin is mixed with the solution of 20mg/3mL, and measuring optical density as stated above is 0.142, promptly contains 1.8 μ mol free amine groups in the 20mg gelatin approximately.
6.1.2.2 gelatin succinylation:
Gelatin (200mg) is dissolved in 50mmol/L sodium borate buffer liquid (10ml, pH=8.5) in, succinyl oxide (20mg) adds in batches, regulate with 1mol/L NaOH, make solution keep pH8.0-8.5, reaction 5h with fully dialysis of 50mmol/L sodium borate buffer liquid (pH8.5) (dialysis is three times in the 48h), obtains succinyl gelatin solution.
6.1.2.3 gelatinase activation analysis:
Add above-mentioned succinyl gelatin solution 55 μ L (containing 200 μ g succinyl gelatins approximately) in 96 orifice plates respectively, enzyme solution (the 3mg enzyme is dissolved among 50mmol/L sodium borate buffer liquid (pH=8.5) 100ml), 50mmol/L sodium borate buffer liquid (pH=8.5) is supplied 150 μ L, 37 ℃ of hatching 30min, add 0.03%TNBS solution 50 μ L, room temperature is placed 20min, measures optical density, result such as table 3, table 4 in 450nm wavelength place.
Table 3
Blank group
Table 4
Optical density in No. 1 hole is 0.418, is suitable for optical density and measures, so the volume of selected enzyme solution is 5 μ L.
6.1.2.4 pressing down enzyme detects:
Add above-mentioned succinyl gelatin solution 55 μ L in 96 orifice plates respectively, gelatinase solution 5 μ L, the compound of different gradient concentrations, 50mmol/L sodium borate buffer liquid (pH=8.5) is supplied 150 μ L; 100% group does not contain inhibitor, and blank group only adds 5 μ L gelatinase solution, all supplies 150 μ L with sodium borate buffer liquid.37 ℃ of hatching 30min add 0.03%TNBS solution 50 μ L, and room temperature is placed 20min, measure optical density in 450nm wavelength place.Calculate inhibiting rate according to following formula:
According to compound concentration and corresponding inhibition ratio, utilize OriginPro 7.5 software processes, obtain the IC of each compound
50Result such as following table 5:
Table 5
Claims (10)
1. have the quinazolinone small molecules class peptide derivant of matrix metalloproteinase inhibitory activity, it has the structure of following general formula (I):
In the formula: R
1, R
2, R
3And R
4Identical or different, be hydrogen, C independently of one another
1～8Straight or branched alkyl, C
2-8Straight or branched thiazolinyl, C
2-8Straight or branched alkynyl, assorted alkyl, C
3-12Cycloalkyl, following substituting group, and at least one is following substituting group: halogen, nitro, aryl, heteroaryl, hydroxyl, aryloxy, heteroaryl oxygen base, assorted alkoxyl group, amino, C
1～8Straight or branched amino, dialkyl amido, arylamino, heteroaryl amino, C
1～8Alkyl aryl amino, assorted alkylamino, sulfydryl, C
1～8Alkyl thiol, aryl sulfydryl, heteroaryl sulfydryl, assorted alkyl thiol, C
1～8Alkyl sulphonyl, aryl sulfonyl, heteroarylsulfonyl, C
1～8Alkane sulfoxide group, aryl sulfoxide group, heteroaryl sulfoxide group, cyano group, C
1～8Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, C
1～8Alkoxyl group or C
1～8Haloalkyl;
R
5For carboxyl becomes methyl esters/ethyl substituted natural L-amino acid residue, other primary amine groups that replace arbitrarily or any other secondary amine that replace; Wherein natural L-amino acid residue comprises 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 and L-tryptophane; Other primary amine groups that replace comprise arylamino, heteroaryl amino, C arbitrarily
1～8Alkyl aryl amino, assorted alkylamino, C
1-8Straight or branched alkylamino, pentamethylene base amino, hexanaphthene amino, γ-An Jidingsuan methyl esters and 6-aminocaprolc acid methyl esters; Other secondary amine that replace comprise the two C of replacement of N-arbitrarily
1-4Alkylamino, morpholinyl, piperazinyl and substituted piperazinyl;
R
6Be pharmaceutically acceptable mineral acid or organic acid.
2. according to the described Quinoxalinone derivative of claim 1, it is characterized in that R with matrix metalloproteinase inhibitory activity
6Be hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, heavy sulfuric acid, phosphoric acid, carbonic acid, stable hydrocarbon acid, unsaturated hydrocarbons acid, polyacid or various replacement organic carboxyl acid.
3. according to the described Quinoxalinone derivative of claim 1, it is characterized in that, comprise following compounds with matrix metalloproteinase inhibitory activity;
(R)-methyl 4-methyl-2-((S)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-Phenylpropionamide) methyl valerate,
(S)-methyl 3-(4-oxybenzene)-2-((S)-2-(2-(3-methyl-2-oxygen-quinoline beautiful jade-1-(2H)-yl) acetamido)-3-Phenylpropionamide) methyl propionate,
(S)-methyl 4-(2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-Phenylpropionamide) methyl-butyrate,
(S)-methyl 6-(2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-Phenylpropionamide) methyl caproate,
(R)-methyl 4-((S)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-Phenylpropionamide)-4-methylmercapto butyric acid methyl esters,
(S)-N-(3, the 4-dichlorophenyl)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide,
(S)-N-(4-chloro-phenyl-)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide,
(S)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-p-toluene propionic acid amide,
(S)-N-(3-chloro-4-fluorophenyl)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide,
(S)-N-(4-bromophenyl)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide,
(S)-N-(3, the 4-difluorophenyl)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide,
(S)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-N, 3-diphenylprop acid amides,
(S)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-o-toluene propionic acid amide,
(S)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-m-toluene propionic acid amide,
(S)-N-sec.-propyl-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide,
(S, E)-N-(1-(4-cinnamyl piperazine-1-yl)-1-oxygen-3 hydrocinnamyl-2-yl)-2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) ethanamide,
(R)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-propyl group propionic acid amide,
(R)-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-propyl group propionic acid amide,
(R)-N-butyl-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide,
(S)-and N, N-diethyl-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide.
4. according to the described preparation method of claim 1, it is characterized in that may further comprise the steps with quinazolinone small molecules class peptide derivant of matrix metalloproteinase inhibitory activity:
(1) use 2-, 3-, 4-, 5-position respectively by R
1, R
2, R
3, R
4O-Phenylene Diamine that replaces and Pyruvic Acid Methyl ester be heating reflux reaction Cheng Huan in certain solvent, resulting product again with ethyl chloroacetate or ethyl bromoacetate under the weak base catalyst effect, heating reflux reaction prepares compound (II) in ethanol or acetone solvent;
(2) compound (II) under the basic catalyst effect in certain solvent, obtain compound (III) 60～100 ℃ of following hydrolysis;
(3) compound (III) is under the effect of alkali, condensing agent CDI or condensing agent EDCHCl+HOBt or condensing agent DCC or condensing agent IBCF, in reaction solvent with the phenylalanine methyl ester hydrochloride condensation, obtain compound (IV), then compound (IV) under the basic catalyst effect in aqueous ethanolic solution or methanol aqueous solution or THF 60～100 ℃ of following hydrolysis obtain compound (V);
(4) compound (V) obtains target product (I) with the condensation of various amino acid methyl ester hydrochloride in reaction solvent under the effect of alkali, condensing agent CDI or condensing agent EDCHCl+HOBt or condensing agent DCC or condensing agent IBCF; Perhaps earlier in reaction solvent, with SOCl
2Or PCl
3Reaction obtains compound (VI), and compound (VI) obtains (I) with various amino-complex condensation reactions under the basic catalyst effect then;
5. according to the described preparation method of claim 4 with quinazolinone small molecules class peptide derivant of matrix metalloproteinase inhibitory activity, it is characterized in that, solvent described in the step (1) is dehydrated alcohol, anhydrous tetrahydro furan, anhydrous methylene chloride or anhydrous 1, the 4-dioxane; The consumption of described solvent is that 2-, 3-, 4-, the 5-position of every mmole is respectively by R
1, R
2, R
3, R
4The O-Phenylene Diamine that replaces is with 6～7mL solvent; Described 2-, 3-, 4-, 5-position are respectively by R
1, R
2, R
3, R
4The O-Phenylene Diamine that replaces and the mol ratio of Pyruvic Acid Methyl ester consumption are 1: 1.1～1.2; Described weak base catalyst is weak mineral alkali; The mol ratio of described annulation product and bromo or chloracetic acid ethyl ester and weak base catalyst consumption is 1: 1.1～1.2: 1.1～1.2; The consumption of described ethanol or acetone solvent is that the annulation product of every mmole is with 8～10mL solvent.
6. according to the described preparation method of claim 4, it is characterized in that the solvent described in the step (2) is V with quinazolinone small molecules class peptide derivant of matrix metalloproteinase inhibitory activity
Water: V
Ethanol=1: 1～5 aqueous ethanolic solution or V
Water: V
Methyl alcohol=1: 1～5 methanol aqueous solution or THF, consumption is that the compound (II) of every mmole is with 8～10mL solvent, used basic catalyst is potassium hydroxide, sodium hydroxide or lithium hydroxide, and described compound (II) is 1: 1.2～2 with the mol ratio of basic catalyst consumption.
7. according to the described preparation method of claim 4 with quinazolinone small molecules class peptide derivant of matrix metalloproteinase inhibitory activity, it is characterized in that, solvent described in the step (3) is anhydrous DCM, THF or DMF, and consumption is that the compound (III) of every mmole is with 8～15mL solvent; Used alkali is triethylamine, N-methylmorpholine, salt of wormwood or yellow soda ash; Described compound (III) is 1: 1.2～1.5: 1.2～1.5: 1.2～1.5 with the mol ratio of the consumption of phenylalanine methyl ester hydrochloride and condensing agent and alkali; Described aqueous ethanolic solution is V
Water: V
Ethanol=1: 1～5, methanol aqueous solution is V
Water: V
Methyl alcohol=1: 1～5, described aqueous ethanolic solution or methanol aqueous solution or THF consumption are that the compound (IV) of every mmole is with 8～10mL, used basic catalyst is potassium hydroxide, sodium hydroxide or lithium hydroxide, and compound (IV) is 1: 1.2～2 with the mol ratio of basic catalyst consumption.
8. according to the described preparation method of claim 4 with quinazolinone small molecules class peptide derivant of matrix metalloproteinase inhibitory activity, it is characterized in that, alkali described in the step (4) is triethylamine, N-methylmorpholine, salt of wormwood or yellow soda ash, described compound (V) is 1: 1.2～1.5: 1.2～1.5: 1.2～1.5 with the mol ratio of the consumption of various amino acid methyl ester hydrochlorides and condensing agent and alkali, described basic catalyst is t-BuOK, potassium hydroxide, sodium hydroxide or lithium hydroxide, described compound (VI) is 1: 1.2～1.5 with the mol ratio of basic catalyst consumption, described compound (VI) and various amino-complexs and SOCl
2/ PCl
3The mol ratio of consumption be 1: 1.2～1.5: 1.2～1.5, described reaction solvent is anhydrous DCM, anhydrous THF, dry DMF or anhydrous dioxane, the compound (V) that consumption is every mmole is with 8～10mL solvent.
9. preparing the especially medicine of human diseases of prevention or the treatment Mammals relevant, the particularly application in the medicine of preparation prevention or treatment cancer, inflammation, multiple sclerosis disease, various tissue ulcer, various tissue ulcers venereal disease disease and periodontopathy according to the described quinazolinone small molecules class peptide derivant of claim 1 with the matrix metal proteinase activity unconventionality expression with matrix metalloproteinase inhibitory activity.
10. pharmaceutical composition, it is characterized in that, except that containing one or more pharmaceutically acceptable carriers or vehicle, also comprise at least a kind of contain therapeutic dose according to the described quinazolinone small molecules class peptide derivant of claim 1 with matrix metalloproteinase inhibitory activity.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101948418A (en) * | 2010-08-06 | 2011-01-19 | 山东大学 | Hydroxyproline structure-containing HIV-1 protease inhibitor as well as preparation method and application thereof |
| CN110981819A (en) * | 2019-12-24 | 2020-04-10 | 广西师范大学 | Quinoxaline signal channel inhibitor and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101514192B (en) * | 2009-04-02 | 2012-05-23 | 山东大学 | Quinoxalinone derivative with activity for reversing tumor cell multidrug resistance and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101948418A (en) * | 2010-08-06 | 2011-01-19 | 山东大学 | Hydroxyproline structure-containing HIV-1 protease inhibitor as well as preparation method and application thereof |
| CN101948418B (en) * | 2010-08-06 | 2012-06-13 | 山东大学 | Hydroxyproline structure-containing HIV-1 protease inhibitor as well as preparation method and application thereof |
| CN110981819A (en) * | 2019-12-24 | 2020-04-10 | 广西师范大学 | Quinoxaline signal channel inhibitor and preparation method and application thereof |
| CN110981819B (en) * | 2019-12-24 | 2022-07-01 | 广西师范大学 | Quinoxaline signal channel inhibitor and preparation method and application thereof |
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