CN101701032B - 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. The formula (I) is shown in the description.
Description
Technical field
The present invention relates to quinazolinone small molecules class peptide matrix metallo-proteinase inhibitor and its preparation method and application, belong to pharmaceutical chemistry technical field.
Background technology
Malignant tumour is one of principal disease causing mankind's death, finds the cancer therapy drug that the selectivity of high-efficiency low-toxicity is high 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 in tumor growth, invasion and attack, transfer and cancerous tissue angiogenic growth, has brought into play crucial effect.Found at present 28 kinds of mammiferous MMP hypotypes, the MMPs family member who so classifies numerous, and because the high expression level of MMPs has participated in the numerous physiological processs of human body, it is obviously inappropriate therefore suppressing all MMPs family members.People recognize the importance of exploitation specificity MMPs inhibitor thus.At present the research of MMP inhibitor is concentrated on and designed and synthesized the high specific inhibitor of a certain MMPs family member selectivity, thereby reduce toxic side effect, raising effect selectivity.
Confirmed MMP-2(gelatin enzyme A) closely related with the malignant phenotype of invasive tumor and cancer patients's poor prognosis, it has participated in the transfer of tumour cell to the invasion and attack of basilar membrane, matrix and cancer cells.In healthy tissues, do not express MMP-2, and in 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 shot design and find specificity and inhibitor that selectivity is high, is a class very promising in 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 likely become therapeutic index higher can be used for clinical medicine.
Another object of the present invention is to provide the preparation method and application of this analog derivative.
The technical scheme that the present invention takes is:
The quinazolinone small molecules class peptide derivant with matrix metalloproteinase inhibitory activity, it has the structure of following general formula (I):
In 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 sulfoxid es base, 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 the natural L-amino acid residue of methyl esters/ethyl substituted, other primary amine groups that replace arbitrarily or any other secondary amine that replace; Wherein natural L-amino acid residue comprises Serine, L-arginine, L-threonine, L-glycine, L-Aspartic acid, ALANINE, L-glutaminate, Valine, TYR, L-Leu, ILE, Cys, altheine, L-Phe, Pidolidone, METHIONINE, L-Histidine, L-PROLINE, L-oxyproline, 1B and L-Trp; Other primary amine groups that replace arbitrarily comprise arylamino, heteroaryl amino, C
1～8alkyl aryl amino, assorted alkylamino, C
1-8straight or branched alkylamino, pentamethylene base are amino, hexanaphthene is amino, γ-aminobutyric acid methyl esters and 6-aminocaprolc acid methyl esters; Other secondary amine that replace arbitrarily comprise the two C of replacement of N-
1-4alkylamino, morpholinyl, piperazinyl and substituted piperazinyl;
(3) R
6for 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, pearly-lustre resin acid, stearic acid, eicosanoic acid, docosoic, cerinic acid, myricyl acid), unsaturated hydrocarbons acid (as loses resin acid, β-crotonic acid 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, Acetylformic acid, 2-hydroxyl-1,2,3-, the third three acid, fumaric acid, gluconic acid, saccharic acid, phenylformic acid, toluylic acid, 2 hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, methylsulfonic acid, ethyl sulfonic acid, cyclohexyl-sulfinic acid, Phenylsulfonic acid, tosic acid, coffic acid, bar is acid not, oxysuccinic acid, citric acid, xitix, pseudolaricis acid, chlorogenic acid etc.).
In the present invention, above-mentioned term implication is as follows:
Assorted alkyl refers to saturated or undersaturated, side chain or straight chain, substituted or unsubstitutedly at least contain a heteroatomic alkyl.
Aryl refers to 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, cyclic group replacement or unsubstituted, and this ring can be monocycle or condensed ring, bridged ring or volution or contain heteroatomic ring system.Monocycle is 3～9 atoms preferably, and many rings are 7～13 atoms preferably, and heteroatoms refers to nitrogen, sulphur, phosphorus, oxygen etc.
Heteroaryl is aromatic heterocycle, can be monocycle or encircle more, preferred heteroaryl comprises: thienyl, pyrryl, furyl, pyridyl, pyrazine, thiazolyl, quinolyl, isoquinoline 99.9, pyrimidyl, tetrazole base, benzofuryl, benzothiazolyl, indyl, piperazinyl, tetrahydrochysene piperazinyl etc.
The described preferred following compounds of quinazolinone small molecules class peptide derivant with matrix metalloproteinase inhibitory activity:
(R)-methyl 4-methyl-2-((R)-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-quinoxaline-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-(3,4-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-(the chloro-4-fluorophenyl of 3-)-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-(3,4-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)-N, N-diethyl-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-Phenylpropionamide.
The preparation method with the quinazolinone small molecules class peptide derivant of matrix metalloproteinase inhibitory activity, comprises the following steps:
(1) use 2-, 3-, 4-, 5-position respectively by R
1, R
2, R
3, R
4the O-Phenylene Diamine replacing and Pyruvic Acid Methyl ester be heating reflux reaction Cheng Huan in certain solvent, resulting product again with ethyl chloroacetate or ethyl bromoacetate under weak base catalyst effect, in ethanol or acetone solvent, heating reflux reaction prepares compound (II);
(2) compound (II) is under basic catalyst effect in certain solvent, and at 60～100 ℃, hydrolysis obtains compound (III);
(3) compound (III) is at alkali, condensing agent CDI or condensing agent EDCHCl+HOBt(EDCHCl and HOBt mol ratio 1:1) or the effect of condensing agent DCC or condensing agent IBCF under, in reaction solvent with phenylalanine methyl ester hydrochloride condensation, obtain compound (IV), then compound (IV) is hydrolyzed and obtains compound (V) at 60～100 ℃ under basic catalyst effect in aqueous ethanolic solution or methanol aqueous solution or THF;
(4) compound (V) is at alkali, condensing agent CDI or condensing agent EDCHCl+HOBt(EDCHCl and HOBt mol ratio 1:1) or the effect of condensing agent DCC or condensing agent IBCF under, in reaction solvent, obtain target product (I) with various amino acid methyl ester hydrochloride condensations; Or first in reaction solvent, with SOCl
2or PCl
3reaction obtains compound (VI), and then compound (VI) obtains (I) with various amino-complex condensation reactions under basic catalyst effect.
Solvent described in above-mentioned steps (1) is dehydrated alcohol, anhydrous tetrahydro furan, anhydrous methylene chloride or anhydrous Isosorbide-5-Nitrae-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
46～7mL the solvent for O-Phenylene Diamine replacing; Described 2-, 3-, 4-, 5-position are respectively by R
1, R
2, R
3, R
4the O-Phenylene Diamine replacing and the mol ratio of Pyruvic Acid Methyl ester consumption are 1:1.1～1.2; Described weak base catalyst is weak mineral alkali, preferably sodium carbonate or salt of wormwood; The mol ratio of described annulation product and bromo or ethyl chloroacetate and weak base catalyst consumption is 1:1.1～1.2:1.1～1.2; 8～10mL solvent for annulation product that described ethanol or the consumption of acetone solvent are every mmole.
Solvent described in step (2) is preferentially selected aqueous ethanolic solution (V
water: V
ethanol=1:1～5) or methanol aqueous solution (V
water: V
methyl alcohol=1:1～5) or THF, consumption is 8～10mL solvent for compound (II) of every mmole, basic catalyst used 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 step (3) is anhydrous DCM, THF or DMF, 8～15mL solvent for the compound that consumption is every mmole (III); Alkali used is triethylamine, N-methylmorpholine, salt of wormwood or sodium carbonate; 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=1:1～5,8～10mL for compound (IV) that described aqueous ethanolic solution or methanol aqueous solution or THF consumption are every mmole, basic catalyst used 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 step (4) is triethylamine, N-methylmorpholine, salt of wormwood or sodium carbonate, 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, consumption is 8～10mL solvent for compound (V) of every mmole.
The quinazolinone small molecules class peptide derivant with matrix metalloproteinase inhibitory activity of the present invention, the syntheti c 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 a matrix metalloproteinase inhibitory activity is preparation prevention or the treatment Mammals relevant to matrix metal proteinase activity the unconventionality expression especially medicine of human diseases, particularly in preparation prevention or treat the application in the medicine of cancer, inflammation, multiple sclerosis, various tissue ulcer, various tissue ulcers venereal disease disease and periodontopathy.These compounds of the present invention can suppress at least one mammiferous matrix metalloproteinase, preferably MMP-2.Therefore, the present invention's design contains the pharmaceutically acceptable pharmaceutical composition that formula (I) structural compounds is main active ingredient.
A pharmaceutical composition, except containing one or more pharmaceutically acceptable carriers or vehicle, also at least comprises the quinazolinone small molecules class peptide derivant that a kind of the present invention who contains therapeutic dose has matrix metalloproteinase inhibitory activity.
This kind of composition can be made into oral preparations and parenteral formulations, can be tablet, pill, capsule or injection.
The medicine that the present invention comprises 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 using can be solid or liquid.
Typical solid carrier comprises lactose, terra alba, sucrose, talcum, gel, agar, pectin, gum arabic, Magnesium Stearate, stearic acid etc.Solid carrier also can comprise that 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 encapsulating material.In powder, carrier is pulverizing solid, and it mixes with pulverizing activeconstituents.In tablet, activeconstituents mixes with suitable ratio with the carrier with necessary compression property, with 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.
Typical liquid vehicle comprises syrup, peanut oil, sweet oil, water etc.Liquid vehicle is for the preparation of 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 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, 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.Carrier for administered parenterally can also be for grease be as ethyl oleate and sec.-propyl myristate.Aseptic liquid vehicle is for the aseptic fluid composition of parenteral admin.For the liquid vehicle of pressurized compositions, it 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.During injection, can push or inject gradually by single, entering the intravenously perfusion of 30 minutes.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 etc.When preparation is when oral, generally acknowledge PHOSALPG-50(phospholipid and 1,2-propylene glycol is concentrated, A.Nattermann & Cie.GmbH) 0.01% tween 80 in, for the preparation of the acceptable oral preparations of other compounds, can be adapted to the preparation of the various compounds of the present invention.
While giving the compounds of this invention, can use medicament forms miscellaneous.If use solid carrier, preparation can be tablet, is placed into powder or piller form or lozenge or lozenge form in hard capsule.The amount of solid carrier changes to a great extent, but preferably from about 25mg to about 1g.If use liquid vehicle, preparation can be syrup, emulsion, soft gelatin capsule, the 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 to organic or inorganic aqueous acid, 0.3M succsinic acid or citric acid solution.Optionally, acid derivative can be dissolved in suitable basic solution.If can not get soluble form, compound can be dissolved in to 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 or the strong fatty acid ester of glycerine etc.
Various release systems are known and can be used for compound or the administration of its various preparations, and these preparations comprise tablet, capsule, injectable solution, the capsule in liposome, particulate, microcapsule etc.The method of introducing includes, but are not limited to skin, intracutaneous, muscle, endoperitoneal, intravenous, subcutaneous, nasal cavity, lung, peridural, eyes and (conventionally preferred) 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 etc.) absorb or the support by carrying medicament and can administration together with its biologically active agent.Can whole body or topical.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.
Accompanying drawing explanation
Fig. 1 is the canonical plotting of gelatin free ammonia based assays.
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
Below in conjunction with embodiment, further illustrate the present invention.
(R) preparation method of-methyl 4-methyl-2-((S)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-Phenylpropionamide) methyl valerate (in table 1, compound 1)
Take O-Phenylene Diamine (10.81g, 0.10mol), add in 250ml dehydrated alcohol, stirring at normal temperature 15min, to dissolving, adds Pyruvic Acid Ethyl ester (12.77g, 0.11mol), has yellow solid to generate, and continues to stir 4h, reacts complete.Suction filtration, obtains light yellow solid, and ethyl alcohol recrystallization obtains 3-methyl-quinoxaline-2 (1H)-one, and productive rate is 92.7%, m.p.=241-243 ℃; Take 3-methyl-quinoxaline-2 (1H)-one (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 oil bath condition, TLC detection reaction is complete; remove solvent under reduced pressure; add 100ml water and the extraction of 200ml ethyl acetate three times, ethyl acetate is spin-dried for to obtain solid, with ethyl alcohol recrystallization, obtains 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-ethyl acetate; productive rate is 73.2%, m.p.=120-122 ℃; Take potassium hydroxide solid (2.24g, 0.04mol), add 40ml distilled water, stirring and dissolving, standby.Take 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-ethyl acetate (4.93g, 0.02mol), add 80ml dehydrated alcohol, be suspension, stirring at normal temperature 10min, add the potassium hydroxide aqueous solution of preparation in advance, 40 ℃ of reaction 4h, are spin-dried for solvent, add 20ml water, with 4N hydrochloric acid, adjust pH=2, filter, filter cake washes with water, with tetrahydrofuran (THF) recrystallization, obtains 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-acetic acid, productive rate: 87.3%, m.p.=225～227 ℃; Take 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-acetic acid (2.18g, 0.01mol), HOBT(1.62g, 0.012mol), be suspended in 60ml anhydrous methylene chloride, after stirring at normal temperature 1h, add L-Phe methyl ester hydrochloride (2.37g, 0.011mol), EDCI (2.3g, 0.012mol), anhydrous triethylamine (2.53g, 0.025mol), continues to stir 10h, after TLC detection reaction, methylene dichloride is removed in decompression, uses 100ml acetic acid ethyl dissolution, uses successively 1mol/L citric acid solution (2 * 50ml), saturated NaHCO
3solution extraction (2 * 50ml), saturated NaCl solution (2 * 50ml) washing, organic layer is with removing solvent after anhydrous magnesium sulfate drying under reduced pressure, by recrystallizing methanol, obtain (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-methyl phenylpropionate, yield is 72.3%, m.p.=209-210 ℃.Take potassium hydroxide solid (2.24g, 0.04mol), add 50ml distilled water, stirring and dissolving, standby.Take compound (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-methyl phenylpropionate (7.59g, 0.02mol), add dehydrated alcohol (100ml), stirring at normal temperature 10min, add the potassium hydroxide solution of preparation in advance, continue to stir 4h, react complete.Remove solvent under reduced pressure, add 50ml distilled water, with 4N hydrochloric acid, regulate pH=2 left and right, filter, filter cake washes with water, with tetrahydrofuran (THF) recrystallization, obtain (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-phenylpropionic acid, yield is 85.2%, m.p.=225-227 ℃.Take (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 150ml anhydrous methylene chloride, after stirring at normal temperature 1h, add (R)-methyl 2-amino-4-methylvaleric acid methyl ester hydrochloride (1.998, 0.011mol), EDCI (2.108g, 0.011mol), anhydrous triethylamine (2.53g, 0.025mol), continue to stir 10h, after TLC detection reaction, methylene dichloride is removed in decompression, use 150ml acetic acid ethyl dissolution, use successively 1mol/L citric acid solution (2 * 50ml), saturated NaHCO
3solution extraction (2 * 50ml), saturated NaCl solution (2 * 50ml) washing, organic layer is with removing solvent after anhydrous magnesium sulfate drying under reduced pressure, column chromatography (eluent: ethyl acetate/petroleum ether=1/6), obtain yellow solid, productive rate: 53.1%, m.p.=241-242 ℃, ESI-MS492.6 (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) preparation method of-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-p-toluene propionic acid amide (in table 1, compound 10)
Take O-Phenylene Diamine (10.81g, 0.10mol), add 250ml dehydrated alcohol; stirring at normal temperature 15min is to dissolving; add Pyruvic Acid Ethyl ester (12.77g, 0.11mol), have yellow solid to generate; continue to stir 4h; TLC detection reaction is complete, suction filtration, and ethyl alcohol recrystallization obtains light yellow solid 3-methyl-quinoxaline-2 (1H)-one; productive rate is 92.7%, m.p.=241-243 ℃; Take 3-methyl-quinoxaline-2 (1H)-one (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 oil bath condition, TLC detection reaction is complete; remove solvent under reduced pressure; add 100ml water and the extraction of 200ml ethyl acetate three times, ethyl acetate is spin-dried for to obtain solid, with ethyl alcohol recrystallization, obtains 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-ethyl acetate; productive rate is 73.2%, m.p.=120-122 ℃; Take potassium hydroxide solid (2.24g, 0.04mol), add 40ml distilled water, stirring and dissolving, standby.Take 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-ethyl acetate (4.93g, 0.02mol), add 80ml dehydrated alcohol, be suspension, stirring at normal temperature 10min, add the potassium hydroxide aqueous solution of preparation in advance, 40 ℃ of reaction 4h, are spin-dried for solvent, add 20ml water, with 4N hydrochloric acid, adjust pH=2, filter, filter cake washes with water, with tetrahydrofuran (THF) recrystallization, obtains 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-acetic acid, productive rate: 87.3%, m.p.=225-227 ℃; Take 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-acetic acid (2.18g, 0.01mol), HOBT(1.62g, 0.012mol), be suspended in 60ml anhydrous methylene chloride, after stirring at normal temperature 1h, add L-Phe methyl ester hydrochloride (2.37g, 0.011mol), EDCI (2.3g, 0.012mol), anhydrous triethylamine (2.53g, 0.025mol), continues to stir 10h, after TLC detection reaction, methylene dichloride is removed in decompression, uses 100ml acetic acid ethyl dissolution, uses successively 1mol/L citric acid solution (2 * 50ml), saturated NaHCO
3solution extraction (2 * 50ml), saturated NaCl solution (2 * 50ml) washing, organic layer is with removing solvent after anhydrous magnesium sulfate drying under reduced pressure, by recrystallizing methanol, obtain (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-methyl phenylpropionate, yield is 72.3%, m.p.=209-210 ℃.Take potassium hydroxide solid (2.24g, 0.04mol), add 50ml distilled water, stirring and dissolving, standby.Take compound (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-methyl phenylpropionate (7.59g, 0.02mol), add dehydrated alcohol (100ml), stirring at normal temperature 10min, add the potassium hydroxide solution of preparation in advance, continue to stir 4h, react complete.Remove solvent under reduced pressure, add 50ml distilled water, with 4N hydrochloric acid, regulate pH=2 left and right, filter, filter cake washes with water, with tetrahydrofuran (THF) recrystallization, obtain (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-phenylpropionic acid, yield is 85.2%, m.p.=225-227 ℃.Take (S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-phenylpropionic acid (0.73g, 0.002mol), add 20ml anhydrous methylene chloride, then by constant pressure funnel, be slowly added dropwise to 10ml sulfur oxychloride, stirring at normal temperature 0.5h, TLC detection reaction is complete.Remove solvent under reduced pressure, obtain yellow-green colour solid (R)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-phenylpropyl alcohol acyl chlorides, productive rate is 88.7%.Take para-totuidine (0.11g, 1mmol) be dissolved in 20ml anhydrous methylene chloride, add potassium tert.-butoxide (0.11g in batches, 1.02mmol), stirring at normal temperature 10min, take (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 TLC detection reaction, remove solvent under reduced pressure, column chromatography (eluent: petrol ether/ethyl acetate=3/1), obtain white solid, productive rate is 32.2%.m.p.=277-278℃，ESI-MS455.3(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) preparation method of-N-(the chloro-4-fluorophenyl of 3-)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-hydrocinnamamide (in table 1, compound 11)
(S) embodiment 2 is shown in the preparation of-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-phenylpropyl alcohol acyl chlorides, take the chloro-4-fluoroaniline of 3-(0.15g, 1mmol) be dissolved in 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) the acetamido)-3-phenylpropyl alcohol acyl chlorides (0.38g having prepared in batches, 1mmol), continue to stir 10h, after TLC detection reaction, remove solvent under reduced pressure, add 30ml ethyl acetate to make to dissolve, with the saturated NaCl extraction of 20ml 2 times, organic layer is with after anhydrous magnesium sulfate drying, remove solvent under reduced pressure, column chromatography (eluent: petrol ether/ethyl acetate=5/1), obtain white solid (R)-N-(the chloro-4-fluorophenyl of 3-)-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-hydrocinnamamide, yield is 47.1%.m.p.=251～253℃，ESI-MS493.9(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).
(R) preparation method of-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-(o-tolyl) propionic acid amide (in table 1, compound 15)
(S) embodiment 2 is shown in the preparation of-2-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido)-3-phenylpropyl alcohol acyl chlorides.Take o-toluidine (0.107g, 1mmol) be dissolved in 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) the acetamido)-3-phenylpropyl alcohol acyl chlorides (0.38g having prepared in batches, 1mmol), continue to stir 10h, after TLC detection reaction, remove solvent under reduced pressure, add 30ml ethyl acetate to make to dissolve, with the saturated NaCl extraction of 20ml 2 times, organic layer is with after anhydrous magnesium sulfate drying, remove solvent under reduced pressure, column chromatography (eluent: petrol ether/ethyl acetate=4/1), obtain white solid, productive rate is 51.8%.m.p.=239～242℃，ESI-MS454.7(M+H)，
1H-NMR:(DMSO-d
6,ppm)δ:2.07(s,3H,CH
3),2.45(s3H,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) preparation method of-2-(2-(3-methyl-2-oxygen quinoxaline-1 (2H)-yl) acetamido)-3-phenyl-N-propyl group propionic acid amide (in table 1, compound 23)
(S)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acetamido) embodiment 1 is shown in the preparation of-phenylpropionic acid, take (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 150ml anhydrous methylene chloride, after stirring at normal temperature 1h, add propylamine (0.65g, 0.011mol), EDCI (2.108g, 0.011mol), anhydrous triethylamine (2.53g, 0.025mol), continue to stir 10h, after TLC detection reaction, methylene dichloride is removed in decompression, use 150ml acetic acid ethyl dissolution, use successively 1mol/L citric acid solution (2 * 50ml), saturated NaHCO
3solution extraction (2 * 50ml), saturated NaCl solution (2 * 50ml) washing, organic layer is with removing solvent after anhydrous magnesium sulfate drying under reduced pressure, and column chromatography (eluent: ethyl acetate/petroleum ether=1/6 is to 1/3), obtains white solid, productive rate: 49.8%, m.p.=241-242 ℃, ESI-MS407.4 (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), 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).
Embodiment 6 presses down enzyme test
6.1 target compound suppresses gelatinase activity test (In vitro)
6.1.1 principle: succinyl gelatin has been proved to be and can be hydrolyzed by MMP-2, the height of the free amine group concentration that peptide bond hydrolysis produces is proportionate with enzymic activity.Free amine group in succinyl oxide protection gelatin, the uncle's ammonia and 2,4 exposing after hydrolysis; 6-trinitro-benzene-sulfonic acid (TNBS) reaction solution; by detecting the optical density at 450nm wavelength place, determine amino content, thereby determine the activity of MMP-2, indirectly reflect the inhibition situation of compound to MMP-2.
6.1.2 materials and methods:
MMP-2 is purchased from biotech company of Xin Jing section, and TNBS, gelatin are purchased from sigma company
6.1.2.1 gelatin free ammonia based assays:
Glycine is dissolved in 50mmol/L sodium borate buffer liquid (5ml, pH8.5), is mixed with 0.007mol/L solution, gets different volumes glycine solution and reacts 30min with TNBS, and test sample, in Table 2, is made 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 as stated above optical density is 0.142, in 20mg gelatin, approximately contains 1.8 μ mol free amine groups.
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, with 1mol/L NaOH, regulate, make solution keep pH8.0-8.5, reaction 5h, with fully dialysis of 50mmol/L sodium borate buffer liquid (pH8.5) (in 48h, dialysis is three times), obtains succinyl gelatin solution.
6.1.2.3 gelatinase activity analysis:
In 96 orifice plates, add respectively above-mentioned succinyl gelatin solution 55 μ L (approximately containing 200 μ g succinyl gelatins), enzyme solution (3mg enzyme is dissolved in 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 in 450nm wavelength place, and result is as table 3, table 4.
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:
In 96 orifice plates, add respectively above-mentioned succinyl gelatin solution 55 μ L, 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 with sodium borate buffer liquid, supplies 150 μ L.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.According to following formula, calculate inhibiting rate:
According to compound concentration and corresponding inhibiting rate, utilize OriginPro7.5 software processes, obtain the IC of each compound
50.Result is as following table 5:
Table 5
Claims (4)
1. the quinazolinone small molecules class peptide derivant with matrix metalloproteinase inhibitory activity, described matrix metalloproteinase is MMP-2, derivative has the structure of following general formula (I):
In formula: R
1, R
2, R
3and R
4for hydrogen;
R
5for the secondary amine of amino acid methyl ester class substituting group, substituted anilinic, fatty amido or replacement, amino acid methyl ester class substituting group is:
or
substituted anilinic is:
Fat amido is:
the secondary amine replacing is:
R
6for hydrogen or pharmaceutically acceptable mineral acid or organic acid.
2. according to the quinazolinone small molecules class peptide derivant with matrix metalloproteinase inhibitory activity claimed in claim 1, it is characterized in that,
R
6for hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, heavy sulfuric acid, phosphoric acid, carbonic acid, stable hydrocarbon acid, unsaturated hydrocarbons are sour, polyacid or various replacement organic carboxyl acid.
3. the application at the medicine of preparation prevention or the treatment mammalian diseases relevant to Matrix Metalloproteinase-2 Activity unconventionality expression according to the quinazolinone small molecules class peptide derivant with matrix metalloproteinase inhibitory activity claimed in claim 1.
4. a pharmaceutical composition, it is characterized in that, except containing one or more pharmaceutically acceptable carriers or vehicle, also at least comprise a kind of contain therapeutic dose according to the quinazolinone small molecules class peptide derivant with matrix metalloproteinase inhibitory activity claimed in claim 1.
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| G.K.Rao et al.Synthesis and evaluation of N"-((substituted phenyl)methylidene)-2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetohydrazide for possible antibacterial and antifungal activities.《InternationalJournal of Biological Chemistry》.2009,第3卷(第2期),71-77. * |
| Hongyu Yuan et al.Synthesis and primary evaluation of quinoxalinone.《Med Chem Res》.2009,第18卷671-682. * |
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