CN101704792B - Quinoxalinone derivative with matrix metalloproteinase inhibitory activity and preparation method and application thereof - Google Patents
Quinoxalinone derivative with matrix metalloproteinase inhibitory activity and preparation method and application thereof Download PDFInfo
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- CN101704792B CN101704792B CN200910229537A CN200910229537A CN101704792B CN 101704792 B CN101704792 B CN 101704792B CN 200910229537 A CN200910229537 A CN 200910229537A CN 200910229537 A CN200910229537 A CN 200910229537A CN 101704792 B CN101704792 B CN 101704792B
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Abstract
The invention discloses a quinoxalinone derivative with matrix metalloproteinase inhibitory activity and a preparation method and an application thereof, belonging to the technical field of pharmaceutical chemistry. The derivative has the structure shown in the general formula (I), wherein the meanings of R1, R2, R3, R4, R5 and R6 are shown in the patent specification. The compound of the invention is proven to have specific MMP-2 inhibitory activity in the in vitro enzyme inhibitory activity experiments and to be an effective matrix metalloproteinase inhibitor so that the quinoxalinone derivative is expected to be developed to be a new anti-cancer drug.
Description
Technical field
The present invention relates to have the Quinoxalinone derivative that suppresses the matrix metalloproteinase effect, 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 one type of 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 28 kinds of mammiferous MMP hypotypes at present, the MMPs family member who so classifies numerous, and participated in the numerous physiological processs of human body because of the high expression level of MMPs, it obviously is inappropriate therefore suppressing all MMPs family members.People recognize the importance of exploitation specificity MMPs suppressor factor thus.Present research to the MMP suppressor factor 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.
Malignant phenotype and cancer patients's the poor prognosis that has confirmed MMP-2 (gelatin enzyme A) and invasive tumor 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 suppressor factor of selectivity, is one type very promising in the current anti-tumor angiogenesis drug.
Summary of the invention
The object of the present invention is to provide one type of Quinoxalinone derivative with matrix metalloproteinase inhibitory activity, this compounds can be used as specificity MMP-2 suppressor factor, 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:
Quinoxalinone derivative with matrix metalloproteinase inhibitory activity, it has the structure of following general formula (I):
Wherein: (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
3-12Naphthenic base, 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, cyanic acid, C
1～8Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, C
1～8Alkoxyl group or C
1～8Haloalkyl.
(2) R
5Be pharmaceutically acceptable mineral acid or organic acid; Preferred hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, heavy sulfuric acid, phosphoric acid, acetic acid, propionic acid, oxyacetic acid, 2 hydroxy propanoic acid, 2-oxo propionic acid, oxalic acid, propanedioic acid, fumaric acid, 2-hydroxyl-1; 2, the acid of 3-the third three acid, lactic acid, tartrate, succsinic acid, fumaric acid, glucono-, saccharic acid, phenylformic acid, 2 hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, methylsulfonic acid, ethyl sulfonic acid, cyclohexyl-sulfinic acid, Phenylsulfonic acid, tosic acid, Hydrocerol A, toxilic acid, coffic acid, gallic acid or crust.
(3) R
6Be C
1-C
8The straight or branched alkyl-carbonyl, contain substituent aryl carbonyl, contain substituent heteroaryl carbonyl, have clear and definite bioactive natural carboxylic acid acyl group, contain the inferior acyl group of substituent aliphatics, contain the inferior acyl group of substituent aromatic series, C
1～8The substituted alkylsulfonyl of alkyl, contain substituent aryl sulfonyl, the substituted alkylsulfonyl of heteroaryl.
Described have clear and definite bioactive natural carboxylic acid and comprise alkyl carboxylic acid, aryl carboxylic acid, and heteroaryl carboxylic acid contains protection base or substituent aryl carboxylic acid, and contains protection base or substituent heteroaryl carboxylic acid; Wherein preferably coffee acid, gallic acid, succsinic acid, FLA, styracin, N-hydroxycinnamic acid, PHB, isoferulic acid, TRANSCINNAMIC ACID, phenylpropionic acid, Thioctic Acid, phytic acid, Protocatechuic Acid, Vanillyl acid, gallate-based, Potenlini, glycyrrhetinic acid, rosmarinic acid, ginkgolic acid, equisetic acid, Hydroxycinnamic acid, oleic acid, gallogen, quininic acid, PHCA, shikimic acid, sinapinic acid etc.
Above-mentioned term implication is following 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 the 6-18 carbon atom.
Halogen or halogen comprise fluorine, chlorine, bromine, iodine.
Naphthenic base is saturated or unsaturated, and substituted or unsubstituted cyclic group, this ring can be monocycle or condensed ring, and bridged ring or volution perhaps contain heteroatomic ring system.The preferred 3-9 of a monocycle atom encircles a preferred 7-13 atom 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 Quinoxalinone derivative with matrix metalloproteinase inhibitory activity:
N-(2-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) ethanoyl) benzhydrazide,
2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide,
N-(2-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) ethanoyl) phenylacetyl hydrazine,
2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-N '-(propionyl-2-subunit) acethydrazide,
2,6-two chloro-N '-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) ethanoyl) phenylacetyl hydrazine,
(E)-N '-Ben Yajiaji-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide,
(E)-N '-(furans-2-methylene radical)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide,
(E)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-N '-(2-styrene) acethydrazide,
(E)-N '-(1-(4-bromophenyl) ethylidene)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide,
(E)-N '-(2-hydroxyl-3-ar-methoxy benzylidene-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide,
(E)-N '-(4-methylbenzene methylene radical)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide,
(E)-N '-(4-(dimethylin) Ben Yajiaji)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide,
(E)-N '-(3-oil of mirbane methylene radical)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide,
(E)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-N '-(1-styrene) acethydrazide,
(E)-N '-(2,4-dimethoxy Ben Yajiaji)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide,
(E)-N '-(3,4,5-trimethoxy Ben Yajiaji)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide,
(E)-N '-(2-chlorobenzene methylene radical)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide,
(E)-N '-(3,4 ,-dimethoxy Ben Yajiaji)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide,
(E)-N '-(2,5 ,-dimethoxy Ben Yajiaji)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide,
(E)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl)-N '-(1-(4-nitrophenyl) ethylidene) acethydrazide,
(E)-N '-(1-(3-chloro-phenyl-) ethylidene)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide.
The preparation method of said general formula (I); Be to be starting raw material with the O-Phenylene Diamine; Be reacted into ring with Pyruvic Acid Methyl ester earlier; Resulting midbody obtains compound 3 (structure is following) with ethyl chloroacetate (or METHYL BROMOACETATE) reaction again, obtains final product through hydrazinolysis, acetylization reaction and separation and purification successively again.
Be starting raw material with the O-Phenylene Diamine below, specify the preparation method of this compounds.
The reagent that a uses is Pyruvic Acid Ethyl ester and reaction solvent; The reagent that b uses is ethyl chloroacetate and weak mineral alkali; The reagent that c uses is absolute ethyl alcohol/methyl alcohol and Hydrazine Hydrate 80; The reagent that d uses is R
1CHO and absolute ethyl alcohol/methyl alcohol; The reagent that e uses is R
2COCl and reaction solvent.
Have the preparation method of the Quinoxalinone derivative of matrix metalloproteinase inhibitory activity, may further comprise the steps:
(1) with 2,3,4, the 5-position is respectively by R
1, R
2, R
3, R
4Substituted O-Phenylene Diamine and Pyruvic Acid Methyl ester heating reflux reaction in certain solvent prepares quinazolinone parent nucleus compound (II);
(2) compound (II) and ETHYLE ACETATE bromo or chloro under the weak base catalyst effect in ethanol or acetone solvent heating reflux reaction prepare compound (III);
(3) compound (III) obtains midbody (IV) with the Hydrazine Hydrate 80 of massfraction 30%-80% 70～80 ℃ of reactions in absolute ethyl alcohol or anhydrous methanol reaction solvent;
(4) midbody (IV) and aldehydes or ketones react in 70-90 ℃ of certain solvent, perhaps with acyl chlorides room temperature reaction in certain solvent under the basic catalyst effect, obtain final product (I).
Solvent described in the above-mentioned steps (1) is absolute ethyl alcohol, anhydrous tetrahydro furan, anhydrous methylene chloride or anhydrous 1, the 4-dioxane; The consumption of described solvent be every mmole 2,3,4, the 5-position is respectively by R
1, R
2, R
3, R
4Substituted O-Phenylene Diamine is with 6～7mL solvent; Described 2,3,4,5-position is by R respectively
1, R
2, R
3, R
4The mol ratio of substituted O-Phenylene Diamine and Pyruvic Acid Methyl ester consumption is 1: 1.1～1.2.
Weak base catalyst described in the step (2) is weak mineral alkali, preferred yellow soda ash or salt of wormwood; Described compound (II) is 1: 1.2: 1.2 with the mol ratio of bromo or chloracetic acid ethyl ester and weak base catalyst consumption; The consumption of described ethanol or acetone solvent is that the compound (II) of every mmole is with 8～10mL solvent.
Compound (III) described in the step (3) and Hydrazine Hydrate 80 mol ratio are 1: 2～2.5, the consumption of reaction solvent be the compound (III) of every mmole with 2.5～5mL solvent, the Hydrazine Hydrate 80 of preferred mass mark 80%.
Reaction solvent described in the step (4) is absolute ethyl alcohol, anhydrous methanol, anhydrous tetrahydro furan, anhydrous methylene chloride or anhydrous N; Dinethylformamide; Compound (IV) is 1: 1.2 with the mol ratio of aldehyde (or ketone), and described basic catalyst is yellow soda ash, salt of wormwood or Et
3N, compound (IV) is 1: 1.2: 1.2 with the mol ratio of acyl chlorides and weak base catalyst consumption, the consumption of reaction solvent is the compound of every mmole (IV) with 5～10mL solvent.
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 Quinoxalinone derivative 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 ulcers, various tissue ulcers venereal disease disease and periodontopathy.These compounds of the present invention can suppress at least a Mammals 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 Quinoxalinone derivative that a kind of the present invention who contains therapeutic dose has matrix metalloproteinase inhibitory activity at least.
This kind compsn can be made into oral prepns 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, Triple Pressed Stearic Acid or the like.Solid carrier can comprise that also one or more maybe 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, calcium phosphate, Magnesium Stearate, talcum, sugar, hole sugar, dextrin, starch, gelled fibre is plain, methylcellulose gum, sodium carboxymethyl-cellulose, Vinylpyrrolidone polymer, 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-s, emulsion, syrup.Activeconstituents can dissolve or be suspended in pharmaceutically acceptable liquid vehicle, like water, and organic solvent, 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 (comprising monohydroxy-alcohol and polyvalent alcohol, for example terepthaloyl moietie) and their verivate, and oils (for example fractionated coconut oil and peanut oil).The carrier that is used for administered parenterally can also be grease such as OE 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-s 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 compsn.
Carrier or vehicle can comprise time lag material known in the art, like glyceryl monostearate or glycerol disterate acid, can also comprise wax, TKK 021, Vltra tears, methyl methacrylate or the like.When preparation is used for when oral; Generally acknowledge PHOSALPG-50 (phospholipid and 1; The 2-Ucar 35 concentrates, and 0.01% tween 80 in A.Nattermann&Cie.GmbH) 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-s.
In order to obtain stable water miscible formulation, can compound or its pharmacy acceptable salt be dissolved in the organic or inorganic aqueous acid, 0.3M succsinic acid or citric acid solution.Optionally, the tart verivate can be dissolved in suitable basic soln.If can not get soluble form, can compound 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% TV, Ucar 35, Liquid Macrogol, polysorbate 80, glycerine, polyoxyethylene fatty acid ester, Fatty Alcohol(C12-C14 and C12-C18) or the strong fatty 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 with (preferred usually) oral route.Compound can through any easily or other suitable administration; For example through injecting or bolus injection; Through epithelium or mucous membrane circuit (for example, oral mucosa, rectum and intestines mucosa or the like) absorbs or support through 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.
Embodiment
The compound that use table 1 of the present invention is listed is further explained, but is not limited the present invention.
Table 1
Further specify the present invention below in conjunction with embodiment.
2-(the preparation method of 3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide (lyg-31 in the table 1)
(10.81g 0.10mol), adds in the 250ml absolute ethyl 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, ETHYLE ACETATE revolves dried solid; With ethyl alcohol recrystallization get 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-ETHYLE ACETATE, productive rate is 73.2%, m.p.120-122 ℃; ((2.46g 0.01mol), adds the 50ml absolute ethyl alcohol to 3-methyl-2-oxo quinoxaline-1 (2H)-yl)-ETHYLE ACETATE, and stirring at normal temperature is to dissolving to take by weighing 2-; (5.01g 0.1mol), dropwises to drip 80% Hydrazine Hydrate 80; Back flow reaction 10h, the TLC detection reaction finishes, and removes solvent under reduced pressure; Add 100ml water and 200ml ethyl acetate extraction three times, revolve dried organic solvent and get solid, get white 2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide solid with re-crystallizing in ethyl acetate; Productive rate is 86.4%, m.p.221-224 ℃ of .ESI-MS 233.1 (M+H)
1H-NMR: (DMSO-d
6, ppm) δ: 2.45 (s, 3H, CH
3), 4.28 (d, J=1.8Hz, 2H, NH
2), 4.86 (s, 2H, NCH
2CO), 7.30 (d, J=8.4Hz, 1H, ArH), 7.35 (t, J=7.8Hz, 1H, ArH), 7.54 (t, J=7.2Hz, 1H, ArH), 7.76 (d, J=7.8Hz, 1H, ArH), 9.36 (s, 1H, CONH).
The preparation method of N-(2-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) ethanoyl) phenylacetyl hydrazine (lyg-32 in the table 1)
(10.81g 0.10mol), adds in the 250ml absolute ethyl 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, ETHYLE ACETATE revolves dried solid; With ethyl alcohol recrystallization get 2-(3-methyl-2-oxo quinoxaline-1 (2H)-yl)-ETHYLE ACETATE, productive rate is 73.2%, m.p.120-122 ℃; ((2.46g 0.01mol), adds the 50ml absolute ethyl alcohol to 3-methyl-2-oxo quinoxaline-1 (2H)-yl)-ETHYLE ACETATE to take by weighing 2-; Stirring at normal temperature to the dissolving, drip 80% Hydrazine Hydrate 80 (5.01g, 0.1mol); Dropwise, back flow reaction 10h, the TLC detection reaction finishes; Remove solvent under reduced pressure, add 100ml water and 200ml ethyl acetate extraction three times, ETHYLE ACETATE revolves dried solid; (3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide, productive rate is 86.4%, m.p.221-224 ℃ to get white solid 2-with re-crystallizing in ethyl acetate.Take by weighing 2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide (and 0.23g, 1mmol), soda ash light (0.12g 1.1mmol), adds in the 20ml anhydrous tetrahydro furan, add then phenyllacetyl chloride (0.154g, 1mmol), stirring at normal temperature 12h, reaction finishes.Remove solvent under reduced pressure, obtain pink solid, add the less water washing, filter; Filter cake is used ethyl alcohol recrystallization, obtains white powder N-(2-3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) ethanoyl) phenylacetyl hydrazine, and productive rate is 47.6%, and m.p.276-277 ℃, ESI-MS 351.2 (M+H),
1H-NMR: (DMSO-d
6, ppm) δ: 2.45 (s, 3H, CH
3), 3.453 (s, 2H, CH
2CO), 4.976 (s, 2H, NCH
2CO), 7.21-7.36 (m, 7H, ArH), 7.54 (t, J=7.2Hz, 1H, ArH), 7.76 (d, J=7.8Hz, 1H, ArH), 10.181 (s, 1H, CONH), 10.308 (s, 1H, CONH).
2, the 6-two chloro-N '-(preparation method of 2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) ethanoyl) phenylacetyl hydrazine (lyg-34 in the table 1)
(embodiment 1 is seen in the preparation of 3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide to 2-.Take by weighing 2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide (and 0.23g, 1mmol), soda ash light (0.12g, 1.1mmol); Add in the 20ml anhydrous tetrahydro furan, add 2 then, 6-dichlorobenzoyl chloride (0.209g; 1mmol), stirring at normal temperature 12h, reaction finishes.Remove solvent under reduced pressure, add the less water washing, filter; Filter cake is used ethyl alcohol recrystallization, obtains white powder 2,6-two chloro-N '-(2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) ethanoyl) phenylacetyl hydrazine, productive rate is 57.1%, m.p.294-296 ℃, ESI-MS 405.8 (M+H),
1H-NMR: (DMSO-d
6, ppm) δ: 2.43 (s, 3H, CH
3), 5.048 (s, 2H, NCH
2CO), 7.355-7.38 (m, 2H, ArH), 7.46 (d, J=8.4Hz, 1H, ArH), 7.517-7.582 (m; 2H, ArH), 7.72 (d, J=1.8Hz, 1H, ArH), 7.78 (dd, J=1.8,8.4Hz; 1H, ArH), 10.499 (s, 1H, CONH), 10.57 (s, 1H, CONH).
(E)-N '-Ben Yajiaji-2-(preparation method of 3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide (lyg-35 in the table 1)
(embodiment 1 is seen in the preparation of 3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide to 2-.Take by weighing 2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide (and 0.23g, 1mmol), soda ash light (0.12g, 1.1mmol); Add in the 20ml anhydrous tetrahydro furan, add 2 then, 6-dichlorobenzoyl chloride (0.106g; 1mmol), stirring at normal temperature 12h, reaction finishes.Remove solvent under reduced pressure, add the less water washing, filter; Filter cake is used ethyl alcohol recrystallization, obtain white powder (E) N '-Ben Yajiaji-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide, productive rate is 43.1%, m.p.272-273 ℃, ESI-MS 321.1 (M+H),
1H-NMR: (DMSO-d
6, ppm) δ: 2.47 (s, 3H, CH
3), 5.46 (s, 2H, NCH
2CO), 7.35-7.80 (m, 9H, ArH), 8.08 (s, 1H, ArH), 10.42 (s, 1H, CONH), 10.49 (s, 1H, CONH).
(E) N '-(3,4 ,-dimethoxy Ben Yajiaji)-2-(preparation method of 3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide (lyg-47 in the table 1)
(embodiment 1 is seen in the preparation of 3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide to 2-.Take by weighing 2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide (and 0.23g, 1mmol), soda ash light (0.12g, 1.1mmol); Add in the 20ml anhydrous tetrahydro furan, add 2 then, 6-dichlorobenzoyl chloride (0.18g; 1mmol), stirring at normal temperature 12h, reaction finishes.Remove solvent under reduced pressure, add the less water washing, filter; Filter cake is used ethyl alcohol recrystallization, obtain white powder (E)-N '-(3,4 ,-dimethoxy Ben Yajiaji)-2-(3-methyl-2-oxygen-quinoxaline-1-(2H)-yl) acethydrazide, productive rate is 49.4%, m.p.284-285 ℃, ESI-MS 381.3 (M+H),
1H-NMR: (DMSO-d
6, ppm) δ: 2.477 (s, 3H, CH
3), 3.809 (s, 3H, OCH
3), 3.811 (s, 3H, OCH
3), 5.460 (s, 2H, NCH
2CO), 7.011-7.034 (m, 1H, ArH), 7.202-7.580 (m, 5H, ArH), 7.792 (d, J=7.2Hz, 1H, ArH), 8.001 (s, 1H, ArH), 11.744 (s, 1H, CH=N).
Press down enzyme test
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-trinitrobenzenesulphonic acid (TNBS) reaction solution; Optical density through detecting the 450nm wavelength is confirmed amino content, thereby confirms the activity of MMP-2, reflects the inhibition situation of compound to MMP-2 indirectly.
6.1.2 through biotech company of section, TNBS, gelatin are available from sigma company available from glad for materials and methods: MMP-2
6.1.2.1 free amino mensuration in the gelatin: glycocoll is dissolved in 50mmol/L sodium borate buffer liquid (5ml; PH=8.5) in, be mixed with 0.007mol/L solution, get different volumes glycine solution and TNBS reaction 30min; Specimen is seen table 2, makes typical curve such as Fig. 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: the 200mg gelatin is dissolved in 50mmol/L sodium borate buffer liquid (10ml; PH=8.5) in, the 20mg succinyl oxide is added in batches, regulate with 1mol/L NaOH; Make solution keep pH=8.0～8.5; 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 the 450nm wavelength.
Table 3
Blank control 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 suppressor factor, and blank control 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, measures optical density in the 450nm wavelength.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 (3)
1. have the Quinoxalinone derivative of matrix metalloproteinase inhibitory activity, it is characterized in that, following structural formula compound:
2. according to the described application of Quinoxalinone derivative in the medicine for preparing prevention or the treatment mammal disease relevant of claim 1 with the matrix metal proteinase activity unconventionality expression with matrix metalloproteinase inhibitory activity.
3. 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 Quinoxalinone derivative of claim 1 with matrix metalloproteinase inhibitory activity.
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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.《International journal of biological chemistry》.2009,第3卷(第2期),71-77. * |
| M. Z. A. BADR, et al..Synthesis and chemistry of some novel quinoxalinone derivatives and their antimicrobial effects.《J. Indian Chem. Soc.》.1990,第67卷216-219. * |
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