CN101926802A - Application of quinazoline compounds - Google Patents
Application of quinazoline compounds Download PDFInfo
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- CN101926802A CN101926802A CN2009100533236A CN200910053323A CN101926802A CN 101926802 A CN101926802 A CN 101926802A CN 2009100533236 A CN2009100533236 A CN 2009100533236A CN 200910053323 A CN200910053323 A CN 200910053323A CN 101926802 A CN101926802 A CN 101926802A
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Abstract
The invention relates to the technical field of drugs, in particular to application of quinazoline compounds. The invention discloses application of the quinazoline compounds shown in the general formula I or pharmaceutically acceptable salt, prodrugs or isomers thereof in preparing mitotic inhibitors. The quinazoline compounds shown in the general formula I or pharmaceutically acceptable salt, prodrugs or isomers have the effect of inhibiting tubulin polymerization and can effectively inhibit mitosis.
Description
Technical field
The present invention relates to medical technical field, relate in particular to a kind of purposes of quinazoline compounds.
Background technology
Mitosis is the steps necessary of cell proliferation.Body makes mitosis controlled in order by the accurate regulatory mechanism of strictness.Studies show that the mitosis regulation and control are disorderly to play an important role in the disease that cellular abnormality propagation causes.Spindle and dependency structure in the fission process mainly are made up of microtubule.Microtubule then is made of tubulin (tubulin).Clinical practice proves, is one of the most effective anti-cell hyper-proliferative medicine at the active mitotic inhibitor of tubulin.
Studies show that have chemical compound lot can disturb the function of tubulin.They belong to mitotic inhibitor, suppress cell proliferation by the polymerization that influences spindle microtubule.Usually the microtubule reactive compound minute is made two big classes, and the one, microtubule destabilizer, the inhibition micropipe aggregation comprises vinblastine, Colchicine etc. during higher concentration.The 2nd, microtubule stabilizer comprises taxanes and Ai Bo mycin class etc.Paclitaxel and derivant thereof can impel tubulin to be gathered into microtubule rapidly, and are attached to the depolymerization that suppresses microtubule on the microtubule, thereby cell mitogen is ended.
Though it is domestic, abroad to the existing a lot of research reports of microtubule polymerization micromolecular inhibitor (also can be described as mitotic inhibitor), but since the tubulin polymerization inhibitor of different chemical structures in vivo distribution and the bioavailability in the different tissues very big-difference is arranged, therefore they also have nothing in common with each other to the therapeutic effect and the secondary toxic action of the cell hyperproliferation disease of different tissue sources.Though the medicine at the mitosis spindle microtubule is used widely clinically, these medicines also have many unsatisfactory parts.The dissolubility of paclitaxel is very poor, erious adverse reaction and the easy drug resistance that produces.Proved that Colchicine class scope of application in the anti-cell hyperproliferation disease is very narrow.Therefore, need the further mechanism of research cell tubulin polymerization, develop the more better mitotic inhibitor medicine of multiple-effect fruit.
Summary of the invention
The present invention aims to provide the purposes of a kind of noval chemical compound in preparation mitotic inhibitor.
The invention provides a kind of quinazoline compounds or its pharmaceutically acceptable salt or prodrug or the purposes of its isomer in preparation mitotic inhibitor shown in general structure I,
Wherein, R
1One of be chosen as in H, alkyl amino-carbonyl, sulfonyl, alkyl sulphonyl, alkyl sulphinyl, amino-sulfonyl, the acyl group;
R
2Can be-NO
2,-NHSO
2R ,-NRSO
2R ,-NHR or-one of among the OR;
R
3Can be H, alkyl, alkenyl, heterocyclic radical ,-OR or
One of in;
R
4In 2,3,4,5 or 6 replacements of phenyl ring, can be nothing ,-OR, halogen, alkyl, amino, aminoalkyl, alkyl amino-carbonyl, alkyl sulphonyl, alkyl sulphinyl, amino-sulfonyl, aryl alkyl, one of in cycloalkyl aryl, heteroaryl or the heterocyclic radical;
One of R can be alkyl, aryl, aryl alkyl, in cycloalkyl aryl, heteroaryl or the heterocyclic radical;
In above group, can not be substituted or be replaced separately by one or more substituent groups, these substituent groups comprise: halogen ,=O ,=S ,-CN ,-NO
2,-CF
3,-OCF
3, alkyl, alkenyl, alkynyl group, haloalkyl, haloalkenyl group, halo alkynyl, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, alkene oxygen base, alkynyloxy group, amino, alkyl amino, sulfonyl, alkyl sulphonyl, amino-sulfonyl, alkoxyalkyl ,-COOH ,-SH and acyl group.
In some preferences, described R
1Be H.
In some preferences, described R
2Can be-NO
2
In some preferences, described R
3For
The time, R
4For-OR is in 3,4 or 5 replacements of phenyl ring, and preferably in phenyl ring 3 or 4 replacements, R can be alkyl or aryl, is preferably methyl.
In another preference, described quinazoline compounds can be following compounds:
In another preference, mitotic inhibitor of the present invention is the tubulin polymerization inhibitor, can treat the cellular abnormality hyperplasia, include but not limited to treat the medicine of autoimmune disease, inflammation, osteopathia, metabolic disease, nerve and neurodegenerative disease, cardiovascular diseases, allergy or asthma.
Described autoimmune disease is a psoriasis, rheumatoid arthritis, systemic lupus erythematosus (sle), dermatomyositis, scleroderma, multiple sclerosis, myasthenia gravis, demyelination, primary adrenocortical atrophy, chronic first shape inflammation, juvenile onset diabetes, chronic non-specific ulcerative colitis, chronic active hepatitis, bad habit anemia and atrophic gastritis, autoimmune glomerulonephritis, lung nephrorrhagia syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, the special property sent out leukopenia.
Description of drawings
LJK-11 is to the effect of microtubule polymerization among the embodiment shown in Figure 1.
LJK-11 is to the fluidic cell testing result of people's gastric cancer HGC cell cycle among the embodiment shown in Figure 2.
LJK-11 is to the inhibitory action of kinds of tumor cells growth among the embodiment shown in Figure 3.
The specific embodiment
The inventor finds that through extensive and deep research the quinazoline compounds shown in the general structure I or its pharmaceutically acceptable salt or prodrug or its isomer have the effect that suppresses cell mitogen, can effectively suppress the abnormality proliferation of cell.On this basis, finish the present invention.
Part term definition used in the present invention is as follows:
" cellular abnormality hyperplasia " generally is meant the disease that is grown to feature widely with the sexual abnormality out of control of cell, includes but not limited to autoimmune disease, inflammation, osteopathia, metabolic disease, nerve and neurodegenerative disease, cardiovascular diseases, allergy or asthma.
" halogen " is meant fluorine, chlorine, bromine and iodine.
" alkyl " is meant straight chain when being used as the part of a group or a group or has the aliphatic hydrocarbon group of side chain.Preferential selection alkyl is C
1-C
14Alkyl; More preferably be chosen as: C
1-C
10Alkyl; Override is chosen as C
1-C
6, unless otherwise.Straight chain or and have a C of side chain
1-C
6The example of alkyl includes, but are not limited to: methyl, ethyl, n-pro-pyl, 2-propyl group, normal-butyl, isobutyl group, tertiary butyl, hexyl etc." alkyl amino " comprises two kinds of alkyl monosubstituted amino and dialkyl amidos, unless otherwise." alkyl monosubstituted amino " is meant: (alkyl-NH)-group; " dialkyl amido " is meant: ((alkyl) 2N)-group.Wherein, alkyl is seen the relevant definition of this paper.This alkyl group is preferentially selected C
1-C
6Alkyl group.Example includes, but are not limited to: N-methylamino, N-ethylamino-, N-isopropylamine base, N, N-(diethyl) amido etc." aminoalkyl " is meant: (amino-alkyl)-group.Wherein, alkyl is seen the relevant definition of this paper.Example includes, but are not limited to: amino-ethyl, 1-aminopropyl, 1-aminopropyl etc.
" arylamino " comprises two kinds of list-arylamino and two-arylaminos, except as otherwise noted.List-arylamino is meant: (aryl-) group of NH-; Two-arylamino is meant the group of formula (aryl) 2N-; This paper relevant portion is seen in the definition of aryl.
" acyl group " comprise (alkyl-CO)-group and (aryl-CO)-group, except as otherwise noted.Wherein alkyl or aryl is all seen relevant definition herein.The example of acyl group includes, but are not limited to: acetyl group, propiono, isobutyryl, benzoyl etc.
" amide groups " comprise (alkyl-CONH)-group and (aryl-CONH)-group, except as otherwise noted.Wherein, alkyl or aryl is all seen relevant definition herein.The example of amide groups includes, but are not limited to: acetamido, propionamido-, amide-based small, isobutyl amide, benzamido etc.
" thiazolinyl " is meant the aliphatic hydrocarbon group that contains a carbon-to-carbon double bond at least during as a group or a group a part of, can be straight chain and also can have side chain.Preferential selection has C
2-C
14Thiazolinyl.C
2-C
12Then better; That the most preferentially select is C
2-C
6Thiazolinyl.This group can contain a plurality of pairs of keys and its conformation can respectively do for oneself E or Z in its main chain.The example of alkenyl group includes, but are not limited to: vinyl, acrylic etc.
" alkoxyl " be meant (alkyl-O)-group.Wherein, alkyl is seen the relevant definition of this paper.C
1-C
6Alkoxyl be preferential the selection.The example includes, but are not limited to: methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy etc.
" alkene oxygen base " be meant (thiazolinyl-O)-group.Wherein, thiazolinyl is seen the relevant definition of this paper.C
1-C
6Alkene oxygen base be preferential the selection.
" alkynyloxy group " be meant (alkynyl-O)-group.Wherein, alkynyl is seen the relevant definition of this paper.C
1-C
6Alkynyloxy group be preferential the selection.
" alkoxy carbonyl group " be meant (alkyl-O-C (O))-group.Wherein, alkyl is seen the relevant definition of this paper.The preferential alkyl group of selecting is C
1-C
6Alkyl.The example includes, but are not limited to: methoxycarbonyl group, carbethoxyl group etc.
" alkyl sulphinyl " be meant (alkyl-S (O))-group.Wherein, alkyl is seen the relevant definition of this paper.The preferential alkyl of selecting is C
1-C
6Alkyl group.The alkyl sulphinyl group includes, but are not limited to: methylsulfinyl, ethyl sulfinyl etc.
" alkyl sulphonyl " is meant (alkyl-S (O)
2-O)-group.Wherein, alkyl is seen the relevant definition of this paper.Should the preferential alkyl of selecting be C
1-C
6Alkyl group.The example includes, but are not limited to: mesyl, ethylsulfonyl etc.
" alkyl amino aryl " is meant alkyl amino-aromatic yl group.Wherein, alkyl amino is seen the relevant definition of this paper.
" cycloalkyl " is meant the carbocyclic ring of monocycle, condensed ring or the volution of saturated or fractional saturation.The ring of forming with 3-9 carbon atom is preferential the selection.Example includes, but are not limited to: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.
" cycloalkyl-alkyl " is meant cycloalkyl-alkyl group.Wherein, cycloalkyl is seen the relevant definition of this paper with moieties.Monocycle alkyl alkyl group includes, but are not limited to: cyclopropyl methyl, cyclopentyl-methyl, cyclohexyl methyl, suberyl methyl etc.
" Heterocyclylalkyl " is meant that containing one at least is selected from N, S, the heteroatomic cycloalkyl of O.Preferably contain 1-3 hetero atom.Preferred ring is 3-14 person's ring, and more preferably the ring of Xuan Zeing is 4-7 person's ring.Heterocyclylalkyl includes, but are not limited to: pyrrolidinyl, pyrrolin base, nafoxidine base, pyrazoline base, piperidyl, morpholine tetrahydrofuran base, tetrahydrochysene thio-furan base, THP trtrahydropyranyl etc.
" heterocycloalkenyl " is meant the Heterocyclylalkyl that contains two keys at least.Heterocyclylalkyl is seen the relevant definition of this paper.
" Heterocyclylalkyl alkyl " is meant: (Heterocyclylalkyl-alkyl)-group.Wherein, Heterocyclylalkyl is seen the relevant definition of this paper with moieties.The Heterocyclylalkyl alkyl group includes, but are not limited to: (2-tetrahydrofuran base) methyl, (2-tetrahydrochysene thio-furan base) methyl etc.
" assorted alkyl " is meant straight chain or contains the group of branched alkyl, and in main chain, contain one or more S of being selected from least, the hetero atom of O and N.Preferential selection contains 2-14 atomic link.Assorted alkyl includes, but are not limited to: ethers, thioether class, alkyl esters, second or trialkyl amines, alkyl sulfinic acid class etc.
" aryl " is meant as the part of a group or a group: the monocycle or the condensed ring of (1) armaticity; Preferential armaticity carbocyclic ring (annular atoms is the ring-shaped structure of carbon) of selecting to have 5-12 carbon atom.The example of aryl includes, but are not limited to: phenyl, naphthyl; (2) can the saturated carbocyclic ring in coupling part, for example: phenyl and C
5-7Cycloalkyl or C
5-7Cycloalkenyl groups system condenses mutually and forms a circulus.Example includes, but are not limited to: tetralyl, indenyl or hydrogen indenyl etc.Aromatic yl group can be replaced by one or more substituent groups.
" aryl alkenyl " is meant: (aryl-thiazolinyl)-group.Wherein, aryl is seen the relevant definition of this paper with thiazolinyl.Exemplary aryl alkenyl group includes, but are not limited to: phenyl acrylic etc.
" aralkyl " is meant: (aryl-alkyl)-group.Wherein, aryl is seen the relevant definition of this paper with moieties.Exemplary aromatic alkyl group includes, but are not limited to: benzyl, phenethyl, 1-menaphthyl etc.
" cycloalkenyl group " is meant non-armaticity monocycle or multi-ring ring system.It contains a carbon-to-carbon double bond at least and every ring preferably has 5-10 carbon atom.Exemplary monocycle shape cyclenes basic ring includes, but are not limited to: cyclopentenes, cyclohexene or cycloheptene.Cycloalkenyl group group can be replaced by one or more substituent groups.
" heteroaryl " is meant monocycle or condensed multi-ring aromatic heterocycle.The preferential selection contained one or more N of being selected from, and O is or/and heteroatomic 5-7 person's aromatic rings of S.Typical heteroaryl substituent group comprises example, but is not limited to: furyl, thienyl, pyrroles, pyrazoles, triazole, thiazole, pyridine, pyrimidine, pyrazine, indole, benzimidazole etc.
" heteroarylalkyl " is meant: (heteroaryl-alkyl)-group.Wherein, heteroaryl is seen the relevant definition of this paper with moieties.Exemplary heteroarylalkyl group includes, but are not limited to: furfuryl, 3-furylmethyl, 2-picolyl etc.
Chemical compound of the present invention can adopt following synthetic route:
Specifically, from 3-chloro-2-aminotoluene, through amido protecting, oxidation, take off the N-protected base, be cyclized into the quinazoline ring, nitrated and synthetic the obtaining of aromatic ring nucleophilic substitution 6 step reaction.At first, the commercial raw material 3-chloro-2-aminotoluene that can sell is at atent solvent such as halogenated alkane, toluene, benzene, oxolane, dioxane or ether, acetic acid or N, go up the N-protected base in the N-dimethyl methyl phthalein amine equal solvent, protecting group is first phthalidyl, the second phthalidyl of the protection amino used always or replaces second phthalidyl, CBZ, BOC, benzyl or substituted benzyl, FMOC, temperature is 0 a ℃～room temperature, or is heated to solvent refluxing; Benzyl reflux in potassium permanganate solution is oxidized to benzoic acid (oxidising agent can also be dichromic acid acid potassium, chromic acid, sodium metaperiodate etc. then, reaction temperature is controlled at 0 ℃～120 ℃, and solvent is halogenated hydrocarbons, toluene, acetonitrile, acetic acid and water).Slough the N-protected base under certain condition (to the first phthalidyl of N-protected; second phthalidyl or replacement second phthalidyl; CBZ; BOC sloughs protecting group under acid condition; first phthalidyl to N-protected; benzyl or substituted benzyl are sloughed protecting group with catalytic hydrogenation; FMOC to N-protected sloughs protecting group under alkali condition; the solvent halogenated hydrocarbons; oxolane; 1; the 4-dioxane; methanol; ethanol; temperature is that room temperature arrives the solvent refluxing temperature); 2-amino-6-chlorobenzoic acid that obtains and the cyclisation at high temperature of first phthalein amine are quinazoline; it is further nitrated again that (nitrating agent can be that fuming nitric aicd and concentrated sulphuric acid are 0 ℃～room temperature; or bismuth subnitrate and thionyl chloride; or Chile saltpeter; Lanthanum (III) nitrate and concentrated nitric acid; or Chile saltpeter; copper nitrate and concentrated hydrochloric acid; water used in solvent; halogenated hydrocarbons or oxolane; temperature is 0 ℃～room temperature) obtain 8-nitro one 5-chloro-quinazoline; amine or alcohol carry out the aryl nucleophilic substitution as nucleopilic reagent to the 5-chlorine of quinazoline and obtain different 5-substituent groups-8-nitro-quinazoline compound (reaction dissolvent is with atent solvent such as oxolane; ether; toluene; acetonitrile; 1; 4-dioxane or N; nucleophilic substitution takes place 40 ℃～100 ℃ heating in N-dimethyl methyl phthalein amine); 8-position nitro can further be reduced to amino, and (Reducing agent is Pd/C hydrogenation; iron powder and acetic acid; iron powder and ammonium chloride; zinc powder and ammonium chloride; hydrazine hydrate; ammonium formate; water used in solvent; ethanol; methanol or acetonitrile, temperature is at 40 ℃～100 ℃) and further be converted into sulfonamide.
Term " pharmaceutically acceptable salt " is meant that above-claimed cpd can keep original biological activity and be suitable for some salt of medical usage.The pharmaceutically acceptable salt of the chemical compound that general formula (I) is represented has two kinds of formation forms: the one, with the salt of acid formation; Another is the salt that forms with alkali or alkali metal.Comprise mineral acid and organic acid with the acid of the represented compound formation pharmaceutically acceptable salt of general formula (I).Suitable mineral acid comprises: hydrochloric acid, sulphuric acid and phosphoric acid.Appropriate organic can be selected from aliphatic, cycloaliphatic, armaticity, heterocyclic carboxylic acid and sulfonic acid class organic acid; The example includes but not limited to: formic acid, acetic acid, propanoic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, glycine, arginine, citric acid, fumaric acid, alkyl sulfonic acid etc.Comprise with the alkali metal of the represented compound formation pharmaceutically acceptable salt of general formula (I): lithium, sodium, potassium, magnesium, calcium, aluminum or zinc etc.
The present invention includes represented chemical compound of general formula (I) and possible various isomery patterns thereof.Comprise: the geometric isomer of non-mirror image isomer, mirror image isomer, tautomer and " E " or " Z " configurational isomer etc.
The present invention includes represented chemical compound of general formula (I) and possible raceme thereof or/and the mirror image isomerism thing/or/and the mixture of non-mirror image isomerism thing.
In addition, the represented chemical compound of general formula (I) is also contained the solvation and the non-solvent pattern of this chemical compound on using.Therefore, the various chemical compound with specified structure that includes comprises its hydration and anhydrous mould assembly formula.
Except the represented chemical compound of general formula (I), different specific embodiments comprise: pharmaceutically acceptable salt, the active metabolite of prodrug and these chemical compounds.Pharmaceutically acceptable salt with these metabolite.
" prodrug " is the represented derivant of a kind of general formula (I), by means of metabolic mode in vivo it become the represented chemical compound of general formula (I) in vivo transforming (for example: by hydrolysis, reduction or oxidation).For example, general formula (I) chemical compound represented, that contain oh group and acid reaction can be prepared into corresponding ester.Corresponding ester is prodrug, can be hydrolyzed to parent drug in vivo.The acid that is fit to prepare " prodrug " includes but not limited to: acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, oxalic acid, salicylic acid, succinic acid, fumaric acid, maleic acid, methylene-bis-beta-hydroxyethyl base naphthoic acid, gentisic acid, hydroxyethylsulfonic acid., methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid etc.
Purposes
Quinazoline compounds shown in the general structure I of the present invention or its pharmaceutically acceptable salt or prodrug or its isomer have the effect that suppresses cell mitogen, can effectively suppress the abnormality proliferation of cell.
The effective dose of used active component can change with the order of severity of mode of administration and disease to be treated.For most of large mammal, the accumulated dose that imposes effective ingredient every day is about 0.01-1000mg.Usually, the scope of adult's clinical administration amount is 0.01-200mg/ day, is preferably 0.05-100mg/ day.
Usually, when the present composition is used for such use, they can make the pharmaceutical dosage form of different way of administration with one or more pharmaceutically acceptable carriers or mixed with excipients, as tablet, capsule, powder, granule, syrup, solution, oral liquid, spirit, tincture, aerosol, powder spray, injection, injectable sterile powder, suppository etc.
" pharmaceutically acceptable " composition is to be applicable to people and/or animal and not have the material that excessive bad side reaction (as toxicity, stimulation and allergy) promptly has rational benefit/risk ratio." pharmaceutically acceptable carrier " is acceptable solvent, suspending agent or the excipient pharmaceutically or on the food that is used for diterpene ginkgolide of the present invention or its physiologically acceptable salt are sent to the animal or human.Carrier can be a liquid or solid.
Chemical compound of the present invention can be through oral, intravenous, intramuscular or subcutaneous route administration.
But the dosage form of oral administration administration is in the above-mentioned dosage form: tablet, capsule, powder, granule, syrup, solution, spirit.Solid-state carrier comprises: starch, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, sucrose, kaolin, micropowder silica gel, Pulvis Talci, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, polyvinylpyrrolidone.And liquid carrier comprises: sterilized water, ethanol, Polyethylene Glycol, nonionic surfactant and edible oil (as Semen Maydis oil, Oleum Arachidis hypogaeae semen and Oleum sesami).Normally used adjuvant comprises in the process of pharmaceutical compositions: flavoring agent, coloring agent, antiseptic (as oxybenzene alkyl butyl ester, sodium benzoate, sorbic acid) and antioxidant (as vitamin E, vitamin C, sodium pyrosulfite and dibenzylatiooluene).
The dosage form that can be used for injection administration in the above-mentioned dosage form comprises: injection, injectable sterile powder, they are that medicine and one or more pharmaceutically acceptable mixed with excipients are made form for drug administration by injection.Solvent comprises: sterilized water, ethanol, glycerol, propylene glycol, Polyethylene Glycol.In addition, also need add antibacterial (as benzyl alcohol, butyl hydroxybenzoate, thimerosal), isoosmotic adjusting agent (as sodium chloride, glucose), suspending agent (as sodium carboxymethyl cellulose, methylcellulose), solubilizing agent (tween 80, lecithin), antioxidant (as vitamin E, vitamin C, sodium pyrosulfite) and filler (as lactose, mannitol).
From being easy to prepare the position with administration, preferred pharmaceutical composition is a solid-state composition, and especially tablet and solid are filled or the capsule of liquid filling.The preferred oral administration.
The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can combination in any.All features that this case description is disclosed can with any composition forms and usefulness, each feature that is disclosed in the description can anyly provide the alternative characteristics of identical, impartial or similar purpose to replace.Therefore removing has special instruction, and the feature that is disclosed only is the general example of equalization or similar features.
Major advantage of the present invention is:
Quinazoline compounds shown in the general structure I of the present invention or its pharmaceutically acceptable salt or prodrug or its isomer have the effect that suppresses cell mitogen, can effectively suppress the abnormality proliferation of cell.
Below in conjunction with specific embodiment, further set forth the present invention.These embodiment only are used to the present invention is described and are not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.
| Numbering | Chemical compound |
| LJK-4 | 4-hydroxyl-5-anilino--8-nitro-quinazoline |
| LJK-6 | 4-hydroxyl-5-m-chloroaniline base-8-nitro-quinazoline |
| LJK-11 | 4-hydroxyl-5-(to methoxyl group) anilino--8-nitro-quinazoline |
| LJK-12 | 4-hydroxyl-5-(to amino) anilino--8-nitro-quinazoline |
| LJK-13 | 4-hydroxyl-5-(to benzyloxy) anilino--8-nitro-quinazoline |
Experimental apparatus: the multi-functional microplate reader of Tecan GENios Pro
Experiment reagent: Tubulin Polymerization Assay Kit (Cat.#CDS03 and BK006)
Experimental technique:
1,37 ℃ of preheating 96 orifice plates, 30 minutes;
2,4 ℃ of pre-cooling tubulin polymerization solution (Tubulin Polymerization Buffer):
General?Tubulin?Buffer(750μl)：80mM?PIPES(pH6.9)，2mMMgcl
2，0.5mM?EGTA；
Tubulin?Glycerol?Buffer(250μl)：15％glycerol?in?GeneralTubulin?Buffer；
GTP?Stock(200mM，10μl)：1mM?GTP；
3, preheating 500 μ l General Tubulin Buffer are to room temperature;
4, be divided into 5 groups at random: (1) matched group: every hole adds 5 μ l General Tubulin Buffer; (2) LJK-11 group: every hole adds 10 μ l LJK-11, and final concentration is respectively 200 μ M, 100 μ M, 25 μ M, 5 μ M, 1 μ M, hatches 2 minutes for 37 ℃; (3) colchicine group: draw among the General Tubulin Buffer that 10 μ l colchicine are dissolved in 190 μ l, every hole adds the colchicine solution after the 10 μ l dilution, to final concentration be 10 μ M; (4) paclitaxel group is drawn among the General Tubulin Buffer that 10 μ l paclitaxels are dissolved in 190 μ l, and every hole adds the paclitaxel solution after the 10 μ l dilution, to final concentration be 10 μ M; (5) Nocodazole group is drawn among the General Tubulin Buffer that 10 μ lNocodazole are dissolved in 190 μ l, and every hole adds the Nocodazole solution after the 10 μ l dilution, to final concentration be 10 μ M; More than 5 experimental grouies, establish 2 multiple holes for every group;
5, get the tubulin of 2 pipes, 200 μ l packing,, again it is positioned on ice as for dissolving 1 minute fast under the room temperature;
6, tubulin dilution is dissolved in the tubulin polymerization solution of 840 μ l pre-coolings, to final concentration be 3mg/ml;
7, every hole adds 100 μ l tubulins, immediately 96 orifice plates is put into microplate reader, the dynamic curve of record tubulin polymerization.
The data of experimental result: Fig. 1 show that LJK-11 can significantly suppress the polymerization of tubulin, and effect is better than mitotic inhibitor Nocodazole, compare with the inhibition effect of colchicine, there was no significant difference, and under different concentration, suppress effect and present tangible dose dependent.
Embodiment 2 LJK-11 are to the influence of people's gastric cancer HGC cell cycle
In vitro culture HGC cell when growth conditions is good, digests and inoculates 1 * 10
5Individual cell is in the 6cm culture dish, and it is adherent to spend the night.Deng cell state good after, inhale and go culture medium, add LJK-11 with the culture medium dilution, final concentration is respectively 5 μ M, 25 μ M, 50 μ M, negative control hole adds culture medium, cultivates 24h for 37 ℃.Observation of cell metamorphosis under the mirror.(0.25% pancreatin/0.02%EDTA), blow down gently moves into centrifuge tube, the centrifugal 5min of 2000rpm, PBS washing 2 times, the centrifugal 5min of 1000rpm with trypsin digestion cell.Slowly add 75% ethanol (20 ℃ of pre-coolings), 800 μ l in cell precipitation, vibration (Vortex) makes it to form unicellular as far as possible while dripping.4 ℃ fixedly spend the night after, the centrifugal 5min of 1000rpm, the PBS washed twice, centrifugal.Be resuspended in 300 μ l PBS, add the RNase (final concentration is 50 μ g/ml) that boiled in advance, hatch 30min for 37 ℃.300 order nylon net filters add propidium iodide (PI) (final concentration is 25 μ g/ml), 4 ℃ of lucifuge 1h, and flow cytometer detects cell cycle.
After experimental result: LJK-11 acted on HGC cell 24h, it is round that cell all becomes, and part is floating, and collecting cell carries out flow cytometer and detects.The result shows (as Fig. 2), and after the LJK-11 effect, G1, S phase cell obviously reduce, G2 phase cell obviously increases, illustrate that LJK-11 respectively under 5 μ M, 25 μ M, 50 μ M dosage, makes people's gastric cancer HGC cell stagnate the phase in G2-M, stop tumor cell to carry out normal mitosis.
Embodiment 3 is subjected to the inhibitory action of reagent thing to the kinds of tumor cells growth
In vitro culture human breast carcinoma MDA-MB-453 cell, human cervical carcinoma Hela cell, people's lung cancer A549 cell, people's gastric cancer HGC cell.Cell grows to the logarithmic growth after date, collecting cell, and centrifugal 5 minutes of 1000rpm abandons supernatant, and an amount of culture medium suspends, and adjusts cell concentration to 3.5x10
3/ ml.With cell suspension inoculation in 96 porocyte culture plates, every hole 100 μ l, place (37 ℃ of cell culture incubators, after cultivating 24h 5%CO2), add medicine LJK-11 to be measured (final concentration is respectively 1 μ M, 5 μ M, 10 μ M, 20 μ M, 40 μ M, 60 μ M, 80 μ M, 100 μ M), LJK-4 (final concentration is 40 μ M), LJK-6 (final concentration is 40 μ M), LJK-12 (final concentration is 40 μ M), LJK-13 (final concentration is 40 μ M), it is 0.5%DMSO that negative control group adds final concentration, and each group is all established 3 multiple holes.After cultivating 72h in the incubator, every hole adds the MTT 20 μ l of 5mg/ml, places 4h for 37 ℃.Every hole adds 200 μ l DMSO, 37 ℃ of shaking table vibration 30min, and 492nm/620nm surveys absorbance (OD).Utilization PrismGraphpad statistical software calculates the EC50 value.
Table 1 LJK-4 is to the inhibitory action of kinds of tumor cells growth
Table 2 LJK-6 is to the inhibitory action of kinds of tumor cells growth
Table 3 LJK-12 is to the inhibitory action of kinds of tumor cells growth
Table 4 LJK-13 is to the inhibitory action of kinds of tumor cells growth
Experimental result: as Fig. 3 and table 1,2,3, shown in 4, after adding is subjected to the reagent thing in various tumor cell culture liquid, the OD value of medication group all is lower than the blank group, LJK-4 is described, LJK-6, LJK-12, LJK-13 external to human breast carcinoma MDA-MB-453 cell, the human cervical carcinoma Hela cell, people's lung cancer A549 cell, people's gastric cancer HGC cell all has the effect of very strong its growth of inhibition, LJK-11 is to the human cervical carcinoma Hela cell, people's lung cancer A549 cell, people's gastric cancer HGC cell all has the obvious suppression effect, and is then not obvious to human breast carcinoma MDA-MB-453 cyto-inhibition.
Embodiment 4 LJK-11 are to the influence of Cavia porcellus ear skin silver bits sample skin lesion model due to the Propranolol
Laboratory animal: body weight is 20 of 300-450g albino guinea-pigs, and is male, provided by Shanghai Slac Experimental Animal Co., Ltd..
Experimental drug: the LJK-11 emulsifiable paste is by this prepared in laboratory (LJK-11 content is 0.5%), and dexamethasone acetate ointment is produced by Shanghai General Pharmaceutical Co., ltd., and Propranolol is by Dongbei Pharmaceutical General Factory production.
Get propranolol hydrochloride 5g and be dissolved in an amount of 50% the ethanol liquid, add Azone-propylene glycol 5mL as compound accelerant, adding PVPK30 5g is filmogen, adds 50% ethanol liquid at last and makes into 100mL, stirs evenly promptly.Get 20 male guinea pigs, be divided into 4 groups, promptly normal control group, model group, Dexamethasone group, LJK-11 organize, and except that the normal control group, all the other each groups are coated with general bitter edible plant Luo Er liniment in left side auricle (0.3g/cm with glass rod
2), 2 times/day, continuous 2 weeks are to cause ear skin silver bits sample skin lesion model.After this begin medication, normal control group and not medication of model group, LJK-11 group administration every day 2 times (0.2g/ only), Dexamethasone group administration every day 2 times (0.2g/ only), after 2 weeks of medication, get the Guinea Pig Left wide skin of picking up the ears, (X400) is with micrometer continent epidermal thickness under light microscopic, be converted into actual (real) thickness (mm) then, carry out group difference relatively.The statistical analysis measurement data is represented with x ± s, adopts t check carrying out statistical analysis.
Table 5 LJK-11 emulsifiable paste is to the influence of Cavia porcellus ear epidermal thickness (x ± s)
| Group | Number of animals | Epidermal thickness |
| The |
5 | 0.205±0.046 |
| |
5 | 0.397±0.051** |
| The LJK-11 |
5 | 0.229±0.034△△ |
| |
5 | 0.282±0.049△△ |
Annotate: * * compares with the blank group, p＜0.01;
△ △ compares with model group, p＜0.01.
Experimental result: psoriatic basic pathology characteristics are the too fast and parakeratosis of epidermal cell proliferation, if can suppress the hypertrophy or the parakeratosis of epidermis cell, promptly may have the psoriatic pharmacological action of treatment.The psoriatic external used medicine of treatment mainly comprise glucocorticoids, tretinoin etc., but the glucocorticoid external can cause many side effect at present, as suppressing hypothalmus-pituitary-adrenal axis.The LJK-11 emulsifiable paste can effectively improve Cavia porcellus ear epidermal thickness, and therapeutic effect and glucocorticoid are suitable, and have no side effect.
The preparation of tablet
Utilize routine techniques, mix following component, direct compression then, the pharmaceutical composition of preparation tablet form, its prescription is as follows:
Embodiment 6
The preparation of injection
1. sodium sulfite is added in the 500ml water for injection, adds sodium carboxymethyl cellulose, mixing, soaked overnight (24 hours), complete molten after, filter with 210 order nylon cloths;
2. with 1. heating in water bath of solution, add tween 80, mixing;
3. to the water-bath boiling, add LJK-11, mixing continues heating 30 minutes, takes out and is cooled to room temperature, G
3Sintered glass funnel filters;
4. add the injection water to 1000ml, mixing, embedding is with 100 ℃ of sterilizations in 30 minutes.
Embodiment 7
The preparation of water-in-oil type emulsifiable paste
Prescription (200g):
LJK-11 2g
Sorbester p17 2g
Chlorocresol 0.4g
Cera Flava 15g
Liquid Paraffin 50g
White vaseline 10g
Glyceryl monostearate 30g
5% sodium hydroxide is an amount of
Distilled water 88g
Method for making:
1, is oil phase with Cera Flava, glyceryl monostearate, liquid Paraffin, white vaseline and sorbester p17, puts in the evaporating dish, be heated in the water-bath about 80 ℃.
2, LJK-11 is added an amount of 5% sodium hydroxide and be dissolved in the distilled water, add chlorocresol,, stir and make dissolving, be water in also heating in the water-bath about 80 ℃.
3, under about 80 ℃, water is slowly added in the oil phase, and in water-bath, constantly be stirred to the semi-solid that is creamy white, at room temperature be stirred to nearly condensation again, promptly.
Scope of the present invention is not subjected to the restriction of described specific embodiments, and described embodiment is only desired also to comprise the method and the component of functional equivalent in the scope of the invention as the single example of illustrating various aspects of the present invention.In fact, except content as herein described, those skilled in the art can easily grasp multiple improvement of the present invention with reference to above description and accompanying drawing.Described improvement also falls within the scope of appended claims.Every piece of list of references mentioned above is listed this paper in as a reference all in full.
Claims (11)
1. quinazoline compounds or its pharmaceutically acceptable salt or prodrug or the purposes of its isomer in preparation mitotic inhibitor medicine shown in general structure I,
Wherein, R
1One of be chosen as in H, alkyl amino-carbonyl, sulfonyl, alkyl sulphonyl, alkyl sulphinyl, amino-sulfonyl, the acyl group;
R
2Can be-NO
2,-NHSO
2R ,-NRSO
2R ,-NHR or-one of among the OR;
R
3Can be H, alkyl, alkenyl, heterocyclic radical ,-OR or
One of in;
R
4In 2,3,4,5 or 6 replacements of phenyl ring, can be nothing ,-OR, halogen, alkyl, amino, aminoalkyl, alkyl amino-carbonyl, alkyl sulphonyl, alkyl sulphinyl, amino-sulfonyl, aryl alkyl, one of in cycloalkyl aryl, heteroaryl or the heterocyclic radical;
One of R can be alkyl, aryl, aryl alkyl, in cycloalkyl aryl, heteroaryl or the heterocyclic radical;
In above group, can not be substituted or be replaced separately by one or more substituent groups, these substituent groups comprise: halogen ,=O ,=S ,-CN ,-NO
2,-CF
3,-OCF
3, alkyl, alkenyl, alkynyl group, haloalkyl, haloalkenyl group, halo alkynyl, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, alkene oxygen base, alkynyloxy group, amino, alkyl amino, sulfonyl, alkyl sulphonyl, amino-sulfonyl, alkoxyalkyl ,-COOH ,-SH and acyl group.
2. purposes as claimed in claim 1 is characterized in that described R
1Be H.
3. purposes as claimed in claim 1 is characterized in that described R
2Can be-NO
2
4. purposes as claimed in claim 1 is characterized in that described R
3For
The time, R
4For-OR is in 3,4 or 5 replacements of phenyl ring, and R can be alkyl or aryl.
5. purposes as claimed in claim 4 is characterized in that described R
4For-OR is in phenyl ring 3 or 4 replacements, and R can be methyl.
6. purposes as claimed in claim 1 is characterized in that described quinazoline compounds can be in the following compounds: 4-hydroxyl-5-anilino--8-nitro-quinazoline, 4-hydroxyl-5-m-chloroaniline base-8-nitro-quinazoline, 4-hydroxyl-5-(to methoxyl group) anilino--8-nitro-quinazoline, 4-hydroxyl-5-(to amino) anilino--8-nitro-quinazoline, 4-hydroxyl-5-(to benzyloxy) anilino--8-nitro-quinazoline.
7. purposes as claimed in claim 1 is characterized in that described quinazoline compounds is 4-hydroxyl-5-(to methoxyl group) anilino--8-nitro-quinazoline.
8. as each described purposes of claim 1-7, it is characterized in that described mitotic inhibitor is the tubulin polymerization inhibitor.
9. as each described purposes of claim 1-7, it is characterized in that described mitotic inhibitor can be the medicine of treatment cellular abnormality hyperplasia.
10. purposes as claimed in claim 9, described cellular abnormality hyperplasia can be autoimmune disease, inflammation, osteopathia, metabolic disease, nerve and neurodegenerative disease, cardiovascular diseases, allergy or asthma.
11. purposes as claimed in claim 10, described autoimmune disease are psoriasis, rheumatoid arthritis, systemic lupus erythematosus (sle), dermatomyositis, scleroderma, multiple sclerosis, myasthenia gravis, demyelination, primary adrenocortical atrophy, chronic first shape inflammation, juvenile onset diabetes, chronic non-specific ulcerative colitis, chronic active hepatitis, bad habit anemia and atrophic gastritis, autoimmune glomerulonephritis, lung nephrorrhagia syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, the special property sent out leukopenia.
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|---|---|---|---|
| CN2009100533236A CN101926802A (en) | 2009-06-18 | 2009-06-18 | Application of quinazoline compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100533236A CN101926802A (en) | 2009-06-18 | 2009-06-18 | Application of quinazoline compounds |
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|---|---|
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Family
ID=43366407
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702115A (en) * | 2012-05-24 | 2012-10-03 | 盛世泰科生物医药技术(苏州)有限公司 | Synthetic method of 4-chloro-7-fluoro-6-nitro quinazoline |
| CN103102315A (en) * | 2012-11-01 | 2013-05-15 | 云南大学 | Quinazoline arylurea and preparation method and application thereof |
| CN105175400A (en) * | 2015-09-29 | 2015-12-23 | 河北神威药业有限公司 | Preparation method of Afatinib intermediate |
| CN110092727A (en) * | 2019-04-24 | 2019-08-06 | 深圳市第二人民医院 | The synthetic method of laquinimod intermediate 2-amino -6- chlorobenzoic acid |
-
2009
- 2009-06-18 CN CN2009100533236A patent/CN101926802A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702115A (en) * | 2012-05-24 | 2012-10-03 | 盛世泰科生物医药技术(苏州)有限公司 | Synthetic method of 4-chloro-7-fluoro-6-nitro quinazoline |
| CN103102315A (en) * | 2012-11-01 | 2013-05-15 | 云南大学 | Quinazoline arylurea and preparation method and application thereof |
| CN103102315B (en) * | 2012-11-01 | 2016-01-20 | 云南大学 | A kind of Quinazoline arylurea and its production and use |
| CN105175400A (en) * | 2015-09-29 | 2015-12-23 | 河北神威药业有限公司 | Preparation method of Afatinib intermediate |
| CN105175400B (en) * | 2015-09-29 | 2018-04-10 | 河北神威药业有限公司 | A kind of preparation method of afatinib intermediate |
| CN110092727A (en) * | 2019-04-24 | 2019-08-06 | 深圳市第二人民医院 | The synthetic method of laquinimod intermediate 2-amino -6- chlorobenzoic acid |
| CN110092727B (en) * | 2019-04-24 | 2022-07-08 | 深圳市第二人民医院 | Synthetic method of laquinimod intermediate 2-amino-6-chlorobenzoic acid |
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