CN103755647A - C2-bit derivative of 4(3H)-quinazolinone and preparation method and application thereof - Google Patents

C2-bit derivative of 4(3H)-quinazolinone and preparation method and application thereof Download PDF

Info

Publication number
CN103755647A
CN103755647A CN201410035735.8A CN201410035735A CN103755647A CN 103755647 A CN103755647 A CN 103755647A CN 201410035735 A CN201410035735 A CN 201410035735A CN 103755647 A CN103755647 A CN 103755647A
Authority
CN
China
Prior art keywords
dihydro
methyl esters
oxo quinazoline
compound
dithio
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201410035735.8A
Other languages
Chinese (zh)
Other versions
CN103755647B (en
Inventor
曹胜利
许兴智
廖蓟
刘翠环
高曼
丁盼盼
毛蓓蓓
赵金
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SHENYANG SUNSHINE PHARMACEUTICAL Co.,Ltd.
Original Assignee
Capital Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Capital Normal University filed Critical Capital Normal University
Priority to CN201410035735.8A priority Critical patent/CN103755647B/en
Publication of CN103755647A publication Critical patent/CN103755647A/en
Application granted granted Critical
Publication of CN103755647B publication Critical patent/CN103755647B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention discloses a C2-bit derivative of 4(3H)-quinazolinone as shown in a general formula (I), wherein detailed definitions of R<1> to R<5> are shown in the specifications. Moreover, the invention further discloses a preparation method and a medicinal composition of the compound. The compound shown in the general formula (I) has the effect of inhibiting the proliferation of human lung cancer (A-549), human breast cancer (MFC-7), human colon cancer (HT29 and HCT-116) and human cervical cancer (HeLa) cells, and can be taken as an anti-tumor medicament.

Description

C2 bit derivant of 4 (3H)-quinazolinones and its production and use
Technical field
The present invention relates to pharmaceutical chemistry field, more specifically to the C2 bit derivant of 4 (3H)-quinazolinones, and preparation method thereof and and their application in antitumor drug.
Background technology
In C5 or C6 position, be connected with the quinazoline derivant of different side chains, by suppressing folic acid dependent enzyme, present anti-tumor activity, for example ZD1694(structural formula 1) [Cunningham, D., Zalcberg, J., Maroun, J., James, R., Clarke, S., Maughan T.S., Vincent M., Schulz J., Baron, M.G., Facchini, T.Efficacy, tolerability and management of raltitrexed monotherapy in patients with advanced colorectal cancer:a review of phase II/III trials.Eur.J.Cancer2002, 38, 478-486], AG337(structural formula 1) [S.Webber, C.A.Bartlett, T.J.Boritzki, J.A.Hilliard, E.F.Howland, A.L.Johnston, M.Kosa, S.A.Margosiak, C.A.Morse, B.V.Shetty, AG337, a novel lipophilic thymidylate synthase inhibitor:in vitro and in vivo preclinical studies, Cancer Chemother.Pharmacol.1996, 37, 509-517] (structural formula 1).The inventor was once incorporated into the C6 position of 4 (3H)-quinazolinones using dithiocarbamates as side chain, synthesized the dithiocarbamates derivative (structural formula 2) of 4 (3H)-quinazolinones as ester group component, the propagation of human leukaemia K562 cell is had to significant restraining effect (Cao Shengli, 4-Quinazol derivative and the application in antitumor drug thereof, China Patent No.: ZL200510053618.5).And 4 (3H)-quinazolinones are connected with amino, the 4-quinazolinone-6-methylamino dithiocarbamate compounds (structural formula 3) forming, the propagation of people's lung cancer A549, human breast carcinoma MCF-7, colorectal carcinoma HT29, Cervical Cancer HeLa Cells is had to significant restraining effect (Cao Shengli, Xu Xingzhi, Liao Ji, Wang Yao, Han Ying, Zhao Baoli, Liu Hongqin, Chen Linlin, Li little Rong, 4-quinazolinone-6-methylamino dithiocarbamate and medicinal compositions thereof and purposes, China Patent No.: ZL201010034364.3).
Figure BDA0000461850580000021
The structure of structural formula 1.ZD1694, AG337
Figure BDA0000461850580000022
Structural formula 2.4 (3H)-quinazolinone is as the dithiocarbamates derivative of ester group component
Figure BDA0000461850580000023
Structural formula 3.4 (3H)-quinazolinone is as the dithiocarbamates derivative of amino group
Summary of the invention
The inventor is through a large amount of research trials, dithiocarbamates side chain is introduced to the C2 position of 4 (3H)-quinazolinones, synthesized 4 (3H)-Quinazol derivatives, this derivative is inhibited to the propagation of people's lung cancer A549, breast cancer cell MCF-7, cervical cancer HeLa, colorectal carcinoma HT-29 and HCT-116 cell.
The object of this invention is to provide a kind of C2 bit derivant of 4 (3H)-quinazolinones.
Another object of the present invention is to provide the preparation method of the C2 bit derivant of above-mentioned 4 (3H)-quinazolinones.
Another object of the present invention is to provide the medicinal compositions of the C2 bit derivant that comprises above-mentioned 4 (3H)-quinazolinones.
Another object of the present invention is to provide the C2 bit derivant of above-mentioned 4 (3H)-quinazolinones in the purposes of preparing in cancer therapy drug.
Specifically, the invention provides a kind of C2 bit derivant of 4 (3H)-quinazolinones, as shown in general formula (I):
Figure BDA0000461850580000031
Wherein, in formula (I)
R 2, R 3, R 4and R 5be selected from independently of one another hydrogen, C1-C4 alkyl, C1-C4 alkoxyl group, halogen, nitro or hydroxyl; Here, described C1-C4 alkyl is selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl; Described C1-C4 alkoxyl group is selected from methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy or tert.-butoxy; Described halogen is selected from fluorine, chlorine, bromine or iodine;
Preferably, R 2, R 3, R 4and R 5be selected from independently of one another hydrogen, methyl, methoxyl group, fluorine, chlorine, bromine, iodine, nitro or hydroxyl; More preferably, R 3for methyl, methoxyl group, fluorine, chlorine, bromine, iodine, nitro or hydroxyl, and R 2, R 4and R 5be hydrogen, methyl, methoxyl group, fluorine, chlorine, bromine, iodine, nitro or hydroxyl independently of one another; Or, R 4for methyl, methoxyl group, fluorine, chlorine, bromine, iodine, nitro or hydroxyl, and R 2, R 3and R 5be hydrogen, methyl, methoxyl group, fluorine, chlorine, bromine, iodine, nitro or hydroxyl independently of one another; Or, R 5for methyl, methoxyl group, fluorine, chlorine, bromine, iodine, nitro or hydroxyl, and R 2, R 3and R 4be hydrogen, methyl, methoxyl group, fluorine, chlorine, bromine, iodine, nitro or hydroxyl independently of one another;
R 1for the C1-C4 alkyl of C1-C4 alkyl or replacement, here, described C1-C4 alkyl is selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl, the C1-C4 alkyl of described replacement refers to by the C1-C4 alkyl that heterocycle replaced of the aryl of one or more aryl or replacement or heterocycle or replacement, preferably, R 1for the C1-C4 alkyl replacing, the more preferably methyl for replacing, described aryl is the phenyl of phenyl or replacement, wherein, the phenyl of described replacement refers to that phenyl ring is by one or more C1-4 alkyl, a halogenated c1-4 alkyl arbitrarily, C1-4 alkoxyl group, C1-4 alkyloyl, hydroxyl, halogen (for example fluorine, chlorine, bromine, or iodine), nitro or cyano group replace, and do not limit in the nuclear substituted position of benzene, optionally the substituting group on phenyl ring is connected with each other, more preferably, the phenyl of described replacement is selected from 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 2-p-methoxy-phenyl, 4-nitrophenyl, 4-cyano-phenyl, 4-bromo phenyl, 4-chlorophenyl, 4-difluorophenyl, 2-difluorophenyl, 2, 4-dichloro-phenyl, 2, 4-phenyl-difluoride base, 2, 4-Dimethoxyphenyl, 3, 4, 5-trimethoxyphenyl, or 3, 4-methylenedioxyphenyl,
Described heterocycle is selected from furans, tetrahydrofuran (THF), pyrans, tetrahydropyrans, thiophene, tetramethylene sulfide, thiazole, imidazoles, pyridine or pyrimidine; The heterocycle of described replacement refers to that heterocycle for example, is replaced by one or more C1-4 alkyl, arbitrarily individual halogenated c1-4 alkyl, C1-4 alkoxyl group, C1-4 alkyloyl, hydroxyl, halogen (fluorine, chlorine, bromine or iodine), nitro or cyano group, and does not limit in assorted nuclear substituted position; Preferably, described heterocycle is selected from thiophene, furans or pyridine, is more preferably thiophene-2-base, furans-2-base, pyridine-2-base, pyridin-3-yl or pyridin-4-yl; The heterocycle of described replacement is preferably 6-trifluoromethyl-pyridine-3 base.
As preferably embodiment of one, formula provided by the invention (I) compound is following formula (II) compound:
Figure BDA0000461850580000041
Wherein, R in formula (II) 1definition suc as formula (I) compound.
As preferably embodiment of one, formula provided by the invention (I) compound is following formula (III) compound:
Figure BDA0000461850580000042
Wherein, R in formula (III) 2, R 3, R 4and R 5definition suc as formula (I) compound.
In one embodiment of the present invention, the above-mentioned general formula of one provided by the invention (I) compound, it is selected from following compounds:
Benzylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 1);
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 2) of diphenyl-methyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 3) of 4-methyl-benzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 4) of 4-methoxy-benzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 5) of 2-methoxy-benzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 6) of 2,4-dimethoxy-benzyl;
3,4,5-trimethoxy benzylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 7);
3,4-methylene oxygen dioxy benzylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 8);
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 9) of 4-bromobenzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 10) of 4-chlorobenzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 11) of 2,4-dichloro benzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 12) of 4-luorobenzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 13) of 2-luorobenzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 14) of 2,4-difluorobenzyl;
4-cyano group benzylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 15);
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 16) of 4-nitrobenzyl;
(thiophene-2-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 17);
(furans-2-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 18);
(pyridine-2-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 19);
(pyridin-3-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 20);
(6-(trifluoromethyl) pyridine-2-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 21);
(pyridin-4-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 22);
4-methoxy-benzyl aminodithioformic acid (6-methyl-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 23);
4-methoxy-benzyl aminodithioformic acid (8-methyl-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 24);
4-methoxy-benzyl aminodithioformic acid (6-hydroxyl-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 25);
4-methoxy-benzyl aminodithioformic acid (6-fluoro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 26);
4-methoxy-benzyl aminodithioformic acid (6-chloro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 27);
4-methoxy-benzyl aminodithioformic acid (6-bromo-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 28);
4-methoxy-benzyl aminodithioformic acid (6-iodo-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 29);
4-methoxy-benzyl aminodithioformic acid (6-nitro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 30);
4-methoxy-benzyl aminodithioformic acid (7-nitro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 31);
4-methoxy-benzyl aminodithioformic acid (6,8-bis-chloro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 32); Or
4-methoxy-benzyl aminodithioformic acid (6,7-dimethoxy-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 33).
On the other hand, the invention provides the preparation method of the C2 bit derivant of 4 (3H)-quinazolinones as shown in general formula (I), comprise the steps:
Formula (IV) compound and formula V compound are at CS 2, there is lower reaction in potassiumphosphate, obtains formula (I) compound
Figure BDA0000461850580000071
Substituent X in formula (IV) compound is halogen, is selected from bromine or chlorine;
Substituent R in formula (IV) compound 2, R 3, R 4and R 5definition suc as formula (I) compound;
R in formula V compound 1definition suc as formula (I) compound.
Provided by the invention as shown in general formula (I) preparation method of the C2 bit derivant of 4 (3H)-quinazolinones, wherein, formula (I) compound is formula (II) compound, and, when in formula (IV) compound, X is bromine, can prepare by following technique:
As shown in Scheme 1, by anthranilic acid (VI) and diacetyl oxide heating reflux reaction, obtain benzoxazinone (VII), product does not add separation and purification, is directly used in the next step.After VII and ammoniacal liquor effect, obtain 2-methyl-4 (3H)-quinazolinone (VIII).Take dry DMF as solvent, intermediate VIII reacts at 40 ℃ with NBS, obtains 2-brooethyl-4 (3H)-quinazolinone (IX).In anhydrous K 3pO 4under existence, the amine R of IX and dithiocarbonic anhydride, different replacements 1nH 2reaction obtains compound 1-22.
Figure BDA0000461850580000072
The synthetic route of route 1. compound 1-22
Reagent and reaction conditions: a. (AcO) 2o, refluxes, 2h; B.NH 3h 2o, EtOH(ethanol), room temperature, 48h; C.NBS(N-bromo-succinimide), DMF(N, dinethylformamide), 40 ℃, 24h; d.R 1nH 2, CS 2, K 3pO 4, DMF(N, dinethylformamide), room temperature, 1-3h;
Here, formula (II) compound and R 1nH 2in substituent definition as above.
Provided by the invention as shown in general formula (I) preparation method of the C2 bit derivant of 4 (3H)-quinazolinones, wherein, formula (I) compound is formula (III) compound, and, when in formula (IV) compound, X is chlorine, formula (III) compound can be prepared by following technique:
As shown in Scheme 2, the anthranilic acid (X) that is connected with different substituents is dissolved in dehydrated alcohol, passes into dry HCl gas, heating reflux reaction 6h, obtains being connected with the ethyl o-aminobenzoate (XI) of different substituents.[Wright, S.W. as described in document; Carlo, A.A.; Carty, M.D.; Danley, D.E.; Hageman, D.L.; Karam, G.A.; Levy, C.B.; Mansour, M.N.; Mathiowetz, A.M.; McClure, L.D.; Nestor, N.B.; McPherson, R.K.; Pandit, J.; Pustilnik, L.R.; Schulte, G.K.; Soeller, W.C.; Treadway, J.L.; Wang, I.K.; Bauer, P.H.J.Med.Chem.2002,45 (18), 3865 – 3877.], XI is dissolved in chloromethyl cyanide, pass into dry HCl gas, room temperature reaction 16h, obtains connecting different substituents (R 2) 2-chloromethyl-4 (3H)-quinazolinone (XIIa-k).In anhydrous K 3pO 4under existence, XIIa-k reacts with dithiocarbonic anhydride, 4-methoxybenzylamine, obtains compound 23-33.
Figure BDA0000461850580000081
The synthetic route of route 2. compound 23-33.
Reagent and reaction conditions: a.EtOH, HCl (g); B.ClCH 2cN, HCl (g), room temperature, 16h; C.4-CH 3oC 6h 4cH 2nH 2, CS 2, K 3pO 4, DMF, room temperature, 3h.
The third aspect, the invention provides the medicinal compositions of the C2 bit derivant that one comprises above-mentioned 4 (3H)-quinazolinones.This medicinal compositions comprises formula (I) compound and the pharmaceutically acceptable auxiliary material of significant quantity on pharmacology.To those skilled in the art, these auxiliary materials are all known, for example, and physiological saline, gelatin, Sudan Gum-arabic, lactose, Microcrystalline Cellulose, starch, treated starch, Mierocrystalline cellulose, modified-cellulose, hydroxyethanoic acid sodium, secondary calcium phosphate, Magnesium Stearate, talcum, colloid silica etc.In addition, these compositions also can comprise further: stablizer, wetting agent, emulsifying agent, sweeting agent, flavouring agent, buffer reagent etc.
The medicinal compositions of the C2 bit derivant that comprises above-mentioned 4 (3H)-quinazolinones provided by the invention, as required, can be mixed with solid or liquid form for oral administration, as tablet, pill, oral liquid etc.; For sterile solution, suspension or the emulsion form of parenterai administration, sprays etc.
For example, tablet formulation:
Preparation method is: supplementary material is crossed to 100 mesh sieves, then mix; Ethanol softwood processed with 90%, granulates, and whole grain, adds Magnesium Stearate to mix, compressing tablet and get final product.
Injection formula:
Figure BDA0000461850580000092
Preparation method:
N.F,USP MANNITOL is added in 1600mL water for injection to stirring and dissolving; Embodiment of the present invention compound is added to above-mentioned solution, stirring and dissolving; 4% disodium phosphate soln adjust pH is 4.15; Inject water to 2000mL, add gac, 50 ℃ of insulated and stirred 20min, filtering decarbonization; With the filtering with microporous membrane of 0.22 μ m, embedding.121 ℃, 15min high-temperature heat sterilization.
On the other hand, the invention provides formula (I) compound in the application of preparing in antitumor drug.Compound of the present invention can be used for treating lung cancer, mammary cancer, colorectal carcinoma, liver cancer, cancer of the stomach, ovarian cancer, cervical cancer, oral carcinoma, leukemia etc.
Experimental results show that, the compound of formula of the present invention (I) has anti-tumor activity, propagation to people's lung cancer (A-549), mammary cancer (MCF-7), colorectal carcinoma (HT29, HCT-116) and cervical cancer (HeLa) cell is inhibited, can be used as antitumor drug or as antitumor activity component for antineoplastic pharmaceutical compositions.The reference dose of medication is 0.1-10mg/kg body weight, and using method is oral or intravenous injection.
Embodiment
Carry out by the following examples exemplary illustration embodiment of the present invention, for the ordinary skill in the art, under instruction of the present invention, according to prior art, the improvement that embodiment of the present invention is carried out, still belongs in protection scope of the present invention.
The source of the raw materials of compound using in embodiment is: the anthranilic acid of anthranilic acid, replacement, and the benzylamine of benzylamine, replacement, benzhydrylamine, thiophene, furans or picolyl amine, and other raw material is commercially available chemical reagent.
The people's lung cancer (A-549), mammary cancer (MCF-7), colorectal carcinoma (HT29, HCT-116) and cervical cancer (HeLa) cell that in embodiment, use are replied Beijing key lab from Capital Normal University's DNA damage.
Preparation Example 1
Synthesizing of 2-methyl-4 (3H)-quinazolinone (VIII)
Being housed, reflux condensing tube (above meets anhydrous CaCl 2drying tube) reaction flask in, add anthranilic acid (IIa) (1.37g, 10mmol) and acetic anhydride 10mL, reflux 2h.Be chilled to room temperature, rotary evaporation is removed most of acetic anhydride, and the solid that cooling rear filter collection is separated out is dry, obtains intermediate III 1.47g, and yield 91%, is directly used in next step reaction.
In the mixed solution of 2-Jia base benzoxazinone (VII) (1.47g, 9.1mmol) and dehydrated alcohol (20mL), add 25% ammoniacal liquor 36.8mL, under room temperature, stir 48h.Rotary evaporation is removed most of solvent, cooling, the solid that filter collection is separated out, and dry, ethyl alcohol recrystallization, obtains white solid (IV) 1.12g, yield 76%, m.p.233.2-236.3 ℃ (document m.p.237-239 ℃). 1h NMR (600MHz, DMSO-d 6) δ: 2.61 (s, 2H, CH 3), 7.65 (t, J=7.8Hz, 1H, quin6-H), 7.83 (d, J=7.8Hz, 1H, quin8-H), 7.96 (t, J=7.8Hz, 1H, quin7-H), 8.16 (d, J=7.8Hz, 1H, quin5-H) .ESI-HRMS m/z:C 9h 9n 2o ([M+H] +) calculated value: 161.0715; Measured value: 161.0709.
Synthesizing of 2-brooethyl-4 (3H)-quinazolinone (IX)
By 2-methyl-4 (3H)-quinazolinone (VIII) (6.40g, 40mmol) be dissolved in N, in dinethylformamide (35mL), add N-bromosuccinimide (NBS) (7.12g, 40mmol), in 40 ℃ of reaction 24h.Be cooled to room temperature, the solid that filter collection is separated out, with ether washing, dry, obtain white solid 7.37g, yield 77%, m.p.227.3-230.2 ℃ (document m.p.>300 ℃). 1h NMR (600MHz, DMSO-d 6) δ: 4.41 (s, 2H, CH 2br), 7.55 (t, J=7.8Hz, 1H, quin6-H), 7.67 (d, J=7.8Hz, 1H, quin8-H), 7.84 (t, J=7.8Hz, 1H, quin7-H), 8.12 (d, J=7.8Hz, 1H, quin5-H), 12.57 (br s, 1H, NH) .ESI-HRMS m/z:C 9h 8brN 2o ([M+H] +) calculated value: 238.9820,240.9800; Measured value: 238.9813,240.9790.
The synthetic logical method of the compounds of this invention 1-22
Benzylamine or heterocyclic methyl amine (1.5mmol) are dissolved in to N, in dinethylformamide (20mL), add the anhydrous phosphoric acid potassium (0.40g of porphyrize, 1.89mmol), dithiocarbonic anhydride (0.6mL, 9.98mmol), stirring at room 0.5h, add 2-brooethyl-4 (3H) quinazolinones (IX) (0.36g, 1.5mmol), continue to stir 1-3h.By in reaction solution impouring 150mL distilled water, the solid that filter collection is separated out, dries, and with silica gel column chromatography, purifies, and obtains compound 1-22.
Embodiment 1
Benzylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 1)
Yield: 63%, faint yellow solid, m.p.171.9-174.2 ℃ of (elutriant: CH 2cl 2). 1hNMR (600MHz, DMSO-d 6) δ: 4.45 (s, 2H, SCH 2), 4.85 (d, J=5.4Hz, 2H, CH 2nH), 7.29 (m, 1H, ph4 '-H), 7.33 (m, 4H, ph2 '-H, 3 '-H, 5 '-H, 6 '-H), 7.42 (d, J=7.8Hz, 1H, quin8-H), 7.49 (t, J=7.8Hz, 1H, quin6-H), 7.77 (t, J=7.8Hz, 1H, quin7-H), 8.09 (d, J=7.8Hz, 1H, quin5-H), 10.70 (t, J=5.4Hz, 1H, CH 2nH), 12.41 (s, 1H, NH) .ESI-MS m/z:342[M+H] +. ultimate analysis (C 17h 15n 3oS 20.7H 2o) calculated value: C, 57.67; H, 4.67; N, 11.87. measured value: C, 57.61; H, 4.45; N, 11.67.
Embodiment 2
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 2) of diphenyl-methyl
Yield 70%, yellow solid, m.p.97.2-99.0 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 3.17 (s, 1H, Ph 2cH), 4.48 (s, 2H, SCH 2), 6.93 (d, J=8.4Hz, 1H, quin8-H), 7.29-7.34 (m, 10H, ph-H), 7.49 (t, J=7.8Hz, 1H, quin6-H), 7.74 (t, J=8.4Hz, 1H, quin7-H), 8.09 (d, J=7.8Hz, 1H, quin5-H), 11.12 (d, J=8.4Hz, 1H, CHNH), 12.43 (s, 1H, NH). ultimate analysis (C 23h 19n 3oS 20.3H 2o) calculated value: C, 65.31; H, 4.67; N, 9.93. measured value: C, 65.32; H, 4.84; N, 9.84.
Embodiment 3
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 3) of 4-methyl-benzyl
Yield 51%, off-white color solid, m.p.186.3-187.2 ℃ of (elutriant: CH 2cl 2/ CH 3oH=95:5). 1h NMR (600MHz, DMSO-d 6) δ: 2.29 (s, 3H, CH 3), 4.44 (s, 2H, SCH 2), 4.80 (d, J=5.4Hz, 2H, CH 2nH), 7.14 (d, J=7.8Hz, 2H, ph-H), 7.22 (d, J=7.8Hz, 2H, ph-H), 7.38 (d, J=8.4Hz, 1H, quin8-H), 7.49 (t, J=7.8Hz, 1H, quin6-H), 7.76 (t, J=8.4Hz, 1H, quin7-H), 8.09 (d, J=7.8Hz, 1H, quin5-H), 10.66 (t, J=5.4Hz, 1H, CH 2nH), 12.40 (s, 1H, NH). ultimate analysis (C 18h 17n 3oS 2) calculated value: C, 60.82; H, 4.82; N, 11.82. measured value: C, 60.81; H, 4.92; N, 11.82.
Embodiment 4
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 4) of 4-methoxy-benzyl
Yield: 61%, faint yellow solid, m.p.178.1-179.0 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 3.74 (s, 3H, OCH 3), 4.43 (s, 2H, SCH 2), 4.77 (d, J=5.4Hz, 2H, CH 2nH), 6.89 (d, J=8.4Hz, 2H, ph3 '-H, 5 '-H), 7.27 (d, J=8.4Hz, 2H, ph2 '-H, 6-H), 7.39 (d, J=7.8Hz, 1H, quin8-H), 7.49 (t, J=7.8Hz, 1H, quin6-H), 7.76 (t, J=7.8Hz, 1H, quin7-H), 8.08 (d, J=7.8Hz, 1H, quin5-H), 10.63 (t, J=5.4Hz, 1H, CH 2nH), 12.40 (s, 1H, NH). ultimate analysis (C 18h 17n 3o 2s 2) calculated value: C, 58.20; H, 4.61; N, 11.31. measured value: C, 58.16; H, 4.75; N, 11.11.
Embodiment 5
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 5) of 2-methoxy-benzyl
Yield: 49%, faint yellow solid, m.p.157.0-158.0 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 3.80 (s, 3H, OCH 3), 4.42 (s, 2H, SCH 2), 4.77 (d, J=5.4Hz, 2H, CH 2nH), 6.90 (t, J=7.8Hz, 1H, ph5 '-H), 7.03 (d, J=7.8Hz, 1H, ph3 '-H), 7.21 (d, J=7.8Hz, 1H, ph6 '-H), 7.30 (t, J=7.8Hz, 1H, ph6 '-H), 7.38 (d, J=8.4Hz, 1H, quin8-H), 7.50 (t, J=8.4Hz, 1H, quin6-H), 7.77 (t, J=8.4Hz, 1H, quin7-H), 8.09 (d, J=8.4Hz, 1H, quin5-H), 10.55 (t, J=5.4Hz, 1H, CH 2nH), 12.41 (s, 1H, NH) .ESI-HRMS m/z:C 18h 18n 3o 2s 2([M+H] +) calculated value: 372.0840; Measured value: 372.0833.
Embodiment 6
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 6) of 2,4-dimethoxy-benzyl
Yield: 51%, faint yellow solid, m.p.162.0-163.0 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 3.76 (s, 3H, OCH 3), 3.77 (s, 3H, OCH 3), 4.38 (s, 2H, SCH 2), 4.67 (d, J=5.4Hz, 2H, CH 2nH), 6.48 (dd, J=8.4,2.4Hz, 1H, ph5 '-H), 6.59 (d, J=2.4Hz, 1H, ph3 '-H), 7.15 (d, J=8.4Hz, 1H, ph6 '-H), 7.33 (d, J=7.8Hz, 1H, quin8-H), 7.50 (t, J=7.8Hz, 1H, quin6-H), 7.76 (t, J=7.8Hz, 1H, quin7-H), 8.09 (d, J=7.8Hz, 1H, quin5-H), 10.64 (t, J=5.4Hz, 1H, CH 2nH), 12.40 (s, 1H, NH) .ESI-HRMS m/z:C 19h 20n 3o 3s 2([M+H] +) calculated value: 402.0946; Measured value: 402.0933.
Embodiment 7
3,4,5-trimethoxy benzylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 7)
Yield: 48%, faint yellow solid, m.p.168.0-170.0 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 3.64 (s, 3H, OCH 3), 3.70 (s, 6H, 2OCH 3), 4.44 (s, 2H, SCH 2), 4.76 (d, J=4.8Hz, 2H, CH 2nH), 6.68 (s, 2H, ph2 '-H, 6 '-H), 7.34 (d, J=7.8Hz, 1H, quin8-H), 7.49 (t, J=7.8Hz, 1H, quin6-H), 7.74 (t, J=7.8Hz, 1H, quin7-H), 8.09 (d, J=7.8Hz, 1H, quin5-H), 10.64 (t, J=4.8Hz, 1H, CH 2nH), 12.42 (s, 1H, NH) .ESI-HRMS m/z:C 20h 22n 3o 4s 2([M+H] +) calculated value: 432.1052; Measured value: 432.1038.
Embodiment 8
3,4-methylene oxygen dioxy benzylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 8)
Yield: 47%, faint yellow solid, m.p.176.0-177.0 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 4.43 (s, 2H, SCH 2), 4.74 (d, J=4.8Hz, 2H, CH 2nH), 6.0 (s, 2H, OCH 2o), 6.82 (d, J=7.8Hz, 1H, ph6 '-H), 6.86 (d, J=7.8Hz, 1H, ph5 '-H), 6.90 (s, 1H, ph2 '-H), 7.42 (d, J=7.8Hz, 1H, quin8-H), 7.49 (t, J=7.8Hz, 1H, quin6-H), 7.77 (t, J=7.8Hz, 1H, quin7-H), 8.08 (d, J=7.8Hz, 1H, quin5-H), 10.62 (t, J=4.8Hz, 1H, CH 2nH), 12.41 (s, 1H, NH) .ESI-HRMS m/z:C 18h 16n 3o 3s 2([M+H] +) calculated value: 386.0633; Measured value: 386.0622.
Embodiment 9
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 9) of 4-bromobenzyl
Yield: 71%, faint yellow solid, m.p.192.1-193.2 ℃ of (elutriant: CH 2cl 2/ CH 3oH=95:5). 1h NMR (600MHz, DMSO-d 6) δ: 4.43 (s, 2H, SCH 2), 4.80 (d, J=5.4Hz, 2H, CH 2nH), 7.26 (d, J=8.4Hz, 2H, ph2 '-H, 6 '-H), 7.43 (d, J=7.8Hz, 1H, quin8-H), 7.47 (t, J=7.8Hz, quin6-H), 7.50 (d, J=8.4Hz, 2H, ph3 '-H, 5 '-H), 7.76 (t, J=7.8Hz, 1H, quin7-H), 8.07 (d, J=7.8Hz, 1H, quin5-H), 10.67 (t, J=5.4,1H, CH 2nH), 12.40 (br s, 1H, NH). ultimate analysis (C 17h 14brN 3oS 2) calculated value: C, 48.57; H, 3.36; N, 10.00. measured value: C, 48.79; H, 3.37; N, 9.59.
Embodiment 10
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 10) of 4-chlorobenzyl
Yield: 50%, pink solid, m.p.188.3-190.1 ℃ of (elutriant: CH 2cl 2/ CH 3oH=95:5). 1h NMR (600MHz, DMSO-d 6) δ: 4.45 (s, 2H, SCH 2), 4.84 (d, J=5.4Hz, 2H, CH 2nH), 7.33 (d, J=8.4Hz, 2H, ph2 '-H, 6 '-H), 7.38 (d, J=8.4Hz, 2H, ph3 '-H, 5 '-H), 7.45 (d, J=7.8Hz, 1H, quin8-H), 7.50 (t, J=7.8Hz, 1H, quin6-H), 7.78 (t, J=7.8Hz, 1H, quin7-H), 8.09 (d, J=7.8Hz, 1H, quin5-H), 10.69 (t, J=5.4Hz, 1H, CH 2nH), 12.41 (s, 1H, NH). ultimate analysis (C 17h 14clN 3oS 2) calculated value: C, 54.32; H, 3.75; N, 11.18. measured value: C, 54.48; H, 3.91; N, 11.04.
Embodiment 11
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 11) of 2,4-dichloro benzyl
Yield: 57%, brown solid, m.p.179.8-180.1 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 4.46 (s, 2H, SCH 2), 4.86 (d, J=4.8Hz, 2H, CH 2nH), 7.35 (d, J=8.4Hz, 1H, ph6 '-H), 7.39 (dd, J=8.4,1.8Hz, 1H, ph5 '-H), 7.49 (d, J=7.8Hz, 1H, quin8-H), 7.51 (t, J=7.8Hz, 1H, quin6-H), 7.63 (d, J=1.8Hz, 1H, ph3 '-H), 7.79 (t, J=7.8Hz, 1H, quin7-H), 8.10 (d, J=7.8Hz, 1H, quin5-H), 10.66 (t, J=4.8Hz, 1H, CH 2nH), 12.43 (s, 1H, NH) .ESI-HRMS m/z:C 17h 14cl 2n 3oS 2([M+H] +) calculated value: 409.9955,411.9926; Measured value: 409.9944,411.9911.
Embodiment 12
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 12) of 4-luorobenzyl
Yield: 64.9%, white solid, m.p.167.6-169.2 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 4.45 (s, 2H, SCH 2), 4.83 (d, J=5.4Hz, 2H, CH 2nH), 7.16 (t, J=8.4Hz, 2H, ph3 '-H, 5 '-H), 7.37 (dd, J=8.4,5.4Hz, 2H, ph2 '-H, 6 '-H), 7.45 (d, J=7.8Hz, 1H, quin8-H), 7.50 (t, J=7.8Hz, 1H, quin6-H), 7.78 (td, J=7.8,1.2Hz, 1H, quin7-H), 8.09 (dd, J=7.8,1.2Hz, 1H, quin5-H), 10.68 (t, J=5.4Hz, 1H, CH 2nH), 12.41 (s, 1H, NH). ultimate analysis (C 17h 14fN 3oS 20.7H 2o) calculated value: C, 54.88; H, 4.17; N, 11.29. measured value: C, 55.04; H, 4.19; N, 11.07.
Embodiment 13
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 13) of 2-luorobenzyl
Yield: 69%, faint yellow solid, m.p.159.2-160.4 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 4.45 (s, 2H, SCH 2), 4.86 (d, J=4.8Hz, 2H, CH 2nH), 7.15 (t, J=7.2Hz, 1H, ph3 '-H), 7.21 (t, J=9.0Hz, 1H, ph5 '-H), 7.36 (m, 2H, ph4 '-H, 6 '-H), 7.46 (d, J=7.8Hz, 1H, quin8-H), 7.50 (t, J=7.8Hz, 1H, quin6-H), 7.78 (td, J=7.8,1.2Hz, 1H, quin7-H), 8.09 (dd, J=7.8,1.2Hz, 1H, quin5-H), 10.66 (t, J=4.8Hz, 1H, CH 2nH), 12.41 (s, 1H, NH). ultimate analysis (C 17h 14fN 3oS 2) calculated value: C, 56.81; H, 3.93; N, 11.69. measured value: C, 56.83; H, 3.97; N, 11.60.
Embodiment 14
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 14) of 2,4-difluorobenzyl
Yield: 78%, faint yellow solid, m.p.161.9-162.8 ℃ of (elutriant: CH 2cl 2/ CH 3oH=95:5). 1h NMR (600MHz, DMSO-d 6) δ: 4.45 (s, 2H, SCH 2), 4.82 (d, J=4.8Hz, 2H, CH 2nH), 7.05 (td, J=8.4,1.8Hz, 1H, ph3 '-H), 7.25 (td, J=9.9,1.8Hz, 1H, ph5 '-H), 7.43 (m, 1H, ph6 '-H), 7.50 (m, 2H, quin8-H, 6-H), 7.79 (t, J=7.8Hz, 1H, quin7-H), 8.09 (d, J=7.8Hz, 1H, quin5-H), 10.63 (t, J=4.8Hz, 1H, CH 2nH), 12.41 (s, 1H, NH) .ESI-HRMS m/z:C 17h 14f 2n 3oS 2([M+H] +) calculated value: 378.0546; Measured value: 378.0539.
Embodiment 15
4-cyano group benzylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 15)
Yield: 52%, faint yellow solid, m.p.164.0-166.0 ℃ of (elutriant: CH 2cl 2/ CH 3oH=95:5). 1h NMR (600MHz, DMSO-d 6) δ: 4.47 (s, 2H, SCH 2), 4.94 (d, J=5.4Hz, 2H, CH 2nH), 7.48 (d, J=7.8Hz, 2H, ph2 '-H, 6 '-H), 7.51 (m, 2H, quin6-H, 8-H), 7.79 (m, 3H, ph3 '-H, 5 '-H, quin7-H), 8.09 (d, J=7.8Hz, 1H, quin5-H), 10.75 (t, J=5.4Hz, 1H, CH 2nH), 12.42 (s, 1H, NH) .ESI-HRMS m/z:C 18h 15n 4oS 2([M+H] +) calculated value: 367.0687; Measured value: 367.0678.
Embodiment 16
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 16) of 4-nitrobenzyl
Yield: 41%, faint yellow solid, m.p.178.6-180.2 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 4.48 (s, 2H, SCH 2), 4.99 (d, J=5.4Hz, 2H, CH 2nH), 7.49 (m, 2H, quin8-H, 6-H), 7.52 (d, J=8.4Hz, 2H, ph3 '-H, 5 '-H), 7.78 (t, J=7.8Hz, 1H, quin7-H), 8.09 (d, J=7.8Hz, 1H, quin5-H), 8.18 (d, J=8.4Hz, 2H, ph2 '-H, 6 '-H), 10.79 (t, J=5.4Hz, 1H, CH 2nH), 12.43 (s, 1H, NH). ultimate analysis (C 17h 14n 4o 3s 2) calculated value: C, 52.84; H, 3.65; N, 14.50. measured value: C, 53.05; H, 3.81; N, 14.24.
Embodiment 17
(thiophene-2-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 17)
Yield: 46%, faint yellow solid, m.p.176.0-178.0 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 4.44 (s, 2H, SCH 2), 5.02 (d, J=3.0Hz, 2H, CH 2nH), 6.99 (t, J=4.2Hz, 1H, thiophene4 '-H), 7.10 (d, J=2.4Hz, 1H, thiophene3 '-H), 7.44 (d, J=4.8Hz, 1H, thiophene5 '-H), 7.48 (d, J=7.8Hz, 1H, quin8-H), 7.49 (t, J=7.8Hz, 1H, quin6-H), 7.77 (t, J=7.8Hz, 1H, quin7-H), 8.09 (d, J=7.8Hz, 1H, quin5-H), 10.75 (br s, 1H, CH 2nH), 12.41 (s, 1H, NH) .ESI-HRMS m/z:C 15h 14n 3oS 3([M+H] +) calculated value: 348.0299; Measured value: 348.0293.
Embodiment 18
(furans-2-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 18)
Yield: 48%, faint yellow solid, m.p.166.0-168.0 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 4.40 (s, 2H, SCH 2), 4.80 (d, J=5.4Hz, 2H, NHCH 2), 6.36 (d, J=3.0Hz, 1H, furan3 '-H), 6.40 (m, 1H, furan4 '-H), 7.47 (m, 2H, quin6-H, 8-H), 7.60 (m, 1H, furan5 '-H), 7.76 (td, J=7.8,1.8Hz, 1H, quin7-H), 8.06 (dd, J=7.8,1.8Hz, 1H, quin5-H), 10.64 (t, J=5.4Hz, 1H, CH 2nH), 12.38 (s, 1H, NH) .ESI-HRMS m/z:C 15h 14n 3o 2s 2([M+H] +) calculated value: 332.0527; Measured value: 332.0519.
Embodiment 19
(pyridine-2-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 19)
Yield: 48%, faint yellow solid, m.p.147.0-149.0 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 4.46 (s, 2H, SCH 2), 4.93 (d, J=3.0Hz, 2H, CH 2nH), 7.30 (m, 2H, pyridine3 '-H, 5 '-H), 7.49 (d, J=7.8Hz, 1H, quin8-H), 7.53 (t, J=7.8Hz, 1H, quin6-H), 7.74 (d, J=7.8Hz, 1H, pyridine4 '-H), 7.79 (t, J=7.8Hz, 1H, quin7-H), 8.09 (d, J=7.8Hz, 1H, quin5-H), 8.52 (d, J=4.2Hz, 1H, pyridine6 '-H), 10.80 (br s, 1H, CH 2nH), 12.42 (s, 1H, NH) .ESI-HRMS m/z:C 16h 15n 4oS 2([M+H] +) calculated value: 343.0687; Measured value: 343.0681.
Embodiment 20
(pyridin-3-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 20)
Yield: 52%, faint yellow solid, m.p.180.0-182.0 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 4.46 (s, 2H, SCH 2), 4.87 (d, J=5.4Hz, 2H, CH 2nH), 7.35 (m, 1H, pyridine5 '-H), 7.48 (d, J=7.8Hz, 1H, quin8-H), 7.50 (t, J=7.8Hz, 1H, quin6-H), 7.72 (d, J=7.8Hz, 1H, pyridin4 '-H), 7.78 (t, J=7.8Hz, 1H, quin7-H), 8.09 (d, J=7.8Hz, 1H, quin5-H), 8.49 (d, J=7.8Hz, 1H, pyridine6 '-H), 8.56 (s, 1H, pyridine2 '-H), 10.71 (t, J=5.4Hz, 1H, CH 2nH), 12.42 (s, 1H, NH) .ESI-HRMS m/z:C 16h 15n 4oS 2([M+H] +) calculated value: 343.0687; Measured value: 343.0682.
Embodiment 21
(6-(trifluoromethyl) pyridine-2-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 21)
Yield: 50%, faint yellow solid, m.p.164.0-166.0 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 4.48 (s, 2H, SCH 2), 4.97 (s, 2H, CH 2nH), 7.50 (m, 2H, quin8-H, 6-H), 7.77 (t, J=7.8Hz, 1H, quin7-H), 7.87 (d, J=7.8Hz, 1H, pyridine5 '-H, 7.97 (d, J=7.8Hz, 1H, pyridine4 '-H), 8.09 (d, J=7.8Hz, 1H, quin5-H), 8.73 (s, 1H, pyridine2 '-H), 10.79 (s, 1H, CH 2nH), 12.42 (s, 1H, NH) .ESI-HRMS m/z:C 17h 14f 3n 4oS 2([M+H] +) calculated value: 411.0561; Measured value: 411.0552.
Embodiment 22
(pyridin-4-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 22)
Yield: 50%, faint yellow solid, m.p.148.0-150.0 ℃ of (elutriant: CH 2cl 2/ CH 3oH=98:2). 1h NMR (600MHz, DMSO-d 6) δ: 4.48 (s, 2H, SCH 2), 4.88 (d, J=4.8Hz, 2H, CH 2nH), 7.27 (d, J=4.8Hz, 2H, pyridine3 '-H, 5 '-H), 7.52 (m, 2H, quin8-H, 6-H), 7.80 (t, J=7.8Hz, 1H, quin7-H), 8.10 (d, J=7.8Hz, 1H, quin5-H), 8.73 (d, J=4.8Hz, 2H, pyridine2 '-H, 6 '-H), 10.75 (s, 1H, CH 2nH), 12.43 (s, 1H, NH) .ESI-HRMS m/z:C 16h 15n 4oS 2([M+H] +) calculated value: 343.0687; Measured value: 343.0681.
Preparation Example 2
The synthetic logical method of 2-chloromethyl-4 (3H)-quinazolinone (XIIa-k)
The anthranilic acid (X) that is connected with different substituents (10mmol) is dissolved in dehydrated alcohol (15mL), passes into dry HCl gas, stirred overnight at room temperature, reheats backflow 6h.Add sodium carbonate to regulate pH=8-9, with dichloromethane extraction (15mL v3), merge organic phase, by saturated NaCl solution washing (15mL v2), anhydrous Na 2sO 4dry, rotary evaporation eliminates solvent, obtains the ethyl o-aminobenzoate (XIa-k) of replacement, is directly used in next step reaction.
In the mixed solution of intermediate X Ia-k (10mmol) and chloromethyl cyanide (15mL, 0.25mmol), pass into dry HCl gas, in reaction solution, engender muddiness, after be gel, continue to pass into HCl gas to molten clear, stop ventilation, stirring at room 16h.By in reaction solution impouring 50mL water, under ice-water bath is cooling, regulate pH=7 with strong aqua, the solid that filter collection is separated out, dries, and uses acetic acid recrystallization, obtains intermediate X IIa-k.
2-chloromethyl-6-methyl-4 (3H)-quinazolinone (XIIa)
Yield: 93%, white solid, m.p.242-243 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 4.56 (s, 2H, ClCH 2), 7.44 (t, J=7.2Hz, 1H, quin8-H), 7.70 (d, J=7.2Hz, 1H, quin7-H), 7.97 (d, J=7.2Hz, 1H, quin5-H), 12.56 (br s, 1H, NH) .EI-MSm/z:208[M +].
2-chloromethyl-8-methyl-4 (3H)-quinazolinone (XIIb)
Yield: 91%, white solid, m.p.238-240 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 2.54 (s, 3H, CH 3), 4.56 (s, 2H, ClCH 2), 7.43 (t, J=7.8Hz, 1H, quin6-H), 7.70 (d, J=7.8Hz, 1H, quin7-H), 7.97 (d, J=7.8Hz, 1H, quin5-H), 12.56 (s, 1H, NH) .EI-MS m/z:208[M +].
2-chloromethyl-6-hydroxyl-4 (3H)-quinazolinone (XIIc)
Yield: 95%, white solid, m.p.258-260 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 4.51 (s, 2H, ClCH 2), 7.43 (d, J=7.8Hz, 1H, quin7-H), 7.41 (s, 1H, quin5-H), 7.55 (d, J=7.8Hz, 1H, quin8-H), 10.17 (s, 1H, OH), 12.38 (s, 1H, NH) .EI-MS m/z:210[M +].
Fluoro-4 (the 3H)-quinazolinones (XIId) of 2-chloromethyl-6-
Yield: 86%, white solid, m.p.235-237 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 4.53 (s, 2H, ClCH 2), 7.69-7.76 (m, 2H, quin7-H, 8-H), 8.01 (dd, J=8.4,2.4Hz, 1H, quin5-H), 12.70 (s, 1H, NH) .EI-MS m/z:212[M +].
Chloro-4 (the 3H)-quinazolinones (XIIe) of 2-chloromethyl-6-
Yield: 96%, white solid, m.p.231-232 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 4.56 (s, 2H, ClCH 2), 7.72 (d, J=8.4Hz, 1H, quin8-H), 7.87 (d, J=8.4Hz, 1H, quin7-H), 8.01 (s, 1H, quin5-H), 12.78 (s, 1H, NH) .EI-MS m/z:228[M +].
Bromo-4 (the 3H)-quinazolinones (XIIf) of 2-chloromethyl-6-
Yield: 88%, white solid, m.p.254-256 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 4.55 (s, 2H, ClCH 2), 7.64 (d, J=8.4Hz, 1H, quin8-H), 7.99 (dd, J=8.4,2.4Hz, 1H, quin7-H), 8.20 (d, J=2.4Hz, 1H, quin5-H), 12.78 (s, 1H, NH) .EI-MS m/z:272[M +].
Iodo-4 (the 3H)-quinazolinones (XIIg) of 2-chloromethyl-6-
Yield: 86%, white solid, m.p.258-260 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 4.54 (s, 2H, ClCH 2), 7.46 (d, J=8.4Hz, 1H, quin8-H), 8.10 (d, J=8.4Hz, 1H, quin7-H), 8.38 (s, 1H, quin5-H), 12.73 (s, 1H, NH) .EI-MS m/z:320[M +].
2-chloromethyl-6-nitro-4 (3H)-quinazolinone (XIIh)
Yield: 83%, white solid, m.p.262-265 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 4.61 (s, 2H, ClCH 2), 7.88 (d, J=9.0Hz, 1H, quin8-H), 8.56 (d, J=9.0Hz, 1H, quin7-H), 8.80 (s, 1H, quin5-H), 13.09 (s, 1H, NH) .EI-MS m/z:239[M +].
2-chloromethyl-7-nitro-4 (3H)-quinazolinone (XIIi)
Yield: 84%, white solid, m.p.251-252 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 4.59 (s, 2H, ClCH 2), 8.26 (d, J=8.4Hz, 1H, quin5-H), 8.34 (d, J=9.0Hz, 1H, quin6-H), 8.38 (s, 1H, quin8-H), 13.0 (s, 1H, NH) .EI-MS m/z:239[M +].
2-chloromethyl-6, chloro-4 (the 3H)-quinazolinones (XIIj) of 8-bis-
Yield: 75%, white solid, m.p.227-230 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 4.58 (s, 2H, ClCH 2), 8.02 (s, 1H, quin7-H), 8.15 (s, 1H, quin5-H), 13.01 (s, 1H, NH) .EI-MS m/z:239[M +].
2-chloromethyl-6,7-dimethoxy-4 ' (3H)-quinazolinone (XIIk)
Yield: 94%, white solid, m.p.216-218 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 3.88 (s, 3H, OCH 3), 3.91 (s, 3H, OCH 3), 4.52 (s, 2H, ClCH 2), 7.17 (s, 1H, quin8-H), 7.44 (s, 1H, quin5-H), 12.43 (s, 1H, NH) .EI-MS m/z:239[M +].
The synthetic logical method of the compounds of this invention 23-33
4-anisole methylamine (1.0mmol) is dissolved in to N, in dinethylformamide (10mL), add the anhydrous phosphoric acid potassium (0.26g of porphyrize, 1.0mmol), dithiocarbonic anhydride (0.4mL, 6.65mmol), stirring at room 0.5h, add be connected with different substituents 2-chloromethyl-4 (3H) quinazolinones (XIIa-k) (1.0mmol), continue to stir 1-3h.By in reaction solution impouring 100mL water, the solid that filter collection is separated out, dries, with silica gel column chromatography (elutriant: CH 2cl 2/ CH 3oH=95:5) purify, obtain compound 23-33.
Embodiment 23
4-methoxy-benzyl aminodithioformic acid (6-methyl-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 23)
Yield: 46%, white solid, m.p.203-204 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 2.43 (s, 3H, CH 3), 3.74 (s, 3H, OCH 3), 4.40 (s, 2H, SCH 2), 4.77 (d, J=5.4Hz, 2H, NHCH 2), 6.89 (d, J=8.4Hz, 2H, ph3 '-H, 5 '-H), 7.27 (d, J=8.4Hz, 2H, ph2 '-H, 6 '-H), 7.28 (d, J=8.4Hz, 1H, quin8-H), 7.58 (d, J=8.4Hz, 1H, quin7-H), 7.88 (s, 1H, quin5-H), 10.63 (t, J=5.4Hz, 1H, CH 2nH), 12.30 (s, 1H, NH) .ESI-HRMS m/z:C 19h 20n 3o 2s 2([M+H] +) calculated value: 386.0997; Measured value: 386.0988.
Embodiment 24
4-methoxy-benzyl aminodithioformic acid (8-methyl-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 24)
Yield: 52%, white solid, m.p.189-190 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 2.43 (s, 3H, CH 3), 3.72 (s, 3H, OCH 3), 4.46 (s, 2H, SCH 2), 4.78 (d, J=5.4Hz, 2H, NHCH 2), 6.85 (d, J=9.0Hz, 2H, ph3 '-H, 5 '-H), 7.22 (d, J=9.0Hz, 2H, ph2 '-H, 6 '-H), 7.38 (t, J=7.8Hz, 1H, quin6-H), 7.64 (d, J=7.2Hz, 1H, quin7-H), 7.93 (d, J=7.8Hz, 1H, quin5-H), 10.53 (t, J=5.4Hz, 1H, CH 2n-H), 12.36 (s, 1H, NH) .ESI-HRMS m/z:C 19h 20n 3o 2s 2([M+H] +) calculated value: 386.0997; Measured value: 386.0990.
Embodiment 25
4-methoxy-benzyl aminodithioformic acid (6-hydroxyl-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 25)
Yield: 49%, white solid, m.p.175-176 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 3.74 (s, 3H, OCH 3), 4.36 (s, 2H, SCH 2), 4.77 (d, J=5.4Hz, 2H, NHCH 2), 6.89 (d, J=8.4Hz, 2H, ph3 '-H, 5 '-H), 7.19 (dd, J=8.4,1.2Hz, 1H, quin7-H), 7.21 (d, J=8.4Hz, 1H, quin8-H), 7.27 (d, J=8.4Hz, 2H, ph2 '-H, 6 '-H), 7.36 (d, J=1.2Hz, 1H, quin5-H), 10.07 (s, 1H, OH), 10.63 (t, J=5.4Hz, 1H, CH 2nH), 12.19 (s, 1H, NH) .ESI-HRMS m/z:C 18h 18n 3o 3s 2([M+H] +) calculated value: 388.0790; Measured value: 388.0783.
Embodiment 26
4-methoxy-benzyl aminodithioformic acid (6-fluoro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 26)
Yield: 56%, faint yellow solid, m.p.195-196 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 3.74 (s, 3H, OCH 3), 4.44 (s, 2H, SCH 2), 4.76 (d, J=5.4Hz, 2H, NHCH 2), 6.89 (d, J=8.4Hz, 2H, ph3 '-H, 5 '-H), 7.26 (d, J=8.4Hz, 2H, ph2 '-H, 6 '-H), 7.50 (dd, J=9.0,4.8Hz, 1H, quin8-H), 7.65 (td, J=9.0,3.0Hz, 1H, quin7-H), 7.76 (dd, J=8.4,3.0Hz, 1H, quin5-H), 10.58 (t, J=5.4Hz, 1H, CH 2nH), 12.54 (s, 1H, NH) .ESI-HRMS m/z:C 18h 17fN 3o 2s 2([M+H] +) calculated value: 390.0746; Measured value: 390.0734.
Embodiment 27
4-methoxy-benzyl aminodithioformic acid (6-chloro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 27)
Yield: 46%, faint yellow solid, m.p.174-175 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 3.74 (s, 3H, OCH 3), 4.44 (s, 2H, SCH 2), 4.76 (d, J=5.4Hz, 2H, NHCH 2), 6.89 (d, J=8.4Hz, 2H, ph3 '-H, 5 '-H), 7.25 (d, J=8.4Hz, 2H, ph2 '-H, 6 '-H), 7.46 (d, J=8.4Hz, 1H, quin8-H), 7.80 (d, J=8.4Hz, 1H, quin7-H), 8.02 (s, 1H, quin5-H), 10.57 (t, J=5.4Hz, 1H, CH 2nH), 12.60 (s, 1H, NH) .ESI-HRMS m/z:C 18h 17clN 3o 2s 2([M+H] +) calculated value: 406.0451,408.0421; Measured value: 406.0438,408.0405.
Embodiment 28
4-methoxy-benzyl aminodithioformic acid (6-bromo-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 28)
Yield: 47%, faint yellow solid, m.p.217-218 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 3.73 (s, 3H, OCH 3), 4.44 (s, 2H, SCH 2), 4.76 (d, J=4.2Hz, 2H, NHCH 2), 6.88 (d, J=7.8Hz, 2H, ph3 '-H, 5 '-H), 7.25 (d, J=7.8Hz, 2H, ph2 '-H, 6 '-H), 7.38 (d, J=8.4Hz, 1H, quin8-H), 7.90 (d, J=8.4Hz, 1H, quin7-H), 8.15 (s, 1H, quin5-H), 10.57 (t, J=4.2Hz, 1H, CH 2nH), 12.59 (s, 1H, NH) .ESI-HRMS m/z:C 18h 17brN 3o 2s 2([M+H] +) calculated value: 449.9946,451.9925; Measured value: 449.9933,451.9909.
Embodiment 29
4-methoxy-benzyl aminodithioformic acid (6-iodo-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 29)
Yield: 59%, faint yellow solid, m.p.206-207 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 3.74 (s, 3H, OCH 3), 4.42 (s, 2H, SCH 2), 4.76 (d, J=4.2Hz, 2H, NHCH 2), 6.88 (d, J=8.4Hz, 2H, ph3 '-H, 5 '-H), 7.21 (d, J=8.4Hz, 1H, quin8-H), 7.25 (d, J=8.4Hz, 2H, ph2 '-H, 6 '-H), 8.04 (d, J=8.4Hz, 1H, quin7-H), 8.34 (s, 1H, quin5-H), 10.57 (t, J=4.2Hz, 1H, CH 2nH), 12.56 (s, 1H, NH) .ESI-HRMS m/z:C 18h 17iN 3o 2s 2([M+H] +) calculated value: 497.9807; Measured value: 497.9794.
Embodiment 30
4-methoxy-benzyl aminodithioformic acid (6-nitro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 30)
Yield: 42%, faint yellow solid, m.p.167-168 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 3.73 (s, 3H, OCH 3), 4.52 (s, 2H, SCH 2), 4.76 (d, J=4.8Hz, 2H, NHCH 2), 6.89 (d, J=8.4Hz, 2H, ph3 '-H, 5 '-H), 7.25 (d, J=8.4Hz, 2H, ph2 '-H, 6 '-H), 7.66 (d, J=9.0Hz, 1H, quin8-H), 8.50 (dd, J=9.0,2.4Hz, 1H, quin7-H), 8.78 (d, J=2.4Hz, 1H, quin5-H), 10.57 (t, J=4.8Hz, 1H, CH 2nH), 12.92 (s, 1H, NH) .ESI-HRMS m/z:C 18h 17n 4o 4s 2([M+H] +) calculated value: 417.0691; Measured value: 417.0679.
Embodiment 31
4-methoxy-benzyl aminodithioformic acid (7-nitro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 31)
Yield: 56%, faint yellow solid, m.p.142-143 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 3.72 (s, 3H, OCH 3), 4.48 (s, 2H, SCH 2), 4.77 (d, J=5.4Hz, 2H, NHCH 2), 6.87 (d, J=8.4Hz, 2H, ph3 '-H, 5 '-H), 7.25 (d, J=8.4Hz, 2H, ph2 '-H, 6 '-H), 8.11 (d, J=2.4Hz, 1H, quin8-H), 8.21 (dd, J=8.4,2.4Hz, 1H, quin6-H), 8.30 (d, J=8.4Hz, 1H, quin5-H), 10.54 (t, J=5.4Hz, 1H, CH 2nH), 12.83 (s, 1H, NH) .ESI-HRMS m/z:C 18h 17n 4o 4s 2([M+H] +) calculated value: 417.0691; Measured value: 417.0679.
Embodiment 32
4-methoxy-benzyl aminodithioformic acid (6,8-bis-chloro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 32)
Yield: 69%, faint yellow solid, m.p.206-207 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 3.73 (s, 3H, OCH 3), 4.48 (s, 2H, SCH 2), 4.78 (s, 2H, NCH 2), 6.87 (br s, 2H, ph3 '-H, 5 '-H), 7.23 (br s, ph2 '-H, 6 '-H), 7.99 (s, 1H, quin7-H), 8.10 (s, 1H, quin5-H), 10.61 (s, 1H, CH 2nH), 12.83 (s, 1H, NH) .ESI-HRMSm/z:C 18h 16cl 2n 3o 2s 2([M+H] +) calculated value: 440.0061,442.0031; Measured value: 440.0051,442.0018.
Embodiment 33
4-methoxy-benzyl aminodithioformic acid (6,7-dimethoxy-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters (compound 33)
Yield: 58%, faint yellow solid, m.p.193-195 ℃. 1h NMR (600MHz, DMSO-d 6) δ: 3.72 (s, 3H, OCH 3), 3.84 (s, 3H, OCH 3), 3.86 (s, 3H, OCH 3), 4.40 (s, 2H, SCH 2), 4.77 (d, J=4.8Hz, 2H, NHCH 2), 6.88 (s, 1H, quin8-H), 6.89 (d, J=8.4Hz, 2H, ph3 '-H, 5 '-H), 7.28 (d, J=8.4Hz, 2H, ph2 '-H, 6 '-H), 7.41 (s, 1H, quin5-H), 10.63 (t, J=4.8Hz, 1H, CH 2nH), 12.24 (s, 1H, NH) .ESI-HRMS m/z:C 20h 22n 3o 4s 2([M+H] +) calculated value: 432.1052; Measured value: 432.1041.
Test example
Antiproliferative activity
Adopt following mtt assay to measure the 503nhibiting concentration (IC of formula I compound to people's lung cancer A549, mammary cancer MCF-7, cervical cancer HeLa, colorectal carcinoma HT-29 and HCT-116 cell proliferation 50), use 5 FU 5 fluorouracil (5-FU) as positive control.
Select the adherent tumour cell of exponential phase of growth, after tryptic digestion, use containing the RPMI1640 nutrient solution of 10% calf serum and be made into 5 × 10 4～10 × 10 4the cell suspension of individual cell/mL, is seeded in the set experimental port of 96 well culture plates, and every hole adds 90PL, and this bottom outlet (adding 90PL nutrient solution) is set simultaneously.In 37 ℃, 5%CO 2under environment, cultivate 24h.During preparation sample solution, each compound is formulated as to the solution of different concns with nutrient solution, control group is the nutrient solution containing 2%DMSO.In sample well, add 10PL sample solution, add 10PL to contain the nutrient solution of 2%DMSO in control wells, add 10PL nutrient solution in this bottom outlet, every hole arranges 3 multiple holes, in 37 ℃, and 5%CO 2lower cultivation 72h.In each hole, add the 20PL MTT solution (CellTiter of Promega company
Figure BDA0000461850580000261
aQ ueoussingle solution cell proliferation detecting kit), 37 ℃ are continued to cultivate 2h.Measure optical density(OD) (OD) value of each hole at wavelength 492nm place with enzyme-linked immunosorbent assay instrument.Be calculated as follows cell proliferation inhibition rate (Inhibition Rate, IR%), then with SPSS mathematical statistics software, obtain half-inhibition concentration (IC 50value), the results are shown in Table 1 and table 2.In kind obtain the IC of 5 FU 5 fluorouracil 50value, numerical value is listed in table 1 and table 2.
IR%=[1-(OD sample sets-OD background group)/(OD control group-OD background group)] × 100%
Table 1. compound 1-22(formula II compound) antiproliferative activity to A549, MCF-7, HeLa, HT-29 and HCT-116 cell
Figure BDA0000461850580000271
Table 2. compound 23-33(formula III compound) antiproliferative activity to A549, MCF-7, HeLa, HT-29 and HCT-116 cell
Figure BDA0000461850580000272
Figure BDA0000461850580000281
In addition, tubulin assembly assay (Tublin polymerization assay, Cat.#BK006P, Versinon1.2,1/7/2011, www.cytoskeleton.com) result shows, for example compound 4 of the compounds of this invention can obviously promote tubulin polymerization under 15 μ M concentration, therefore, compound of the present invention not only has antiproliferative activity to A549, MCF-7, HeLa, HT-29 and HCT-116 cell, and, the tumor cell line of resistance is also had to antiproliferative activity.
In sum; these are only preferred embodiment of the present invention, be not intended to limit protection scope of the present invention, therefore; all any modifications of doing within the spirit and principles in the present invention, be equal to replacement, improvement etc., within protection scope of the present invention all should be included in.

Claims (10)

1. the C2 bit derivant of 4 (3H)-quinazolinones shown in a general formula (I):
Wherein:
R 2, R 3, R 4and R 5be selected from independently of one another hydrogen, C1-C4 alkyl, C1-C4 alkoxyl group, halogen, nitro or hydroxyl;
R 1for the C1-C4 alkyl of C1-C4 alkyl or replacement.
2. derivative according to claim 1, wherein, R in formula (I) 2, R 3, R 4and R 5be selected from independently of one another hydrogen, methyl, methoxyl group, fluorine, chlorine, bromine, iodine, nitro or hydroxyl.
3. derivative according to claim 1, wherein, R 1for the C1-C4 alkyl replacing, the C1-C4 alkyl of described replacement refers to by the C1-C4 alkyl that heterocycle replaced of the aryl of one or more aryl or replacement or heterocycle or replacement.
4. derivative according to claim 3, wherein, R 1for the methyl replacing, described aryl is the phenyl of phenyl or replacement, wherein, the phenyl of described replacement refers to that phenyl ring is by one or more C1-4 alkyl, a halogenated c1-4 alkyl arbitrarily, C1-4 alkoxyl group, C1-4 alkyloyl, hydroxyl, halogen, nitro or cyano group replace, and do not limit in the nuclear substituted position of benzene, optionally the substituting group on phenyl ring is connected with each other, more preferably, the phenyl of described replacement is selected from 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 2-p-methoxy-phenyl, 4-nitrophenyl, 4-cyano-phenyl, 4-bromo phenyl, 4-chlorophenyl, 4-difluorophenyl, 2-difluorophenyl, 2, 4-dichloro-phenyl, 2, 4-phenyl-difluoride base, 2, 4-Dimethoxyphenyl, 3, 4, 5-trimethoxyphenyl, or 3, 4-methylenedioxyphenyl,
Described heterocycle is selected from furans, tetrahydrofuran (THF), pyrans, tetrahydropyrans, thiophene, tetramethylene sulfide, thiazole, imidazoles, pyridine or pyrimidine; The heterocycle of described replacement refers to that heterocycle is replaced by one or more C1-4 alkyl, arbitrarily individual halogenated c1-4 alkyl, C1-4 alkoxyl group, C1-4 alkyloyl, hydroxyl, halogen, nitro or cyano group, and does not limit in assorted nuclear substituted position; Preferably, described heterocycle is selected from thiophene, furans or pyridine, is more preferably thiophene-2-base, furans-2-base, pyridine-2-base, pyridin-3-yl or pyridin-4-yl; The heterocycle of described replacement is preferably 6-trifluoromethyl-pyridine-3 base.
5. derivative according to claim 1, wherein, formula (I) is following formula (II) compound:
Figure FDA0000461850570000021
Wherein, R in formula (II) 1definition as defined in claim 1 formula (I) compound.
6. derivative according to claim 1, wherein, formula (I) is following formula (III) compound:
Figure FDA0000461850570000022
Wherein, R in formula (III) 2, R 3, R 4and R 5definition as defined in claim 1 formula (I) compound.
7. derivative as claimed in claim 1, is selected from following compound:
Benzylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters of diphenyl-methyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters of 4-methyl-benzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters of 4-methoxy-benzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters of 2-methoxy-benzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters of 2,4-dimethoxy-benzyl;
3,4,5-trimethoxy benzylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
3,4-methylene oxygen dioxy benzylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters of 4-bromobenzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters of 4-chlorobenzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters of 2,4-dichloro benzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters of 4-luorobenzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters of 2-luorobenzyl;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters of 2,4-difluorobenzyl;
4-cyano group benzylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
Amino dithio (3, the 4-dihydro-4-oxo quinazoline-2-yl) methyl esters of 4-nitrobenzyl;
(thiophene-2-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
(furans-2-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
(pyridine-2-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
(pyridin-3-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
(6-(trifluoromethyl) pyridine-2-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
(pyridin-4-yl) methylamino dithio (3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
4-methoxy-benzyl aminodithioformic acid (6-methyl-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
4-methoxy-benzyl aminodithioformic acid (8-methyl-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
4-methoxy-benzyl aminodithioformic acid (6-hydroxyl-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
4-methoxy-benzyl aminodithioformic acid (6-fluoro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
4-methoxy-benzyl aminodithioformic acid (6-chloro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
4-methoxy-benzyl aminodithioformic acid (6-bromo-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
4-methoxy-benzyl aminodithioformic acid (6-iodo-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
4-methoxy-benzyl aminodithioformic acid (6-nitro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
4-methoxy-benzyl aminodithioformic acid (7-nitro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters;
4-methoxy-benzyl aminodithioformic acid (6,8-bis-chloro-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters; Or
4-methoxy-benzyl aminodithioformic acid (6,7-dimethoxy-3,4-dihydro-4-oxo quinazoline-2-yl) methyl esters.
8. the preparation method of derivative described in arbitrary claim in claim 1 to 7, comprises the steps:
Formula (IV) compound and formula V compound are at CS 2, there is lower reaction in potassiumphosphate, obtains formula (I) compound
Figure FDA0000461850570000041
Substituent X in formula (IV) compound is halogen, is selected from bromine or chlorine;
Substituent R in formula (IV) compound 2, R 3, R 4and R 5definition suc as formula defining in (I) compound;
R in formula V compound 1definition suc as formula defining in (I) compound.
9. one kind comprises in claim 1 to 7 medicinal compositions of derivative described in arbitrary claim.
In claim 1 to 7 described in arbitrary claim derivative in the application of preparing in cancer therapy drug.
CN201410035735.8A 2014-01-24 2014-01-24 C2 bit derivant of 4 (3H)-quinazolinones and its production and use Active CN103755647B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410035735.8A CN103755647B (en) 2014-01-24 2014-01-24 C2 bit derivant of 4 (3H)-quinazolinones and its production and use

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410035735.8A CN103755647B (en) 2014-01-24 2014-01-24 C2 bit derivant of 4 (3H)-quinazolinones and its production and use

Publications (2)

Publication Number Publication Date
CN103755647A true CN103755647A (en) 2014-04-30
CN103755647B CN103755647B (en) 2015-12-09

Family

ID=50523008

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410035735.8A Active CN103755647B (en) 2014-01-24 2014-01-24 C2 bit derivant of 4 (3H)-quinazolinones and its production and use

Country Status (1)

Country Link
CN (1) CN103755647B (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104098587A (en) * 2014-07-16 2014-10-15 首都师范大学 2, 4-diamino-thieno [2, 3-d] pyrimidine derivative as well as preparation method and application thereof
CN104803927A (en) * 2015-03-31 2015-07-29 首都师范大学 Chalcone analogue containing 2-methyl-4-oxo-quinazoline-6-base, and preparation method and application thereof
CN105130982A (en) * 2015-08-24 2015-12-09 华南农业大学 Imidazo heterocyclic amino dithiocarbamate and preparation method therefor
CN108727286A (en) * 2018-07-13 2018-11-02 天津理工大学 A kind of preparation method and application of Quinazol derivative
CN114230557A (en) * 2021-12-31 2022-03-25 深圳大学 Quinazoline-substituted 1,2, 3-triazole derivative, and pharmaceutical composition, preparation method and application thereof
CN115260164A (en) * 2021-05-01 2022-11-01 杭州星鳌生物科技有限公司 Preparation method and structural composition of novel 4 (3H) -quinazolinone analogue and application of analogue in antitumor drugs

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1683344A (en) * 2005-03-09 2005-10-19 首都师范大学 4-quinazolone derivative and its use in anti-tumor medicine
CN102391191A (en) * 2011-09-01 2012-03-28 首都师范大学 Piperazine di-thiocarboxylic acid ester derivative of 2,4-di-aminoquinazoline, as well as preparation method and anti-tumor application of the derivative

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1683344A (en) * 2005-03-09 2005-10-19 首都师范大学 4-quinazolone derivative and its use in anti-tumor medicine
CN102391191A (en) * 2011-09-01 2012-03-28 首都师范大学 Piperazine di-thiocarboxylic acid ester derivative of 2,4-di-aminoquinazoline, as well as preparation method and anti-tumor application of the derivative

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHENG-LI CAO ET AL.: "Synthesis of Substituted Benzylamino- and Heterocyclylmethylamino Carbodithioate Derivatives of 4-(3H)-Quinazolinone and their Cytotoxic Activity", 《ARCH. PHARM. CHEM. LIFE SCI.》 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104098587A (en) * 2014-07-16 2014-10-15 首都师范大学 2, 4-diamino-thieno [2, 3-d] pyrimidine derivative as well as preparation method and application thereof
CN104803927A (en) * 2015-03-31 2015-07-29 首都师范大学 Chalcone analogue containing 2-methyl-4-oxo-quinazoline-6-base, and preparation method and application thereof
CN104803927B (en) * 2015-03-31 2017-11-07 首都师范大学 Chalcone analog of the base containing 2 methyl, 4 oxoquinazolin 6 and its production and use
CN105130982A (en) * 2015-08-24 2015-12-09 华南农业大学 Imidazo heterocyclic amino dithiocarbamate and preparation method therefor
CN105130982B (en) * 2015-08-24 2017-04-05 华南农业大学 A kind of imidazoheterocycles dithiocarbamates and preparation method thereof
CN108727286A (en) * 2018-07-13 2018-11-02 天津理工大学 A kind of preparation method and application of Quinazol derivative
CN115260164A (en) * 2021-05-01 2022-11-01 杭州星鳌生物科技有限公司 Preparation method and structural composition of novel 4 (3H) -quinazolinone analogue and application of analogue in antitumor drugs
CN115260164B (en) * 2021-05-01 2024-03-26 杭州星鳌生物科技有限公司 Preparation method, structural composition and application of novel 4 (3H) -quinazolinone analogue in antitumor drugs
CN114230557A (en) * 2021-12-31 2022-03-25 深圳大学 Quinazoline-substituted 1,2, 3-triazole derivative, and pharmaceutical composition, preparation method and application thereof
CN114230557B (en) * 2021-12-31 2023-01-06 深圳大学 Quinazoline-substituted 1,2,3-triazole derivative, and pharmaceutical composition, preparation method and application thereof

Also Published As

Publication number Publication date
CN103755647B (en) 2015-12-09

Similar Documents

Publication Publication Date Title
CN103755647B (en) C2 bit derivant of 4 (3H)-quinazolinones and its production and use
ES2344007T3 (en) PROTEIN QUINASE INHIBITORS.
CN102391191B (en) Piperazine di-thiocarboxylic acid ester derivative of 2,4-di-aminoquinazoline, as well as preparation method and anti-tumor application of the derivative
AU2015407300B2 (en) 2-Arylamino pyridine, pyridine or triazine derivative, preparation method and use thereof
CN103965120A (en) Quinoline and quinazoline derivative, preparation method, intermediate, composition and application
CA2752885A1 (en) Jak kinase modulating quinazoline derivatives and methods of use thereof
WO1995003283A1 (en) Quinazoline derivatives and their use as anti-cancer agents
CA2604284A1 (en) Protein kinase inhibitors
CA2679489A1 (en) Pyrimidine-2,4-diamine derivatives and their use as jak2 kinase inhibitors
CN103242341A (en) Thieno 2,4-substituted pyrimidine compound, and pharmaceutical composition and application thereof
WO2008055233A1 (en) Protein kinase inhibitors
CN100369919C (en) Tricyclic protein kinase inhibitors
CN103992326B (en) Indole hexahydropyrazine quinazolinone anti-tumor compounds and preparation method thereof
WO2012030918A1 (en) Adenosine a3 receptor modulating compounds and methods of use thereof
CN104803925A (en) 2,4,5-trisubstituted pyrimidine compounds taking FGFRs (fibroblast growth factor receptors) as targets as well as preparation methods and application of 2,4,5-trisubstituted pyrimidine compounds
Gangjee et al. Design, synthesis and biological evaluation of substituted pyrrolo [2, 3-d] pyrimidines as multiple receptor tyrosine kinase inhibitors and antiangiogenic agents
CN104311470A (en) N-substituted indoline-2-keto-3-hydrazine disulfide formate and preparation method and use thereof
CN102942529B (en) 4-(4-substituted piperazine)-5,6,7-trialkoxy quinazoline type compound as well as preparation method and application of 4-(4-substituted piperazine)-5,6,7-trialkoxy quinazoline type compound
CN106831707B (en) Benzheterocycle analog derivative and its medical application as c-Met kinase inhibitor
CA2982862C (en) Preparation and use of kinase inhibitor
CN104803927B (en) Chalcone analog of the base containing 2 methyl, 4 oxoquinazolin 6 and its production and use
CN106349224A (en) JAK kinase inhibitor with 4-amino-(1H)-pyrazole structure and preparation method and application thereof
CN101759654B (en) 4-quinazolinone-6-methylamino dithiocarbamate as well as medical composition and application thereof
CN113880814B (en) Pyrimidine amine compound and application thereof
CN107513040A (en) Substitute the preparation of benzo pyridine compound and the application of molecular targeted anti-tumor medicine

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20210615

Address after: 224500 the third room on the north side of No.56 office building, private venture Park, Tongyu Town, Binhai County, Yancheng City, Jiangsu Province

Patentee after: Binhai Fanggui information technology consulting studio

Address before: Room 1424, 4 / F, Mudan Chuangye building, 2 Huayuan Road, Haidian District, Beijing

Patentee before: Beijing Zhonglian Technology Service Co.,Ltd.

Effective date of registration: 20210615

Address after: Room 1424, 4 / F, Mudan Chuangye building, 2 Huayuan Road, Haidian District, Beijing

Patentee after: Beijing Zhonglian Technology Service Co.,Ltd.

Address before: 100048 No. 105 West Third Ring Road North, Beijing, Haidian District

Patentee before: Capital Normal University

TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20210625

Address after: 110027 No.1-3, No.10 Road, Shenyang Economic and Technological Development Zone, Liaoning Province

Patentee after: SHENYANG SUNSHINE PHARMACEUTICAL Co.,Ltd.

Address before: 224500 the third room on the north side of No.56 office building, private venture Park, Tongyu Town, Binhai County, Yancheng City, Jiangsu Province

Patentee before: Binhai Fanggui information technology consulting studio