CN102391191A - Piperazine di-thiocarboxylic acid ester derivative of 2,4-di-aminoquinazoline, as well as preparation method and anti-tumor application of the derivative - Google Patents
Piperazine di-thiocarboxylic acid ester derivative of 2,4-di-aminoquinazoline, as well as preparation method and anti-tumor application of the derivative Download PDFInfo
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- ARGITQZGLVBTTI-UHFFFAOYSA-N CCc(cc1)cc2c1OCO2 Chemical compound CCc(cc1)cc2c1OCO2 ARGITQZGLVBTTI-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a piperazine di-thiocarboxylic acid ester derivative of 2,4-di-aminoquinazoline, as shown in a general formula (I), wherein R refers to C1-6 straight-chain or branched-chain alkyl group or substituted C1-6 straight-chain or branched-chain alkyl group, or C3-6 naphthenic group, or aryl group or substituted aryl group, or heteroaryl group. In addition, the invention discloses a preparation method and a pharmaceutical composite of the compound, namely piperazine di-thiocarboxylic acid ester derivative. The compound shown in the general formula (I) plays a role in restraining cells of human lung cancer (A-549), human breast cancer (MFC-7) , human colon cancer (HT29 and HCT-116) and human cervical cancer (HeLa) and can serve as an anti-tumor medicament.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, more specifically to 2, the piperazine dithio formate verivate of 4-diamino-quinazoline, and medicinal compsns and their application in antitumor drug.
Background technology
Quinazoline is a kind of important nitrogen-containing heterocycle compound parent, and its various verivates all demonstrate good activity [Connolly, D.J. at antitumor, anti-inflammatory, hypertension and aspect such as antibiotic; Cusack, D.; O ' Sullivan, T.P.; Guiry, P.J.Synthesis of quinazolinones and quinazolines.Tetrahedron 2005,61,10153-10202].Wherein, 2, (dihydrofolate reductase, activity DHFR) have been brought into play important effect [Kompis, I.M. to the verivate of 4-diamino-quinazoline in cancer therapy through suppressing Tetrahydrofolate dehydrogenase; Islam, K.; Then, R.L.DNA and RNA synthesis:antifolates.Chem.Rev.2005,105,593-620].For example, (Trimetrexate TMQ) has obvious curative effects [Itoh, F. to nonsmall-cell lung cancer, mammary cancer etc. to non-classical antifol trimetrexate; Yoshioka, Y.; Yukishige, K.et al.Chem.Pharm.Bull., 1995,43,230-235].
On the other hand, more isolated phytoalexins from cress (crucifers), Brassinin for example wherein contains structure [Pedras, the M.S.C. of dithiocarbamates; Okanga, F.I.; Zaharia, I.L.; Khan, A.Q.Phytoalexins from crucifers:synthesis, biosynthesis, and biotransformation.Phytochemistry 2000,53,161-176].Research shows that Brassinin has chemoprophylaxis effect [Metha, R.G. to cancer; Liu, J.; Constantinou, A.; Thomas, C.F.; Hawthorne, M.; You, M.;
C.; Pezutto, J.M.; Moon, R.C.; Moriarty, M.R.Cancer chemopreventive activity of brassinin, a phytoalexin from cabbage.Carcinogenesis 1995,16,399-404]; To mouse leukemia L1210 and melanin tumour b16 cell inhibited [Sabol, M.; Kutschy, P.; Siegfried, L.;
A.;
M.; Hrbkov á, H.; Dzurilla, M.; Maruskova, R.; Starkova, J.; Paulikova, E.Cytotoxic effect of cruciferous phytoalexins against murine L1210 leukemia and B16 melanoma.Biologia 2000,55,701-707]; And to the propagation of human leukemia T-Jurkat cell inhibited [Pil á tov á, M.;
M.; Kutschy, P.;
A.; Mezencev, R.;
Z.;
M.; Monde, K.; Mirossay, L.;
J.Cruciferous phytoalexins:antiproliferative effects in T-Jurkat leukemic cells.Leuk.Res.2005; 29,415-42l].
The amalgamation of dithiocarbamates structure and quinazolinone has demonstrated important use value in antitumor drug research.For example; Cao Shengli is at Chinese patent (patent No. ZL200510053618.5; 4-Quinazol derivative and the application in antitumor drug thereof) disclose the dithiocarbamates structure fragment as the lipotropy side chain; Be incorporated into 6 of 4-quinazolinone, resulting 4-Quinazol derivative has significant inhibitory effect to people's chronic myelogenous leukemia K562 cell in-vitro growth.In addition, Cao Shengli etc. disclose 4-quinazolinone-6-methylamino dithiocarbamate compounds in one Chinese patent application (application number CN201010034364.3, open day is on June 30th, 2010), and this compounds has anti-tumor activity.
Summary of the invention
The invention provides one type novel 2, the piperazine dithio formate verivate of 4-diamino-quinazoline, this compounds has antitumor action.(patent No. ZL 200510053618.5 with Chinese patent; 4-Quinazol derivative and the application in antitumor drug thereof) and one Chinese patent application (application number CN201010034364.3; Open day is on June 30th, 2010) in the 4-quinazolinone is different with the amalgamation of dithiocarbamates structure; The precursor structure of The compounds of this invention is 2, and 4-diamino-quinazoline has tangible difference with above-mentioned patent.
The purpose of this invention is to provide a kind of 2, the piperazine dithio formate verivate of 4-diamino-quinazoline.
It is above-mentioned 2 that another object of the present invention provides, the preparation method of the piperazine dithio formate verivate of 4-diamino-quinazoline.
Another object of the present invention provide comprise above-mentioned 2, the medicinal compsns of the piperazine dithio formate verivate of 4-diamino-quinazoline.
It is above-mentioned 2 that another object of the present invention provides, the purposes of the piperazine dithio formate verivate of 4-diamino-quinazoline in the preparation cancer therapy drug.
Specifically, the invention provides a kind of 2, the piperazine dithio formate verivate of 4-diamino-quinazoline, shown in general formula (I):
Wherein:
R is C
1-6Straight or branched alkyl or substituted C
1-6Straight or branched alkyl or C
3-6Naphthenic base or aryl or substituted aryl or heteroaryl.
The invention provides a kind of above-mentioned general formula (I) compound, wherein, R is C
1-6The straight or branched alkyl preferably is selected from C
1-4The straight or branched alkyl more preferably is selected from methyl, ethyl, n-propyl or sec.-propyl, particularly preferably is methyl.
The invention provides a kind of above-mentioned general formula (I) compound, wherein, R is by phenyl or 3, the substituted C of 4-methylenedioxyphenyl
1-6The straight or branched alkyl preferably is selected from benzene or 3, the substituted C of 4-methylenedioxyphenyl
1-4The straight or branched alkyl particularly preferably is selected from benzyl or 3,4-Methylenedioxybenzyl (being piperonyl).
In the present invention, described piperonyl is shown below:
The invention provides a kind of above-mentioned general formula (I) compound, wherein, R is C
3-6Naphthenic base preferably is selected from cyclopropyl or cyclohexyl.
The invention provides a kind of above-mentioned general formula (I) compound, wherein, R is aryl or substituted aryl, is preferably phenyl or substituted phenyl, and wherein, said substituted phenyl is meant that it is by one or more C
1-4Alkyl or substituted C
1-4Alkyl, C
1-4Alkoxyl group or substituted C
1-4Alkoxyl group, C
1-4Alkyloyl, hydroxyl, halogen (for example fluorine, chlorine, bromine or iodine), nitro or cyanic acid replace, and substituted position is unqualified on phenyl ring; More preferably be selected from phenyl, 4-tolyl, 2-tolyl, 4-methoxyphenyl, 2; 4-xylyl, 4-chlorophenyl, 2-chlorophenyl, 3; 4-dichloro-phenyl, 4-fluoro phenyl, 2-fluoro phenyl, 2,4-phenyl-difluoride base, 4-acetyl phenyl, 4-nitrophenyl, 2-nitrophenyl or 4-trifluoromethyl.
The invention provides a kind of above-mentioned general formula (I) compound, wherein, R is a heteroaryl, is selected from pyridyl or pyrimidyl; Preferably be selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl.
The invention provides a kind of above-mentioned general formula (I) compound, it is selected from following compounds:
4-N-METHYL PIPERAZINE-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 1);
4-cyclohexyl piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 2);
4-benzyl diethylenediamine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 3);
4-piperonyl piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 4);
4-phenylpiperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 5);
4-(4-hydroxy phenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 6);
4-(4-p-methoxy-phenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 7);
4-(4-aminomethyl phenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 8);
4-(2-aminomethyl phenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 9);
4-(2, the 4-3,5-dimethylphenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 10);
4-(4-chloro-phenyl-) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 11);
4-(2-chloro-phenyl-) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 12);
4-(3, the 4-dichlorophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 13);
4-(4-fluorophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 14);
4-(2-fluorophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 15);
4-(2,4 difluorobenzene base) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 16);
4-(4-acetylphenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 17);
4-(4-nitrophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 18);
4-(2-nitrophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 19);
4-(4-trifluoromethyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 20);
4-(pyridine-2-yl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 21);
Or 4-(pyrimidine-2-base) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 22).
On the other hand, the invention provides shown in general formula (I) 2, the preparation method of the piperazine dithio formate verivate of 4-diamino-quinazoline comprises the steps:
Formula (II) compound and-substituted piperazine (III), CS
2Reaction in the presence of potassiumphosphate obtains formula (I) compound:
Substituent X in formula (II) compound is a halogen, is selected from bromine or chlorine;
The definition of substituent R in formula (III) compound such as above-mentioned formula (I) compound can be selected from C
1-6Straight or branched alkyl or substituted C
1-6Straight or branched alkyl or C
3-6Naphthenic base or aryl or substituted aryl or heteroaryl.
Provided by the invention shown in general formula (I) 2, the preparation method of the piperazine dithio formate verivate of 4-diamino-quinazoline, wherein, formula (II) compound (for example, when X is bromine in formula (II) compound) can prepare through following technology:
The synthesis technique of midbody compound (II)
Reagent and reaction conditions: a.NH
2OHHCl/H
2O refluxes 40 minutes; B.Na
2CO
3, DMF, 125-135 ℃, 2.5 hours; C.H
2NC (=NH) NHCN, HCl/H
2O refluxes 1.5h; D. (CH
3)
3CCOCl, Et
3N, 1, the 4-dioxane refluxes 30 minutes; E.NBS, (PhCO)
2O
2, CCl
4, reflux 10 hours; F.HCl/MeOH refluxes 4 hours.
5-methyl isatin (IV) and oxammonium hydrochloride reaction are formed oxime (V) [Bedford, G.R.; Partridge M.W.A convenient preparation of o-aminoaryl cyanides.J.Chem.Soc.1959; 1633-1634.]; Open loop under alkaline condition then obtains 2-amino-5-methyl benzonitrile (VI) [Zeni, N.S.A.Preparation of o-cyanoanilines from isatin oximes.JP Patent2003064039A; March 5,2003.].(VI) with dicyanodiamide (Dicyanodiamide) reaction, obtain 6-methyl-2,4-diamino-quinazoline (VII) [Werbel, L.M.; Elslager, E.F.; Newton; L.S.Antimalarial agents.Part 62.Synthesis and antimalarial activity of a series of2; 4-diamino-6-[(N-alkylanilino) methyl] quinazolines.J.Heterocycl.Chem.1987; 24 (2), 345-349.].(VII) in dioxane, react, change 6-methyl-2 into, 4-two (trimethyl-acetyl) quinazoline (VIII) with trimethyl-acetyl chloride.(NBS) carries out bromo to VIII with N-bromosuccinimide, makes midbody 6-brooethyl-2,4-two (trimethyl-acetyl) quinazoline (IX).(HCl/MeOH refluxes, and 4h.) removes pivaloyl, obtains 6-brooethyl-2,4-diamino-quinazoline, i.e. formula (II) compound under acidic conditions with intermediate compound I X.
The third aspect, the invention provides a kind of comprise above-mentioned 2, the medicinal compsns of the piperazine dithio formate verivate of 4-diamino-quinazoline.This medicinal compsns comprises formula (I) compound and the acceptable accessories of significant quantity on the pharmacology.To those skilled in the art, these auxiliary materials all are known, for example, and saline water, 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 compsns also can comprise further: stablizer, wetting agent, emulsifying agent, sweeting agent, flavouring agent, buffer reagent etc.
Medicinal compsns of the present invention as required, can be mixed with the solid or the liquid form that are used for oral administration, like tablet, pill, oral liquid etc.; The sterile solution, suspension-s or the emulsion form that are used for parenterai administration, sprays etc.
For example, tablet formulation:
The preparation method is: supplementary material is crossed 100 mesh sieves, mix then; Ethanol system softwood with 90% is granulated, and whole grain adds the Magnesium Stearate mixing, and compressing tablet promptly gets.
The injection prescription:
The preparation method:
N.F,USP MANNITOL is added in the 1600mL water for injection stirring and dissolving; Embodiment of the invention compound is added above-mentioned solution, stirring and dissolving; 4% disodium phosphate soln adjust pH is 4.15; Add the injection 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 ℃, the 15min high-temperature heat sterilization.
On the other hand, the invention provides the application of formula (I) compound in the preparation 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 cancer, white blood disease etc.
The experiment proof; 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 is used for anti-tumor composition as antitumor activity component.The reference dose of medication is the 0.1-10mg/kg body weight, and method of use is oral or intravenous injection.
Embodiment
Below come exemplary illustration embodiment of the present invention through embodiment, for those of ordinary skill in the art, under instruction of the present invention, according to prior art, the improvement to 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 that uses among the embodiment is: 5-methyl isatin (IV) is according to existing method [Cao Shengli, Ma Xueqin, 6-brooethyl-3,4-dihydro-2-methyl-4-oxygen quinazoline synthetic, chemical reagent, 2004,26 (1), 27-28.] preparation.The substituted piperazine of 1-(being the formula III compound) is available from lark prestige Science and Technology Ltd..Other raw material is commercially available chemical reagent.
People's lung cancer (A-549) of using among the embodiment, mammary cancer (MCF-7), colorectal carcinoma (HT29, HCT-116) and cervical cancer (HeLa) cell are replied Beijing key lab from Capital Normal University's dna damage.
Prepare example 1
Synthesizing of 5-methyl-3-(N-oximido) indol-2-one (V)
(2.2g, 13.6mmol), (1.1g 15.8mmol) with 15mL water, stirs reflux 40min down to oxammonium hydrochloride in reaction flask, to add 5-methyl isatin (IV).Be cooled to room temperature, suction filtration gets dark brown solid 2.2g, yield 92%, mp 226.8-227.4 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 2.26 (s, 3H, CH
3), 6.76 (d, J=7.8Hz, 1H, indol-2-one 7-H), 7.16 (d, J=7.8Hz, 1H, indol-2-one 6-H), 7.78 (s, 1H, indol-2-one 4-H), 10.56 (s, 1H, OH), 13.23 (s, 1H, NH).
Synthesizing of 2-amino-5-methyl benzonitrile (VI)
Adding 5-methyl-3-(N-oximido) indol-2-one (V) in reaction flask (1.76g, 10mmol), DMF 5mL, Na
2CO
3(0.1g 0.9mmol), stirs heating down, in 125-135 ℃ of reaction 2.5h.Be cooled to room temperature, in reaction solution, add 20mL water, ethyl acetate extraction (20mL * 3) merges organic phase, saturated common salt water washing, anhydrous Na
2SO
4Dried overnight.Filter, rotary evaporation removes and desolvates, column chromatography purification (elutriant: petrol ether/ethyl acetate=4: 1), get faint yellow solid 1.13g, yield 85%, mp 60.5-61.0 ℃.
1H?NMR(600MHz，CDCl
3)δ：2.33(s，3H，CH
3)，4.25(br?s，2H，NH
2)，6.66(d，J＝8.4Hz，1H，3-H)，7.14(d，J＝8.4Hz，1H，4-H)，7.18(s，1H，6-H)。
6-methyl-2,4-diamino-quinazoline (VII) synthetic
Adding 2-amino-5-methyl benzonitrile (VI) in reaction flask (0.7g, 5.3mmol), Dicyanodiamide (0.45g, 5.3mmol), the hydrochloric acid of 5mL 1mol/L, reflux 1.5h.With hydrochloric acid dilution and the heating of 13mL water and 5mL 1mol/L, filtered while hot.Add the aqueous sodium hydroxide solution of 11mL 2mol/L in the filtrating, have yellow solid to separate out, suction filtration, drying.In the flask that yellow solid is housed, add the formic acid of 8mL water and 2mL 88%, stirring becomes white solid until yellow solid, suction filtration.White solid is dissolved in the 25mL water, adds ammoniacal liquor, stir, have yellow mercury oxide to separate out to strong basicity, suction filtration, drying gets yellow solid 0.43g, yield 48%, mp 258.8-259.4 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 2.33 (s, 3H, CH
3), 5.85 (br s, 2H, NH
2), 7.11 (d, 1H, J=8.3Hz, quinazoline 8-H), 7.15 (br s, 2H, NH
2), 7.32 (d, 1H, J=8.4Hz, quinazoline 7-H), 7.76 (s, 1H, quinazoline 5-H) .ESI-MS m/z:175 [M+H]
+
6-methyl-2,4-two (trimethyl-acetyl) quinazoline (VIII) synthetic
In the 50mL three-necked bottle, add 6-methyl-2, (2.1g, 12.1mmol), (5.0mL, 34.6mmol) with 1,4-dioxane 22mL loads onto the reflux condensing tube that has the Calcium Chloride Powder Anhydrous drying tube to triethylamine to 4-diamino-quinazoline (VII), is heated to boiling under stirring.Slowly dropping is dissolved in 5.5mL 1 in reaction mixture, and the trimethyl-acetyl chloride of 4-dioxane (4.2g, 4.3mL, 34.6mmol), and behind the backflow 30min, filtered while hot, and with 1 of heat, 4-dioxane wash solids is colourless up to washings.Behind the filtrating cool to room temperature, leach the solid of separating out, and with 1, the washing of 4-dioxane, merging filtrate and washing lotion, rotary evaporation removes and desolvates.Resistates adds acetone and stirs, and suction filtration is used the washing with acetone solid, gets bullion.Use acetone recrystallization, get white needle-like crystals 2.3g, yield 54%, mp192.7-193.8 ℃.
1H NMR (200MHz, DMSO-d
6) δ: 1.26 (s, 9H, C (CH
3)
3), 1.27 (s, 9H, C (CH
3)
3), 2.45 (s, 3H, CH
3), 7.43 (d, 1H, J=8.3Hz, quinazoline 8-H), 7.56 (s, 1H, NH), 7.66 (d, 1H, J=8.3Hz, quinazoline 7-H), 7.76 (s, 1H, NH), 8.19 (s, 1H, quinazoline 5-H) .ESI-MS m/z:343 [M+H]
+.C
19H
26N
4O
2Calculated value: C, 66.64; H, 7.65; N, 16.36. detected value: C, 66.65; H, 7.66; N, 16.33.
6-brooethyl-2,4-two (trimethyl-acetyl) quinazoline (IX) synthetic
In reaction flask, add 6-methyl-2, and 4-two (trimethyl-acetyl) quinazoline (VIII) (1.6g, 4.7mmol); N-bromosuccinimide (NBS) (0.88g, 4.9mmol), Lucidol 25mg and tetracol phenixin 40mL; Under the incandescent light irradiation, reflux 10h.Rotary evaporation removes and desolvates, and the hexanaphthene recrystallization gets white solid 1.5g, yield 74%, mp 114.5-115.2 ℃.
1H NMR (200MHz, CDCl
3) δ: 1.35 (s, 9H, C (CH
3)
3), 1.36 (s, 9H, C (CH
3)
3), 4.62 (s, 2H, CH
2Br), 7.45 (d, 1H, J=8.4Hz, quinazoline 8-H), 7.76 (d, 1H, J=8.4Hz, quinazoline 7-H), 8.46 (s, 1H, quinazoline 5-H), 8.66 (br s, 1H, NH), 9.13 (br s, 1H, NH) .ESI-MS m/z:443,445 [M+Na]
+.C
19H
25BrN
4O
21/2H
2O calculated value: C, 53.03; H, 6.09; N, 13.02. detected value: C, 52.63; H, 6.03; N, 12.75.
2,4-diamino--6-brooethyl quinazoline (II) synthetic
With 6-brooethyl-2, (2g 4.8mmol) is suspended in the 10mL THF 4-two (trimethyl-acetyl) quinazoline (IX), and low-grade fever drips saturated hydrogen chloride methanol solution 10mL.After dissolving fully, solid adds entry (2mL), reflux 4h.Rotary evaporation removes and to desolvate, and resistates washs with small amount of acetone, suction filtration, white solid 1.06g, yield 88%, mp＞300 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 4.41 (s, 2H, CH
2Br), 6.54 (s, 2H, NH
2), 7.26 (d, 1H, J=8.4Hz, quinazoline 8-H), 7.53 (d, 1H, J=8.4Hz, quinazoline 7-H), 7.53 (br s, 2H, NH
2), 8.03 (s, 1H, quinazoline 5-H) .ESI-HRMS m/z:C
9H
10BrN
4([M+H]
+) calculated value: 253.0089, detected value: 253.0087.
Synthesizing of formula (I) compound
In reaction flask, adding the substituted piperazine of 1-successively is formula III compound (1.5mmol), N, and dinethylformamide (7.5mL), (0.45mL, 7.5mmol) (0.32g 1.5mmol), stirs 30min under the room temperature to dithiocarbonic anhydride with the anhydrous phosphoric acid potassium of porphyrize.In reaction mixture, add 2, (0.38g 1.5mmol), continues to stir 4h to 4-diamino--6-brooethyl quinazoline (9) under the room temperature.In reaction mixture impouring 100ml water, the solid that the filter collection is separated out is purified through silica gel column chromatography or recrystallization, gets formula (I) compound.
Embodiment 1
4-N-METHYL PIPERAZINE-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 1)
Productive rate 61%, white solid, mp 237.8-239.0 ℃ (column chromatography is purified, elutriant: methylene chloride=80: 20).
1H NMR (200MHz, DMSO-d
6) δ: 2.22 (s, 3H, NCH
3), 2.42 (br s, 4H, piperazine-H), 3.89 (br s, 2H, piperazine-H), 4.22 (br s, 2H, piperazine-H), 4.57 (s, 2H, CH
2S), 7.38 (d, J=8.4Hz, 1H, quinazoline 8-H), 7.51 (br s, 2H, NH
2), 7.76 (d, J=8.4Hz, 1H, quinazoline 7-H), 8.22 (s, 1H, quinazoline 5-H), 8.56 (br s, 2H, NH
2) .ESI-MS m/z:349 [M+H]
+.ESI-HRMS m/z:C
15H
21N
6S
2([M+H]
+) calculated value: 349.1269, detected value: 349.1251.
Embodiment 2
4-cyclohexyl piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 2)
Productive rate 22%, white solid, mp 273.2-275.0 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (600MHz, DMSO-d
6) δ: 1.10 (m, 5H, CH
2), 1.63 (m, 5H, CH
2), 2.57 (s, 2H, piperazine-H), 3.15 (s, 2H, piperazine-H), 3.86 (br s, 2H, piperazine-H), 4.09 (s, 1H, CH), 4.18 (br s, 2H, piperazine-H), 4.55 (s, 2H, CH
2S), 7.38 (d, J=8.4Hz, 1H, quinazoline 8-H), 7.77 (d, J=8.4Hz, 1H, quinazoline 7-H), 8.26 (s, 1H, quinazoline 5-H) .ESI-MS m/z:417 [M+H]
+.ESI-HRMS m/z:C
20H
29N
6S
2([M+H]
+) calculated value: 417.1895, detected value: 417.1884.
Embodiment 3
4-benzyl diethylenediamine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 3)
Productive rate 28%, white solid, mp 268.6-269.0 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (600MHz, DMSO-d
6) δ: 2.44 (br s, 4H, piperazine-H), 3.51 (s, 2H, CH
2Ph), 3.88 (br s, 2H, piperazine-H), 4.22 (br s, 2H, piperazine-H), 4.55 (s, 2H, CH
2S), 7.25 (t, J=6.6Hz, 1H, Ph 4 '-H), 7.30 (m, 4H; Ph 2 ', 3 ', 5 ' and 6 '-H), 7.38 (d, J=8.4Hz, 1H, quinazoline 8-H); (7.77 d, J=8.4Hz, 1H, quinazoline 7-H), 8.25 (s, 1H, quinazoline 5-H) .ESI-MS m/z:425 [M+H]
+.ESI-HRMSm/z:C
21H
25N
6S
2([M+H]
+) calculated value: 425.1582, detected value: 425.1570.
Embodiment 4
4-piperonyl piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 4)
Productive rate 34%, white solid, mp＞300 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (600MHz, DMSO-d
6) δ: 2.42 (s, 4H, piperazine-H), 3.42 (s, 2H, CH
2), 3.87 (br s, 2H, piperazine-H), 4.24 (br s, 2H, piperazine-H), 4.46 (s, 2H, CH
2S), 5.96 (s, 2H, NH
2), 5.99 (s, 2H, NH
2), 6.75 (d, J=7.8Hz, 1H, Ph-H), 6.84 (d, J=7.8Hz, 1H, Ph-H), 6.87 (s, 1H, Ph-H), 7.12 (d, 1H, J=8.4Hz, quinazoline 8-H), 7.22 (br s, 2H, NH
2), 7.47 (d, J=8.4Hz, 1H, quinazoline 7-H), 7.98 (s, 1H, quinazoline 5-H) .ESI-MS m/z:469 [M+H]
+.C
22H
24N
6O
2S
21.8CH
2Cl
2H
2O calculated value: C, 44.70; H, 4.67; N, 13.14. detected value: C, 44.31; H, 4.37; N, 13.46.
Embodiment 5
4-phenylpiperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 5)
Productive rate 58%, white solid, mp 221.4-223.9 ℃ (column chromatography is purified, elutriant: methylene chloride=80: 20).
1H NMR (200MHz, DMSO-d
6) δ: 3.25 (s, 4H, piperazine-H), 4.05 (br s, 2H, piperazine-H), 4.38 (br s, 2H, piperazine-H), 4.55 (s, 2H, CH
2S), 6.83 (d, J=7.2Hz, 1H, Ph-H), 6.93 (d, J=7.7Hz, 2H, Ph-H), 7.23 (m, 3H, quinazoline 8-H and Ph-H), 7.64 (d, J=8.6Hz, 1H, quinazoline 7-H), 8.10 (s, 1H, quinazoline 5-H) .ESI-MS m/z:411 [M+H]
+.ESI-HRMS m/z:C
20H
23N
6S
2([M+H]
+) calculated value: 411.1426, detected value: 411.1420.
Embodiment 6
4-(4-hydroxy phenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 6)
Productive rate 27%, gray solid, mp 248.5-250.2 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (600MHz, DMSO-d
6) δ: 3.04 (br s, 4H, piperazine-H), 4.0 (br s, 2H, piperazine-H), 4.34 (br s, 2H, piperazine-H), 4.52 (s, 2H, CH
2S), 6.56 (br s, 2H, NH
2), 6.65 (d, J=9.0Hz, 2H, Ph 2 ' and 6 '-H), 6.79 (d, J=9.0Hz, 2H, phenyl ring 3 ' and 5 '-H), 7.21 (d, J=8.4Hz, 1H, quinazoline 8-H), 7.59 (d, J=8.4Hz, 1H, quinazoline 7-H), 7.74 (br s, 2H, NH
2), 8.07 (s, 1H, quinazoline 5-H), 8.91 (br s, 1H, OH) .ESI-MS m/z:427 [M+H]
+.ESI-HRMS m/z:C
20H
23N
6OS
2([M+H]
+) calculated value: 427.1375, detected value: 427.1366.
Embodiment 7
4-(4-p-methoxy-phenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 7)
Productive rate 52%, white solid, mp 238.0-239.3 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (600MHz, DMSO-d
6) δ: 3.10 (br s, 4H, piperazine-H), 3.67 (s, 3H, OCH
3), 4.02 (br s, 2H, piperazine-H), 4.36 (br s, 2H, piperazine-H), 4.53 (s, 2H, CH
2S), 6.67 (br s, 2H, NH
2), 6.82 (d, J=9.0Hz, 2H, phenyl ring 2 ' and 6 '-H), 6.90 (d, J=9.0Hz, 2H, phenyl ring 3 ' and 5 '-H), 7.23 (d, J=8.4Hz, 1H, quinazoline 8-H), 7.61 (d, J=8.4Hz, 1H, quinazoline 7-H), 7.86 (br s, 2H, NH
2), 8.09 (s, 1H, quinazoline 5-H) .ESI-MS m/z:441 [M+H]
+.ESI-HRMS m/z:C
21H
25N
6OS
2([M+H]
+) calculated value: 441.1531, detected value: 441.1522.
Embodiment 8
4-(4-aminomethyl phenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 8)
Productive rate 61%, faint yellow solid, mp 227.6-230.0 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (600MHz, DMSO-d
6) δ: 2.18 (s, 3H, CH
3), 3.18 (s, 4H, piperazine-H), 4.02 (br s, 2H, piperazine-H), 4.35 (br s, 2H, piperazine-H), 4.57 (s, 2H, CH
2S), 6.84 (m, 2H, phenyl ring-H), 7.03 (m, 2H, phenyl ring-H), 7.35 (d, 1H, J=8.4Hz, quinazoline 8-H), 7.75 (d, 1H, J=8.4Hz, quinazoline 7-H), 8.23 (s, 1H, quinazoline 5-H) .ESI-MS m/z:425 [M+H]
+.ESI-HRMS m/z:C
21H
25N
6S
2([M+H]
+) calculated value: 425.1582, detected value: 425.1572.
Embodiment 9
4-(2-aminomethyl phenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 9)
Productive rate 30%, faint yellow solid, mp＞300 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (600MHz, DMSO-d
6) δ: 2.27 (s, 3H, CH
3), 2.91 (br s, 4H, piperazine-H), 4.03 (br s, 2H, piperazine-H), 4.37 (br s, 2H, piperazine-H), 4.57 (s, 2H, CH
2S), 6.97 (t, J=7.2Hz, 1H, phenyl ring 4 '-H), 7.0 (d, J=7.2Hz, 1H; Phenyl ring 6 '-H), 713 (t, J=7.2Hz, 1H, phenyl ring 5 '-H), 7.16 (d, J=7.2Hz, 1H; Phenyl ring 3 '-H), 7.33 (d, J=8.4Hz, 1H, quinazoline 8-H), 7.73 (d, J=8.4Hz, 1H; Quinazoline 7-H), 8.22 (s, 1H, quinazoline 5-H), 8.43 (br s, 2H, NH
2) .ESI-MS m/z:425 [M+H]
+.ESI-HRMS m/z:C
21H
25N
6S
2([M+H]
+) calculated value: 425.1582, detected value: 425.1567.
Embodiment 10
4-(2, the 4-3,5-dimethylphenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 10)
Productive rate 54%, white solid, mp 211.2-212.8 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (600MHz, DMSO-d
6) δ: 2.20 (s, 3H, CH
3), 2.24 (s, 3H, CH
3), 2.87 (br s, 4H, piperazine-H), 4.03 (br s, 2H, piperazine-H), 4.38 (br s, 2H, piperazine-H), 4.53 (s, 2H, CH
2S), 6.42 (br s, 2H, NH
2), 6.91 (d, J=8.4Hz, 1H, phenyl ring 6 '-H), 6.94 (d, J=8.4Hz, 1H, phenyl ring 5 '-H), 6.99 (s, 1H, phenyl ring 3 '-H), 7.21 (d, J=8.4Hz, 1H, quinazoline 8-H), 7.58 (d, J=8.4Hz, 1H, quinazoline 7-H), 762 (br s, 2H, NH
2), 8.06 (s, 1H, quinazoline 5-H) .ESI-MS m/z:439 [M+H]
+.ESI-HRMS m/z:C
22H
27N
6S
2([M+H]
+) calculated value: 439.1739, detected value: 439.1728.
Embodiment 11
4-(4-chloro-phenyl-) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 11)
Productive rate 35%, white solid, mp 206.6-208.0 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (300MHz, DMSO-d
6) δ: 3.43 (br s, 4H, piperazine-H), 4.07 (br s, 2H, piperazine-H), 4.41 (br s, 2H, piperazine-H), 4.56 (s, 2H, CH
2S), 6.98 (d, J=9Hz, 2H, phenyl ring 2 ' and 6 '-H), 7.23 (d; J=8.7Hz, 1H, quinazoline 8-H), 7.29 (d, J=9Hz, 2H; Phenyl ring 3 ' and 5 '-H), 7.60 (dd, J=8.7,1.5Hz, 1H, quinazoline 7-H); (8.09 d, J=1.5Hz, 1H, quinazoline 5-H) .ESI-MS m/z:445,447 [M+H]
+.ESI-HRMS m/z:C
20H
22ClN
6S
2([M+H]
+) calculated value: 445.1036, detected value: 445.1028.
Embodiment 12
4-(2-chloro-phenyl-) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 12)
Productive rate 41%, white solid, mp 245.1-246.1 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (300MHz, DMSO-d
6) δ: 3.09 (br s, 4H, piperazine-H), 4.07 (br s, 2H, piperazine-H), 4.40 (br s, 2H, piperazine-H), 4.59 (s, 2H, CH
2S), 7.10 (td, J=7.8,1.2Hz, 1H, phenyl ring 4 '-H), 7.20 (dd, J=7.8,1.2Hz; 1H, phenyl ring 6 '-H), 7.33 (td, J=7.8,1.2Hz, 1H, phenyl ring 5 '-H), 7.35 (d, J=8.4Hz; 1H, quinazoline 8-H), 7.46 (d, J=7.8,1.2Hz, 1H, phenyl ring 3 '-H), 7.75 (d, J=8.4Hz; 1H, quinazoline 7-H), 8.22 (s, 1H, quinazoline 5-H), 8.39 (br s, 2H, NH
2) .ESI-MS m/z:445,447 [M+H]
+.ESI-HRMS m/z:C
20H
22ClN
6S
2([M+H]
+) calculated value: 445.1036, detected value: 445.1032.
Embodiment 13
4-(3, the 4-dichlorophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 13)
Productive rate 27%, pale solid, mp 233.6-236.4 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (300MHz, DMSO-d
6) δ: 3.18 (br s, 4H, piperazine-H), 4.07 (br s, 2H, piperazine-H), 4.36 (br s, 2H, piperazine-H), 4.56 (s, 2H, CH
2S), 6.80 (br s, 2H, NH
2), 6.93 (dd, J=9.0,3.0Hz, 1H, phenyl ring 6 '-H), 7.15 (d, J=3.0Hz, 1H; Phenyl ring 2 '-H), 7.27 (d, J=8.4Hz, 1H, quinazoline 8-H), 7.44 (d, J=9.0Hz, 1H; Phenyl ring 5 '-H), 7.65 (d, J=8.4Hz, 1H, quinazoline 7-H), 7.97 (br s, 2H, NH
2), 8.13 (s, 1H, quinazoline 5-H) .ESI-MS m/z:479,481 [M+H]
+.ESI-HRMSm/z:C
20H
21Cl
2N
6S
2([M+H]
+) calculated value: 479.0646, detected value: 479.0638.
Embodiment 14
4-(4-fluorophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 14)
Productive rate 87%, white solid, mp 249.0-349.8 ℃ (column chromatography is purified, elutriant: methylene chloride=80: 20).
1H NMR (200MHz, DMSO-d
6) δ: 3.21 (br s, 4H, piperazine-H), 4.06 (br, 2H, piperazine-H), 4.37 (br, 2H, piperazine-H), 4.58 (s, 2H, CH
2S), and 6.94-7.13 (m, 4H, phenyl ring-H), 7.32 (d, J=8.4Hz, 1H, quinazoline 8-H), 7.72 (d, J=8.4Hz, 1H, quinazoline 7-H), 8.16 (s, 1H, quinazoline 5-H) .ESI-MS m/z:429 [M+H]
+.C
20H
21FN
6S
21/2H
2O calculated value: C, 54.90; H, 5.07; N, 19.21. detected value: C, 54.90; H, 5.03; N, 18.95.
Embodiment 15
4-(2-fluorophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 15)
Productive rate 73%, white solid, mp 232.3-234.3 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (600MHz, DMSO-d
6) δ: 3.10 (br s, 4H, piperazine-H), 4.05 (br s, 2H, piperazine-H), 4.39 (br s, 2H, piperazine-H), 4.51 (s, 2H, CH
2S), 6.27 (br s, 2H, NH
2), 6.99-7.18 (m, 5H, phenyl ring-H and quinazoline 8-H), 7.49 (br s, 2H, NH
2), 7.56 (d, J=8.4Hz, quinazoline 7-H), 8.03 (s, 1H, quinazoline 5-H) .ESI-MS m/z:429 [M+H]
+.ESI-HRMS m/z:C
20H
22FN
6S
2([M+H]
+) calculated value: 429.1331, detected value: 429.1325.
Embodiment 16
4-(2,4 difluorobenzene base) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 16)
Productive rate 44%, white solid, mp＞300 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (300MHz, DMSO-d
6) δ: 3.06 (br s, 4H, piperazine-H), 4.05 (br s, 2H, piperazine-H), 4.39 (br s, 2H, piperazine-H), 4.54 (s, 2H, CH
2S), 6.80 (brs, 2H, NH
2), 7.00-7.14 (m, 2H, phenyl ring-H), 7.19-7.28 (m, 2H, phenyl ring-H and quinazoline 8-H), 7.63 (dd, J=8.7,1.8Hz, 1H, quinazoline 7-H), 7.90 (m, 2H, NH
2), 8.12 (d, J=1.8Hz, 1H, quinazoline 5-H) .ESI-MS m/z:447 [M+H]
+.ESI-HRMS m/z:C
20H
21F
2N
6S
2([M+H]
+) calculated value: 447.1237, detected value: 447.1235.
Embodiment 17
4-(4-acetylphenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 17)
Productive rate 33%, yellow solid, mp＞300 ℃ (N, dinethylformamide-acetone recrystallization).
1H NMR (300MHz, DMSO-d
6) δ: 2.46 (s, 3H, COCH
3), 3.56 (br s, 4H, piperazine-H), 4.06 (br s, 2H, piperazine-H), 4.38 (br s, 2H, piperazine-H), 4.52 (s, 2H, CH
2S), 6.01 (br s, 2H, NH
2), 6.93 (d, J=9.0Hz, 2H, phenyl ring 2 ' and 6 '-H), 7.14 (d, J=8.4Hz, 1H, quinazoline 8-H), 7.26 (br s, 2H, NH
2), 7.51 (d, J=8.4Hz, 1H, quinazoline 7-H), 7.83 (d, J=9.0Hz, 2H, phenyl ring 3 ' and 5 '-H), 7.96 (s, 1H, quinazoline 5-H) .ESI-MS m/z:453 [M+H]
+.ESI-HRMS m/z:C
22H
25N
6OS
2([M+H]
+) calculated value: 453.1531, detected value: 453.1533.
Embodiment 18
4-(4-nitrophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 18)
Productive rate 28%, yellow solid, mp＞300 ℃ (N, dinethylformamide-acetone recrystallization).
1H NMR (300MHz, DMSO-d
6) δ: 3.69 (br s, 4H, piperazine-H), 4.08 (br s, 2H, piperazine-H), 4.37 (br s, 2H, piperazine-H), 4.51 (s, 2H, CH
2S), 5.99 (br s, 2H, NH
2), 6.93 (d, J=9.6Hz, 2H, phenyl ring 2 ' and 6 '-H), 7.13 (d, J=8.4Hz, 1H, quinazoline 8-H), 7.24 (br s, 2H, NH
2), 7.50 (dd, J=8.4,1.8Hz, 1H, quinazoline 7-H), 7.99 (d, J=1.8Hz, 1H, quinazoline 5-H), 8.09 (d, 2H, J=9.6Hz, the .ESI-MS m/z:456 [M+H] of phenyl ring 3 ' and 5 '-H)
+.ESI-HRMS m/z:C
20H
22N
7O
2S
2([M+H]
+) calculated value: 456.1276, detected value: 456.1273.
Embodiment 19
4-(2-nitrophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 19)
Productive rate 24%, yellow solid, mp＞300 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (600MHz, DMSO-d
6) δ: 3.15 (br s, 4H, piperazine-H), 4.02 (br s, 2H, piperazine-H), 4.32 (br s, 2H, piperazine-H), 4.57 (s, 2H, CH
2S), 6.65 (brs, 2H, NH
2), 7.15 (t, J=7.8Hz, 1H, phenyl ring 4 '-H), 7.23 (d, J=8.4Hz, 1H, quinazoline 8-H), 7.33 (m, 1H, NH
2), 7.59 (t, J=7.8Hz, 1H, phenyl ring 5 '-H), 7.71 (d, J=8.4Hz; 1H, quinazoline 7-H), 7.84 (d, J=7.8Hz, 1H, phenyl ring 6 '-H), 7.89 (d; 1H, J=7.8Hz, phenyl ring 3 '-H), 8.18 (s, 1H, quinazoline 5-H) .ESI-MS m/z:456 [M+H]
+.ESI-HRMS m/z:C
20H
22N
7O
2S
2([M+H]
+) calculated value: 456.1276, detected value: 456.1272.
Embodiment 20
4-(4-trifluoromethyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 20)
Productive rate 43%, mp 263.0-264.0 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (600MHz, DMSO-d
6) δ: 3.47 (br s, 4H, piperazine-H), 4.04 (br s, 2H, piperazine-H), 4.36 (br s, 2H, piperazine-H), 4.56 (s, 2H, CH
2S), 7.01 (d, J=8.4Hz, 2H, phenyl ring 2 ' and 6 '-H), 7.11 (m, 2H, NH
2), 7.29 (d, J=8.4Hz, 1H, quinazoline 8-H), 7.51 (d, J=8.4Hz, 2H, phenyl ring 3 ' and 5 '-H), 7.68 (d, J=8.4Hz, 1H, quinazoline 7-H), 8.17 (s, 1H, quinazoline 5-H) .ESI-MS m/z:479 [M+H]
+.ESI-HRMSm/z:C
21H
22F
3N
6S
2([M+H]
+) calculated value: 479.1299, detected value: 479.1298.
Embodiment 21
4-(pyridine-2-yl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 21)
Productive rate 62%, white solid, mp 238.3-238.8 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (300MHz, DMSO-d
6) δ: 3.65 (br s, 4H, piperazine-H), 4.01 (br s, 2H, piperazine-H), 4.34 (br s, 2H, piperazine-H), 4.52 (s, 2H, CH
2S), 6.40 (br s, 2H, NH
2), 6.67 (t, J=7.2Hz, 1H, pyridine 5 '-H), 6.81 (d, J=7.2Hz, 1H, pyridine 3 '-H), 7.19 (d, J=8.4Hz, 1H, quinazoline 8-H), 7.58 (m, 4H, quinazoline 7-H, pyridine 4 '-H and NH
2), 8.06 (s, 1H, quinazoline 5-H), 8.12 (dd, J=7.2,1.8Hz, 1H, the .ESI-MS m/z:412 [M+H] of pyridine 6 '-H)
+.ESI-HRMS m/z:C
19H
22N
7S
2([M+H]
+) calculated value: 412.1378, detected value: 412.1375.
Embodiment 22
4-(pyrimidine-2-base) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters (compound 22)
Productive rate 35%, white solid, mp 246.2-247.5 ℃ (column chromatography is purified, elutriant: methylene chloride=90: 10).
1H NMR (300MHz, DMSO-d
6) δ: 3.86 (br s, 4H, piperazine-H), 4.01 (br s, 2H, piperazine-H), 4.33 (br s, 2H, piperazine-H), 4.51 (s, 2H, CH
2S), 6.30 (br s, 2H, NH
2), 6.68 (t, J=4.8Hz, 1H, pyrimidine 5 '-H), 7.17 (d, J=8.7Hz, 1H, quinazoline 8-H), 7.52 (br s, 2H, NH
2), 7.55 (dd, J=8.7,1.8Hz, 1H, quinazoline 7-H), 8.04 (d, J=1.8Hz, 1H, quinazoline 5-H), 8.38 (d, J=4.8Hz, 2H, the .ESI-MS m/z:413 [M+H] of pyrimidine 4 ' and 6 '-H)
+.ESI-HRMS m/z:C
18H
21N
8S
2([M+H]
+) calculated value: 413.1331, detected value: 413.1322.
The Test Example The compounds of this invention is to the restraining effect of people's lung cancer (A-549), mammary cancer (MCF-7), colorectal carcinoma (HT29, HCT-116) and cervical cancer (HeLa) cell proliferation
Select the adherent tumour cell of exponential phase of growth for use, behind tryptic digestion, be made into 5 * 10 with the RPMI1640 nutrient solution that contains 10% calf serum
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 90 μ L, and this bottom outlet (promptly adding 90 μ L nutrient solutions) is set simultaneously.In 37 ℃, 5%CO
2Environment is cultivated 24h down.Preparation is during sample solution, and each compound is formulated as the solution of different concns with nutrient solution, and control group is the nutrient solution that contains 2%DMSO.In sample well, add 10 μ L sample solutions, add the nutrient solution that 10 μ L contain 2%DMSO in the control wells, add 10 μ L nutrient solutions in this bottom outlet, every hole is provided with 3 multiple holes, in 37 ℃, and 5%CO
2Under cultivate 72h.In each hole, add the 20 μ L MTT solution (CellTiter of Promega company
AQ
UeousSingle solution cell proliferation detecting kit), 37 ℃ are continued to cultivate 2h.Measure optical density(OD) (OD) value of each hole with enzyme-linked immunosorbent assay instrument at wavelength 492nm place.(Inhibition Rate IR%), obtains half-inhibition concentration (IC with SPSS mathematical statistics software then to calculate cell proliferation inhibition rate by following formula
50Value), the result sees table 1.In kind obtain the IC of 5 FU 5 fluorouracil
50Value, numerical value is listed in the table 1.
IR%=[1-(OD
Sample sets-OD
The background group)/(OD
Control group-OD
The background group)] * 100%
Table 1. compound is to 5 kinds of human carcinoma cell lines' cytotoxic activity (IC
50, μ M)
aIC
50: suppress the required concentration of 50% cell proliferation, be expressed as the mean+/-standard error (means ± S.E.) of at least three experiments.
Claims (10)
1.2, the piperazine dithio formate verivate of 4-diamino-quinazoline, shown in general formula (I):
Wherein:
R is C
1-6Straight or branched alkyl or substituted C
1-6Straight or branched alkyl or C
3-6Naphthenic base or aryl or substituted aryl or heteroaryl.
2. verivate as claimed in claim 1, wherein, R is methyl, ethyl, n-propyl or sec.-propyl.
3. verivate as claimed in claim 1, wherein, R is by phenyl or 3, the substituted C of 4-methylenedioxyphenyl
1-6The straight or branched alkyl preferably is selected from benzene or 3, the substituted C of 4-methylenedioxyphenyl
1-4The straight or branched alkyl.
4. verivate as claimed in claim 1, wherein, R is cyclopropyl or cyclohexyl.
5. verivate as claimed in claim 1, wherein, R is phenyl or substituted phenyl, wherein, said substituted phenyl is meant that it is by one or more C
1-4Alkyl or substituted C
1-4Alkyl, C
1-4Alkoxyl group or substituted C
1-4Alkoxyl group, C
1-4Alkyloyl, hydroxyl, halogen, nitro or cyanic acid replace, and substituted position is unqualified on phenyl ring.
6. verivate as claimed in claim 5; Wherein, R is phenyl, 4-tolyl, 2-tolyl, 4-methoxyphenyl, 2; 4-xylyl, 4-chlorophenyl, 2-chlorophenyl, 3,4-dichloro-phenyl, 4-fluoro phenyl, 2-fluoro phenyl, 2,4-phenyl-difluoride base, 4-acetyl phenyl, 4-nitrophenyl, 2-nitrophenyl or 4-trifluoromethyl.
7. verivate as claimed in claim 1 is selected from following compounds:
4-N-METHYL PIPERAZINE-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-cyclohexyl piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-benzyl diethylenediamine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-piperonyl piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-phenylpiperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(4-hydroxy phenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(4-p-methoxy-phenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(4-aminomethyl phenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(2-aminomethyl phenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(2, the 4-3,5-dimethylphenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(4-chloro-phenyl-) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(2-chloro-phenyl-) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(3, the 4-dichlorophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(4-fluorophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(2-fluorophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(2,4 difluorobenzene base) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(4-acetylphenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(4-nitrophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(2-nitrophenyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(4-trifluoromethyl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
4-(pyridine-2-yl) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters;
Or 4-(pyrimidine-2-base) piperazine-1-dithio formic acid (2,4-diamino-quinazoline-6-yl) methyl esters.
8. the preparation method of the said verivate of arbitrary claim in the claim 1 to 7 comprises the steps:
Formula (II) compound and formula (III) compound, CS
2Reaction obtains formula (I) compound:
Here, the substituent X in formula (II) compound is a halogen;
The definition of substituent R in formula (III) compound such as above-mentioned formula (I) compound.
9. medicinal compsns that comprises the said verivate of arbitrary claim in the claim 1 to 7.
10. the application of the said verivate of arbitrary claim in the preparation cancer therapy drug in the claim 1 to 7.
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| CN103755647A (en) * | 2014-01-24 | 2014-04-30 | 首都师范大学 | C2-bit derivative of 4(3H)-quinazolinone and preparation method and application thereof |
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| CN1328999A (en) * | 2001-05-29 | 2002-01-02 | 北京大学 | Piperazine dithioformates compounds, their preparation method and application in cancer-resisting medicine |
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| CN103755647B (en) * | 2014-01-24 | 2015-12-09 | 首都师范大学 | C2 bit derivant of 4 (3H)-quinazolinones and its production and use |
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| CN107033091A (en) * | 2017-05-16 | 2017-08-11 | 山东理工大学 | A kind of bridged piperazine derivatives and preparation method thereof and purposes |
| CN110272388A (en) * | 2019-07-08 | 2019-09-24 | 桂林医学院 | 4- dithiocarbonic acid piperazine -3- nitro -1,8- naphthalimide derivative and its synthetic method and application |
| CN110317171A (en) * | 2019-07-08 | 2019-10-11 | 桂林医学院 | 4- dithiocarbonic acid piperazine -1,8- naphthalimide derivative and its preparation method and application |
| CN110272388B (en) * | 2019-07-08 | 2022-06-17 | 桂林医学院 | 4-dithioformic acid piperazine-3-nitro-1, 8-naphthalimide derivative and synthesis method and application thereof |
| CN110317171B (en) * | 2019-07-08 | 2022-06-17 | 桂林医学院 | 4-dithioformic acid piperazine-1, 8-naphthalimide derivative and preparation method and application thereof |
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