CN102731415A - Quinazoline-4-piperazine dithioformate and preparation method and purpose thereof - Google Patents
Quinazoline-4-piperazine dithioformate and preparation method and purpose thereof Download PDFInfo
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Abstract
The invention discloses a compound of quinazoline-4-piperazine dithioformate with a general formula shown as formula (1), wherein Y and Z are defined in the specification. Moreover, the invention further discloses a preparation method of the compound above and medicinal compositions of the compound. The compound shown in the general formula (1) has an inhibiting effect on cell proliferation of human lung cancer (A-549), human breast cancer (MFC-7) and human colon cancer (HCT-116) and can be used as a antitumor medicine.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, more particularly, relate to a kind of new quinazoline-4-piperazine dithio formate and preparation method thereof and antiproliferative purposes.
Background technology
(protein kinases PK) influences division, growth, survival and the migration of cell to protein kinase.Tumour cell almost completely depends on the signal of protein kinase and continues propagation, and normal cell seldom utilizes these approach.Therefore, suppress tumor cell proliferation, become the molecular targeted therapeutic strategy of the cancer that receives much attention at present through the kinase whose activity of arrestin.Wherein, quinazoline-4-arylamine class SU11752 successfully is used for treatment for cancer.[1.Fry, D.W.Mechanism of action of erbB tyrosine kinase inhibitors.Exp.Cell.Res., 2003; 284,131-139.2.Morphy, R.Selectively nonselective kinase inhibition:striking the right balance.J.Med.Chem.2010; 53; 1413-1437.] for example, selectivity EGF-R ELISA (epidermal growth factor receptor, EGFR) suppressor factor ZD1939 (Gefitinib; ZD1839) and erlotinib (Erlotinib) respectively at 2003 and 2004; (non-small cell lung cancer, treatment NSCLC) are carried out clinical trial to the tumour of other types at present for local late period or transitivity nonsmall-cell lung cancer by FDA approval.[1.Bauman，J.；Verschraegen，C.；Belinsky，S.；Muller，C.；Rutledge，T.；Fekrazad，M.；Ravindranathan，M.；Lee，S-J.；Jones，D.A?phase?I?study?of?5-azacytidine?and?erlotinib?in?advanced?solid?tumor?malignancies.Cancer?Chemother.Pharmacol.2012，69，547-554.2.Shek，D.；Longmate，J.；Quinn，D.I.；Margolin，K.A.；Twardowski，P.；Gandara，D.R.；Frankel，P.；Pan，C-X.；Lara，P.N.，Jr.A?phase?II?trial?of?gefitinib?and?pegylated?IFNαin?previously?treated?renal?cell?carcinoma.Int.J.Clin.Oncol.2011，16，494-499.]。Nearest research shows that quinazoline-4-bridged piperazine derivatives also has good kinase inhibiting activity.For example, KN1022, CT52923 (Fig.1) [Yu, J.C.; Lokker, N.A.; Hollenbach, S.; Apatira, M.; Li, J.; Betz, A.; Sedlock, D.; Oda, S.; Nomoto, Y.; Matsuno, K.; Ide, S.I.; Tsukuda, E.; Giese; N.A.Efficacy of the novel selective platelet-derived growth factor receptor antagonist CT52923 on cellular proliferation; Migration; And suppression of neointima following vascular injury.J.Pharmacol.Exp.Ther.2001; 298,1172-1178.] be platelet-derived growth factor acceptor (platelet-derived growth factor receptor, the PDGFR) suppressor factor of phosphorylation.Matsuno [Matsuno, K.; Nakajima, T.; Ichimura, M.; Giese, N.A.; Yu, J.C.; Lokker, N.A.; Ushiki, J.; Ide, S.I.; Oda; S.and Nomoto, Y.J.Potent and selective inhibitors of PDGF receptor phosphorylation.2.Synthesis, structure activity relationship; Improvement of aqueous solubility; And biological effects of4-[4-(N-Substituted (thio) carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives.J.Med.Chem.2002,45; 4513-4523.], Pandey [Pandey, A.; Volkots, D.L.; Seroogy, J.M.; Rose, J.W.; Yu, J.C.; Lambing, J.L.; Hutchaleelaha, A.; Hollenbach, S.J.; Abe, K.; Giese; N.A.and Scarborough, R.M.Identification of orally active, potent; And selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family.J.Med.Chem.2002; 45,3772-3793.] etc. the people KN1022 and CT52923 are carried out structural modification, transformation, synthetic a series of analogues; Biological activity result shows that PDGFR is had better inhibited activity.
Research shows that dithiocarbamates compound has tumor prevention and restraining effect, like naturally occurring phytoalexin Brassinin [Sabol, M.; Kutschy, P.; Siegfried, L.; Mirossay, A.; Suchy, M.; Hrbkova, H.; Dzurilla, M.; Maruskova, R.; Starkova, J.; Paulikova, E.Cytotoxic effect of cruciferous phytoalexins against murine L1210 leukemia and B16 melanoma.Biologia, 2000,55,701-707.2.Pilatova, M.; Sarissky, M.; Kutschy, P.; Mirossay, A.; Mezencev, R.; Curillova, Z.; Suchy, M.; Monde, K.; Mirossay, L.; Mojzis, J.Cruciferous phytoalexins:antiproliferative effects in T-Jurkat leukemic cells.Leuk.Res.2005,29,415-421.] and synthetic dithiocarbamates verivate [Hou, X.L.; Ge, Z.M.; Wang, T.M.; Guo, W.; Cui, J.G.; Cheng, T.M.; Lai, C.S.; Li; R.T.Dithiocarbamic acid esters as anticancer agent.Part 1:4-Substituted-piperazine-1-carbodithioic acid 3-cyano-3; 3-diphenyl-propyl esters.Bioorg.Med.Chem.Lett.2006; 16,4214-4219.) [Cao, S.L.; Feng, Y.P.; Jiang, Y.Y.; Liu, S.Y.; Ding, G.Y.; Li, R.T.Synthesis and in vitro antitumor activity of 4 (3H)-quinazolinone derivatives with dithiocarbamate side chains.Bioorg.Med.Chem.Lett.2005,15,1915-1917.].
Summary of the invention
The present invention is on the basis of this study group previous work; Successfully synthesized one type of brand-new quinazoline-4-piperazine dithio formate compound; This compound is inhibited to the propagation of cancer cells such as people's lung cancer, human breast carcinoma and human colon carcinoma, can be used as antitumor drug.
The purpose of this invention is to provide a kind of quinazoline-4-piperazine dithio formate.
Another object of the present invention provides the preparation method of above-mentioned quinazoline-4-piperazine dithio formate.
Another object of the present invention provides the medicinal compsns that comprises above-mentioned quinazoline-4-piperazine dithio formate.
Another object of the present invention has provided the purposes of above-mentioned quinazoline-4-piperazine dithio formate in the preparation cancer therapy drug.
Specifically, the invention provides suc as formula the quinazoline shown in (I)-4-piperazine dithio formate compound:
Wherein, Y is-(CH
2)
n-; Here, n is 1,2,3 or 4, preferably, is 1;
Z is aryl or substituted aryl, heteroaryl or substituted heteroaryl or C3-C7 naphthenic base or substituted C3-C7 naphthenic base.
In embodiments of the invention, the invention provides suc as formula the quinazoline shown in (I)-4-piperazine dithio formate compound, wherein, Z is aryl or substituted aryl, and described aryl is preferably phenyl or naphthyl, more preferably is phenyl; Said substituted aryl is substituted phenyl or substituted naphthyl; Be meant that the optional position is randomly replaced by one or more halogen, cyanic acid, nitro, carboxyl, hydroxyl, C1-C4 alkyl or C1-C4 alkoxyl group on the phenyl or naphthyl, preferably, be 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 3-methoxyphenyl, 4-bromo phenyl, 4-chlorophenyl, 4-fluoro phenyl, 2; 4-phenyl-difluoride base, 3; 4-phenyl-difluoride base, 2,3,4; 5,6-phenyl-pentafluoride base, 4-carboxyl phenyl, 4-cyano-phenyl or 4-nitrophenyl.
In embodiments of the invention; The invention provides suc as formula the quinazoline shown in (I)-4-piperazine dithio formate compound; Wherein, Z is heteroaryl or substituted heteroaryl, and described heteroaryl is furyl, thienyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, tetrazyl, thiazolyl 、 oxazolyl 、 isoxazolyl 、 oxadiazole base, thiadiazolyl group, isothiazolyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, benzothiazolyl, indyl or indazolyl; Said substituted heteroaryl is meant on the optional position of heteroaryl and is randomly replaced by one or more halogen, cyanic acid, nitro, carboxyl, hydroxyl, C1-C4 alkyl or C1-C4 alkoxyl group, preferably, is selected from 2-methylthiazol-4-base.
In embodiments of the invention; The invention provides suc as formula the quinazoline shown in (I)-4-piperazine dithio formate compound, wherein, Z is C3-C7 naphthenic base or substituted C3-C7 naphthenic base; Preferably; Described C3-C7 naphthenic base is Trimetylene base, pentamethylene base or cyclohexyl, more preferably, is cyclohexyl; Said substituted C3-C7 naphthenic base is meant on the optional position of naphthenic base and is replaced by one or more halogen, cyanic acid, nitro, carboxyl, hydroxyl, C1-C4 alkyl or C1-C4 alkoxyl group.
In embodiments of the invention, described halogen or halo are meant fluorine, chlorine, bromine or iodine.Described C1-C4 alkyl is meant methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl.Described C1-C4 alkoxyl group is meant methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy or tert.-butoxy.
In embodiment provided by the invention, particularly preferably, the invention provides following compounds:
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid benzyl ester (compound 1);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-methyl-benzyl ester (compound 2);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-methoxy-benzyl ester (compound 3);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-3-methyl-benzyl ester (compound 4);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-bromobenzyl ester (compound 5);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-chlorine benzyl ester (compound 6);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-luorobenzyl ester (compound 7);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-2,4-difluorobenzyl ester (compound 8);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-3,4-difluorobenzyl ester (compound 9);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-2,3,4,5,6-PFBBR ester (compound 10);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-carboxyl benzyl ester (compound 11);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-cyanic acid benzyl ester (compound 12);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-nitrobenzyl ester (compound 13);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid cyclohexyl methyl ester (compound 14);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio pyridine carboxylic acid-2-ylmethyl ester (compound 15);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio pyridine carboxylic acid-3-ylmethyl ester (compound 16);
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio pyridine carboxylic acid-4-ylmethyl ester (compound 17); Or
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-(2-methylthiazol-4-yl) methyl ester (compound 18).
On the other hand, the invention provides preparation method, comprise the steps: suc as formula the quinazoline shown in (I)-4-piperazine dithio formate compound
Formula (IX) compound, formula (II) compound and dithiocarbonic anhydride reaction obtain formula (I) compound,
Here, definition such as the Chinese style of the present invention (I) of Z and Y are defined in formula (I) compound, formula (II) compound;
X is a chlorine or bromine in formula (II) compound.
In quinazoline provided by the invention-4-piperazine dithio formate compounds process for production thereof, the preparation method of formula (IX) compound can be with reference to following document: [Pandey, A.; Volkots, D.L.; Seroogy, J.M.; Rose, J.W.; Yu, J.C.; Lambing, J.L.; Hutchaleelaha, A.; Hollenbach, S.J.; Abe, K.; Giese; N.A.and Scarborough; R.M.Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family.J.Med.Chem.2002; 45,3772-3793.].
In quinazoline provided by the invention-4-piperazine dithio formate compounds process for production thereof, formula (IX) compound, formula (II) compound and dithiocarbonic anhydride react under alkaline condition, thus the formula of obtaining (I) compound; Here, be meant anhydrous phosphoric acid potassium under the described alkaline condition.
In a kind of preferred manufacturing procedure embodiment, the invention provides the compound method shown in route 1:, obtain 1-(3-chloropropyl) piperidines (formula III compound) with hexahydropyridine and 1-bromo-3-chloropropane reacting by heating in THF.With N, dinethylformamide is a solvent, and in the presence of salt of wormwood, formula III compound and vanillic acid methyl esters generation etherification reaction generate 3-methoxyl group-4-(3-(piperidines-1-yl) propoxy-) oil of Niobe (formula IV compound).Under the ice bath cooling, formula IV compound is nitrated with concentrated nitric acid in Glacial acetic acid min. 99.5, obtains 5-methoxyl group-2-nitro-4-(3-(piperidines-1-yl) propoxy-) oil of Niobe (formula V compound).With formula V compound and the tin protochloride that is dissolved in concentrated hydrochloric acid, stirred overnight at room temperature obtains reduzate 2-amino-5-methoxyl group-4-(3-(piperidines-1-yl) propoxy-) oil of Niobe (formula VI compound).In methanol solution, reacting by heating 9h obtains cyclization product 6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-)-4 (3H)-quinazolinones (formula VII compound) with formula VI compound, triethyl orthoformate and ammonium acetate.Formula VII compound is reflux 15h in the mixed solution of phosphorus pentachloride and POCl3, generates 4-chloro-6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline (formula VIII compound), not purifiedly is used for directly that the step reacts down.In Virahol, back flow reaction 3h obtains 6-methoxyl group-4-(1-piperazine)-7-(3-(piperidines-1-yl) propoxy-) quinazoline (formula IX compound) with piperazine and formula VIII compound.At last, with N, dinethylformamide is a solvent, in the presence of anhydrous phosphoric acid potassium, with formula IX compound and dithiocarbonic anhydride and different halides formula (II) compound room temperature reaction 2h, obtains formula (I) compound, its structure process
1The evaluation of H NMR, ESI-HRMS.
Route 1. reagent and reaction conditions: bromo-3-chloropropane a.1-, salt of wormwood, THF, 45 ℃, 6 hours; B.4-hydroxy 3-methoxybenzene methyl-formiate, salt of wormwood, N, dinethylformamide, 75 ℃, 6 hours; C. concentrated nitric acid, Glacial acetic acid min. 99.5,45 ℃, 6 hours; D. tin protochloride, concentrated hydrochloric acid, normal temperature spends the night; E. triethyl orthoformate, ammonium acetate, methyl alcohol refluxes 9 hours; F. phosphorus pentachloride, POCl3 refluxes 15 hours; G. piperazine, Virahol refluxes 3 hours; H. substituted benzyl bromides/heterocyclic methyl chloro thing hydrochloride, dithiocarbonic anhydride, anhydrous phosphoric acid potassium, N, dinethylformamide, normal temperature, 2 hours.
The third aspect the invention provides a kind of medicinal compsns that comprises above-mentioned suc as formula the quinazoline shown in (I)-4-piperazine dithio formate compound.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 can be selected from, 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.The dosage of medicinal compsns of the present invention is the 0.1mg-1000mg/kg body weight, and the medical practitioner can under instruction of the present invention, formulate appropriate dosage according to the needs of the state of an illness.
Fourth aspect 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 etc.
Through evidence, the invention provides one type of brand-new quinazoline-4-piperazine dithio formate compound, this compound is inhibited to the propagation of cancer cells such as people's lung cancer, human breast carcinoma and human colon carcinoma, can be used as antitumor drug.
Embodiment
Come exemplary illustration embodiment of the present invention by the following examples, for the 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 hydrochloride preparation of compound 15～18 usefulness heterocyclic methyl chloro things, other target compounds are all with substituted bromotoluene preparation.
Raw material sources: piperazine and 1-bromo-3-chloropropane are purchased association's honor chemical industry ltd in Nanjing; The vanillic acid methyl esters is purchased the coupling Science and Technology Ltd. in Beijing; Heterocyclic methyl chloro thing hydrochloride is purchased the blue ltd of green orange in Tianjin; Substituted benzyl bromides is purchased in J&K company or Alfa Aesar company.
Other raw material is commercially available chemical reagent.
People's lung cancer (A-549), mammary cancer (MCF-7) and colorectal carcinoma (HCT-116) cell are replied Beijing key lab from Capital Normal University's dna damage.
Prepare example
The preparation of 1-(3-chloropropyl) piperidines (formula III compound)
(0.43g 5mmol) is dissolved in the THF (15mL), and (0.69g, 5mmol) (0.78g 5mmol), slowly is warming up to about 45 ℃, reaction 6h with 1-bromo-3 chloropropanes to add Anhydrous potassium carbonate under stirring successively with hexahydropyridine.Be cooled to room temperature, suction filtration, filter cake be with washed with dichloromethane (15mL * 2), merging filtrate and washing lotion, and rotary evaporation removes and desolvates, and resistates is with the silica gel column chromatography (elutriant: CH of purifying
2Cl
2/ MeOH=90: 10, v/v), get yellow oily liquid 0.48g, yield 60%.
1HNMR (600MHz, DMSO-d
6) δ: 1.44 (m, 2H, piperidines-H), 1.65 (m, 4H, piperidines-H), 2.44 (m, 2H, CH
2), 3.43 (m, 4H, NCH
2, piperidines-H), 4.15 (m, 4H, CH
2Cl, the .EI-MS m/z:161 [M] of piperidines-H)
+.
The preparation of 3-methoxyl group-4-(3-(piperidines-1-yl) propoxy-) oil of Niobe (formula IV compound)
With 1-(3-chloropropyl) piperidines (III) (0.65g, 4mmol) and vanillic acid methyl esters (0.36g 2mmol) is dissolved in N, in the dinethylformamide (15mL), stirs and to add Anhydrous potassium carbonate down (0.42g 3mmol), is heated to 75 ℃, TLC (silica gel G F
254) monitoring reaction, to raw material point disappearance (6h), finish reaction.Reaction solution is cooled to room temperature, in the slow impouring 30mL frozen water, places in the refrigerator and spend the night under stirring.Remove by filter precipitate, filtrating merges organic phase with ETHYLE ACETATE (25mL * 3) extraction, and with saturated aqueous common salt (20mL * 2) washing, adds anhydrous sodium sulfate drying and spend the night.Suction filtration, rotary evaporation removes and desolvates, and resistates is with silica gel column chromatography purification (elutriant: CH
2Cl
2/ MeOH=90: 10, v/v) get orange red thick liquid 0.32g, yield 52%.
1H NMR (600MHz, CDCl
3) δ: 1.45 (br s, 2H, piperidines-H), 1.62 (m, 4H, piperidines-H), 2.08 (m, 2H, CH
2), 2.44 (br s, 4H, piperidines-H), 2.52 (t, J=6.6Hz, 2H, NCH
2), 3.89 (d, J=1.2Hz, 3H, OCH
3), 3.91 (d, J=1.8Hz, 3H, OCH
3), 4.14 (t, J=6.6Hz, 2H, OCH
2), 6.92 (dd, J=8.4,1.2Hz, 1H, phenyl ring 6-H), 7.54 (s, 1H, phenyl ring 2-H), 7.65 (d, J=8.4Hz, 1H, phenyl ring 5-H) .ESI-MS m/z:308 [M+H]
+.
The preparation of 2-nitro-5-methoxyl group-4-(3-(piperidines-1-yl) propoxy-) oil of Niobe (formula V compound)
Under 0-5 ℃, (0.62g 2mmol) is dissolved in the Glacial acetic acid min. 99.5 (10mL), stirs to drip the dense HNO of 65%-68% down with 3-methoxyl group-4-(3-(1-piperidines) propoxy-) oil of Niobe (IV)
3(0.2mL 2.9mmol), slowly is warming up to 45 ℃, and TLC monitoring reaction process is to raw material point disappearance (6h).Reaction solution is cooled to room temperature, stirs in the following slow impouring 30mL frozen water.With dichloromethane extraction (25mL * 3), merge organic phase, and with saturated common salt water washing (20mL * 2), anhydrous sodium sulfate drying spends the night.Filter, the filtrating rotary evaporation removes and desolvates, and resistates is with silica gel column chromatography purification (elutriant: CH
2Cl
2/ MeOH=98: 2, v/v), get yellow solid 0.52g, yield 72%, m.p.113.8-114.4 ℃.
1HNMR (600MHz, DMSO-d
6) δ: 1.53-1.87 (m, 6H, piperidines-H), 2.16 (m, 2H, CH
2), 2.91-3.47 (m, 6H, NCH
2, piperidines-H), 3.83 (s, 3H, OCH
3), 3.93 (s, 3H, OCH
3), 4.22 (t, J=6.6Hz, 2H, OCH
2), 7.36 (s, 1H, phenyl ring 6-H), 7.67 (s, 1H, phenyl ring 3-H) .EI-MS m/z:352 [M]
+.
The preparation of 2-amino-5-methoxyl group-4-(3-(piperidines-1-yl) propoxy-) oil of Niobe (formula VI compound)
With the SnCl that grinds
22H
2(0.86g 4mmol) is dissolved among the dense HCl (10mL) O, and add 5-methoxyl group-2-nitro-4-(3-(piperidines-1-yl) propoxy-) oil of Niobe (V) under stirring (0.36g, 1mmol), about 0.5h adds, then stirred overnight at room temperature in batches.Reaction mixture adds water (10mL) dilution, and use 2N NaOH to regulate the pH value and be 7-8, the elimination insolubles, filtrating merges organic phase with dichloromethane extraction (20mL * 3), and anhydrous sodium sulfate drying spends the night.Suction filtration, rotary evaporation removes and desolvates, and resistates is with silica gel column chromatography purification (elutriant: CH
2Cl
2/ MeOH=90: 10, v/v), get pale brown look mud shape thing 0.29g, yield 87%.
1H NMR (600MHz, DMSO-d
6) δ: 1.39 (br s, 1H, piperidines-H), 1.71 (br s, 1H, piperidines-H), 1.79 (br s, 4H, piperidines-H), 2.23 (m, 2H, CH
2), 2.89-3.46 (m, 6H, NCH
2, piperidines-H), 3.70 (s, 3H, OCH
3), 3.78 (s, 3H, OCH
3), 4.04 (t, J=6.0Hz, 2H, OCH
2), 4.24 (br s, 2H, NH
2), 6.62 (s, 1H, phenyl ring 3-H), 7.22 (s, 1H, phenyl ring 6-H) .ESI-MS m/z:323 [M+H]
+.
The preparation of 6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-)-4 (3H)-quinazolinones (formula VII compound)
With 2-amino-5-methoxyl group-4-(3-(1-piperidines) propoxy-) oil of Niobe (VI) (0.32g 1mmol) is dissolved in the methyl alcohol (5mL), add successively triethyl orthoformate (0.74g, 5mmol), ammonium acetate (0.23g, 3mmol), reflux, TLC (silica gel G F
254) monitoring reaction, to raw material point disappearance (9h).Be cooled to room temperature, use the methylene dichloride dissolving mixt, be transferred to round-bottomed flask, rotary evaporation is removed most of solvent, and resistates is with silica gel column chromatography purification (elutriant: CH
2Cl
2/ MeOH=90: 10, v/v), get off-white color solid 0.15g, yield 48%, m.p.141-142 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.43 (br s, 2H, piperidines-H), 1.77 (br s, 4H, piperidines-H), 2.25 (br s, 2H, CH
2), 2.87-3.35 (m, 6H, NCH
2, piperidines-H), 3.88 (s, 3H, OCH
3), 4.21 (t, J=6Hz, 2H, OCH
2), 7.16 (s, 1H, quinazoline 8-H), 7.46 (s, 1H, quinazoline 5-H), 7.99 (s, 1H, quinazoline 2-H), 12.16 (s, 1H, NH) .ESI-MS m/z:318 [M+H]
+.
The preparation of 4-chloro-6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline (formula VIII compound)
Phosphorus pentachloride (0.30g, 1.44mmol) and in the mixture of POCl3 (2mL), add 6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4 (3H)-ketone (VII) (0.32g, 1mmol), the about 15h of reflux.Rotary evaporation is removed most of POCl3, and resistates adds anhydrous methylene chloride, and rotary evaporation is to eliminate POCl3.Resistates is dissolved in methylene dichloride, and ice bath uses saturated sodium bicarbonate solution adjusting pH value to be 7-8 down, leaves standstill, and tells organic phase.Water merges organic phase with dichloromethane extraction (5mL * 3), adds anhydrous sodium sulfate drying and spends the night.Suction filtration, rotary evaporation removes and desolvates, and resistates directly is used for step reaction down.
The preparation of 6-methoxyl group-4-(piperazine-1-yl)-7-(3-(piperidines-1-yl) propoxy-) quinazoline (formula IX compound)
Piperazine (0.34g, 4mmol) and in the mixed solution of Virahol (10mL), add in batches 4-chloro-6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline (VIII) (0.34g, 1mmol), backflow 3h.Be cooled to room temperature, rotary evaporation removes and desolvates, and resistates is soluble in water, and with dichloromethane extraction (10mL * 3), organic phase is spent the night with anhydrous sodium sulfate drying.Suction filtration, rotary evaporation removes and desolvates, and resistates is with silica gel column chromatography purification (elutriant: CH
2Cl
2/ MeOH=90: 10, v/v), get yellow solid 0.29g, two step yields 67%, m.p.112.0-114.0 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.38 (br s, 2H, piperidines-H), 1.50 (br s, 4H, piperidines-H), 1.89 (s, 1H, NH), 1.93 (br s, 2H, CH
2), 2.33 (br s, 4H, piperidines-H), 2.40 (br s, 2H, NCH
2), 2.91 (m, 4H, piperazine-H), 3.54 (br s, 4H, piperazine-H), 3.91 (s, 3H, OCH
3), 4.16 (br s, 2H, OCH
2), 7.12 (s, 1H, quinazoline 5-H), 7.19 (s, 1H, quinazoline 8-H), 8.52 (s, 1H, quinazoline 2-H) .ESI-MS m/z:386.2 [M+H]
+.
The synthetic logical method of formula (I) compound of embodiment 1 to 18
At 6-methoxyl group-4-(piperazine-1-yl)-7-(3-(piperidines-1-yl) propoxy-) quinazoline (formula IX compound) (0.5mmol) and N; In the mixed solution of dinethylformamide (5mL); Add dithiocarbonic anhydride (0.30mL; 5.0mmol) and the anhydrous phosphoric acid potassium of porphyrize (0.21g, 1.0mmol), stirring at room 50min.Add different substituted bromo-derivatives or chloro thing (0.5mmol), room temperature continues to stir 0.5-2h (TLC monitors to the disappearance of raw material point).In reaction solution impouring 40mL frozen water, with dichloromethane extraction (15mL * 3), organic phase is washed with saturated sodium-chloride, anhydrous sodium sulfate drying, and suction filtration, rotary evaporation removes and desolvates, and resistates is carried (elutriant: CH with silica gel column chromatography
2Cl
2/ MeOH=95: 5 or 90: 10, v/v), formula I compound.
Embodiment 1
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid benzyl ester (compound 1)
Adopt synthetic logical method, use the benzyl bromine as raw material, yield: 42%, faint yellow solid, m.p.91.0-93.0 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.49 (br s, 2H, piperidines-H), 1.68 (br s, 4H, piperidines-H), 2.15 (br s, 2H, CH
2), 2.91 (m, 6H, piperidines-H, NCH
2), 3.87 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.15 (br s, 2H, piperazine-H), 4.22 (br s, 2H, OCH
2), 4.45 (br s, 2H, piperazine-H), 4.59 (s, 2H, CH
2S), 7.23,7.24 (2s, 2H, quinazoline 5-H, 8-H), 7.28 (t, J=6.6Hz; 1H, phenyl 4-H), 7.33 (t, J=6.6Hz, 2H, phenyl 3-H, 5-H), 7.42 (d; J=6.6Hz, 2H, phenyl 2-H, 6-H), 8.54 (s, 1H, quinazoline 2-H) .ESI-MS m/z:552.2 [M+H]
+.ESI-HRMS m/z:C
29H
38N
5O
2S
2([M+H]
+) calculated value: 552.2467. measured value: 552.2468.
Embodiment 2
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-methyl-benzyl ester (compound 2)
Adopt synthetic logical method, use 4-methyl benzyl bromine as raw material, yield: 63%, faint yellow solid, m.p.62.3-64.0 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.40 (br s, 2H, piperidines-H), 1.53 (br s, 4H, piperidines-H), 1.97 (br s, 2H, CH
2), 2.28 (s, 3H, phenyl-CH
3), 2.42 (br s, 2H, NCH
2), 2.50 (piperidines-H is with the DMSO peak overlapping for br s, 4H), 3.86 (br s, 4H, piperazine-H), 3.92 (s, 3H, OCH
3), 4.13 (br s, 2H, piperazine-H), 4.18 (t, J=6.0Hz, 2H, OCH
2), 4.44 (br s, 2H, piperazine-H), 4.53 (s, 2H, CH
2S), 7.13 (d, J=7.8Hz, 2H, phenyl-H), 7.22 (s, 2H, quinazoline 5-H, 8-H), 7.29 (d, J=7.8Hz, 2H, phenyl-H), 8.53 (s, 1H, quinazoline 2-H) .ESI-HRMS m/z:C
30H
40N
5O
2S
2([M+H]
+) calculated value: 566.2623. measured value: 566.2599.
Embodiment 3
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-methoxy-benzyl ester (compound 3)
Adopt synthetic logical method, use 4-methoxybenzyl bromine as raw material, yield: 32%, faint yellow solid, m.p.60.9-62.3 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.41 (br s, 2H, piperidines-H), 1.55 (br s, 4H, piperidines-H), 1.99 (br s, 2H, CH
2), 2.44 (br s, 2H, NCH
2), 2.50 (piperidines-H is with the DMSO peak overlapping for br s, 4H), 3.74 (s, 3H, phenyl-OCH
3), 3.86 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.13 (br s, 2H, piperazine-H), 4.18 (t, J=6.0Hz, 2H, OCH
2), 4.44 (br s, 2H, piperazine-H), 4.51 (s, 2H, CH
2S), 6.89 (d, J=8.4Hz, 2H, phenyl 3-H, 5-H), 7.22 (s, 2H, quinazoline 5-H, 8-H), 7.34 (d, J=8.4Hz, 2H, phenyl 2-H, 6-H), 8.53 (s, 1H, quinazoline 2-H) .ESI-HRMS m/z:C
30H
40N
5O
3S
2([M+H]
+) calculated value: 582.2573. measured value: 582.2555.
Embodiment 4
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-3-methyl-benzyl ester (compound 4)
Adopt synthetic logical method, use 3-methoxybenzyl bromine as raw material, yield: 52%, faint yellow solid, m.p.53.0-54.9 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.40 (br s, 2H, piperidines-H), 1.54 (m, 4H, piperidines-H), 1.98 (m, 2H, CH
2), 2.47 (br s, 4H, piperidines-H), 2.52 (br s, 2H, NCH
2), 3.74 (s, 3H, phenyl-OCH
3), 3.86 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.14 (br s, 2H, piperazine-H), 4.17 (t, J=6.0Hz, 2H, OCH
2), 4.45 (br s, 2H, piperazine-H), 4.55 (s, 2H, CH
2S), 6.85 (dd, J=7.8,1.8Hz, 1H, phenyl 4-H), 6.99 (d, J=7.8Hz; 1H, phenyl 6-H), 7.00 (s, 1H, phenyl 2-H), 7.22 (s, 2H, quinazoline 5-H; 8-H), 7.24 (t, J=7.8Hz, 1H, phenyl 5-H), 8.54 (s, 1H, quinazoline 2-H) .ESI-HRMS m/z:C
30H
40N
5O
3S
2([M+H]
+) calculated value: 582.2573. measured value: 582.2555.
Embodiment 5
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-bromobenzyl ester (compound 5)
Adopt synthetic logical method, use 4-bromobenzyl bromine as raw material, yield: 26%, faint yellow solid, m.p.77.3-78.5 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.43 (br s, 2H, piperidines-H), 1.59 (br s, 4H, piperidines-H), 2.04 (br s, 2H, CH
2), 2.63 (m, 6H, piperidines-H, NCH
2), 3.87 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.15 (br s, 2H, piperazine-H), 4.19 (t, J=6.0Hz, 2H, OCH
2), 4.44 (br s, 2H, piperazine-H), 4.59 (s, 2H, CH
2S), 7.23 (s, 2H, quinazoline 5-H, 8-H), 7.38 (d, J=7.8Hz, 2H, phenyl 2-H, 6-H), 7.52 (d, J=7.8Hz, 2H, phenyl 3-H, 5-H), 8.54 (s, 1H, quinazoline 2-H) .ESI-HRMS m/z:C
29H
37BrN
5O
2S
2([M+H]
+) calculated value: 630.1572. measured value: 632.1555.
Embodiment 6
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-chlorine benzyl ester (compound 6)
Adopt synthetic logical method, use the 4-bromine chloride as raw material, yield: 30%, yellow solid, m.p.68.1-70.0 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.44 (br s, 2H, piperidines-H), 1.60 (br s, 4H, piperidines-H), 2.06 (br s, 2H, CH
2), 2.66 (br s, 6H, piperidines-H, NCH
2), 3.87 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.15 (br s, 2H, piperazine-H), 4.20 (t, J=6.0Hz, 2H, OCH
2), 4.44 (br s, 2H, piperazine-H), 4.61 (s, 2H, CH
2S), 7.23 (s, 2H, quinazoline 5-H, 8-H), 7.39 (d, J=7.8Hz, 2H, phenyl 2-H, 6-H), 7.45 (d, J=7.8Hz, 2H, phenyl 3-H, 5-H), 8.54 (s, 1H, quinazoline 2-H) .ESI-HRMS m/z:C
29H
37ClN
5O
2S
2([M+H]
+) calculated value: 586.2077. measured value: 586.2090.
Embodiment 7
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-luorobenzyl ester (compound 7)
Adopt synthetic logical method, use the 4-fluorobenzyl bromide as raw material, yield: 52%, faint yellow solid, m.p.80.0-82.2 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.43 (br s, 2H, piperidines-H), 1.54 (br s, 4H, piperidines-H), 2.04 (br s, 2H, CH
2), 2.50 (piperidines-H is with the DMSO peak overlapping for br s, 4H), 2.61 (br s, 2H, NH
2), 3.87 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.14 (br s, 2H, piperazine-H), 4.18 (t, J=6.0Hz, 2H, OCH
2), 4.44 (br s, 2H, piperazine-H), 4.58 (s, 2H, CH
2S), 7.16 (t, J=8.4Hz, 2H, phenyl 3-H, 5-H), 7.22 (s, 2H, quinazoline 5-H, 8-H), 7.46 (dd, J=8.4,6.0Hz, 2H, phenyl 2-H, 6-H), 8.53 (s, 1H, quinazoline 2-H) .ESI-HRMS m/z:C
29H
37FN
5O
2S
2([M+H]
+) calculated value: 570.2373. measured value: 570.2375.
Embodiment 8
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-2,4-difluorobenzyl ester (compound 8)
Adopt synthetic logical method, application 2,4-two fluorobenzyl bromides be as raw material, yield: 32%, and faint yellow solid, m.p.67.3-69.0 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.44 (br s, 2H, piperidines-H), 1.60 (br s, 4H, piperidines-H), 2.05 (br s, 2H, CH
2), 2.62 (m, 6H, piperidines-H, NCH
2), 3.87 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.13 (br s, 2H, piperazine-H), 4.19 (t, J=6.0Hz, 2H, OCH
2), 4.43 (br s, 2H, piperazine-H), 4.58 (s, 2H, CH
2S), 7.08 (t, J=8.4Hz, 1H, phenyl 3-H), 7.23 (s, 2H, quinazoline 5-H, 8-H), 7.27 (t, J=8.4Hz, 1H, phenyl 5-H), 7.60 (m, J=8.4Hz, 1H, phenyl 6-H), 8.53 (s, 1H, quinazoline 2-H) .ESI-HRMS m/z:C
29H
36F
2N
5O
2S
2([M+H]
+) calculated value: 588.2278. measured value: 588.2288.
Embodiment 9
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-3,4-difluorobenzyl ester (compound 9)
Adopt synthetic logical method, use 3,4-two fluorobenzyl bromides are as raw material, yield: 28%, and faint yellow solid, m.p.73.0-74.0 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.50 (br s, 2H, piperidines-H), 1.67 (br s, 4H, piperidines-H), 2.14 (br s, 2H, CH
2), 2.50 (br s, 2H, NCH
2, with the DMSO peak overlapping), 2.93 (br s, 4H, piperidines-H), 3.88 (br s, 4H, piperazine-H), 3.94 (s, 3H, OCH
3), 4.15 (br s, 2H, piperazine-H), 4.22 (t, J=6.0Hz, 2H, OCH
2), 4.44 (br s, 2H, piperazine-H), 4.61 (s, 2H, CH
2S), 7.24 (s, 1H, quinazoline 5-H), 7.25 (s, 1H, quinazoline 8-H), 7.29 (m, 1H, phenyl 2-H), 7.39 (m, J=8.4Hz, 1H, phenyl 6-H), 7.51 (t, J=9.0Hz, 1H, phenyl 5-H), 8.54 (s, 1H, quinazoline 2-H) .ESI-HRMSm/z:C
29H
36F
2N
5O
2S
2([M+H]
+) calculated value: 588.2278. measured value: 588.2290.
Embodiment 10
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-2,3,4,5,6-PFBBR ester (compound 10)
Adopt synthetic logical method, application 2,3,4,5,6-five fluorobenzyl bromides are as raw material, yield: 58%, faint yellow solid, m.p.128.0-131.0 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.48 (br s, 2H, piperidines-H), 1.70 (br s, 4H, piperidines-H), 2.15 (br s, 2H, CH
2), 2.84 (br s, 6H, piperidines-H, NCH
2), 3.87 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.11 (br s, 2H, piperazine-H), 4.21 (t, J=6.0Hz, 2H, OCH
2), 4.42 (br s, 2H, piperazine-H), 4.67 (s, 2H, CH
2S), 7.22 (s, 1H, quinazoline 5-H), 7.23 (s, 1H, quinazoline 8-H), 8.53 (s, 1H, quinazoline 2-H) .ESI-HRMS m/z:C
29H
33F
5N
5O
2S
2([M+H]
+) calculated value: 642.1996. measured value: 642.2009.
Embodiment 11
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-carboxyl benzyl ester (compound 11)
Adopt synthetic logical method, use the 4-bromo methyl acid as raw material, yield: 20%, yellow solid, m.p.62.5-64.3 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.40 (br, 2H, piperidines-H), 1.52 (m, 4H, piperidines-H), 1.96 (m, 2H, CH
2), 2.42 (br s, 4H, piperidines-H), 2.47 (t, J=7.8Hz, 2H, NCH
2), 3.87 (br s, 4H, piperazine-H), 3.92 (s, 3H, OCH
3), 4.18 (m, 4H, piperazine-H, OCH
2), 4.44 (br s, 2H, piperazine-H), 4.68 (s, 2H, CH
2S), 7.21 (s, 1H, quinazoline 5-H), 7.22 (s, 1H, quinazoline 8-H), 7.51 (d, J=8.4Hz, 2H, phenyl 2-H, 6-H), 7.88 (d, J=8.4Hz, 2H, phenyl 3-H, 5-H), 8.53 (s, 1H, quinazoline 2-H) .ESI-HRMS m/z:C
30H
38N
5O
4S
2([M+H]
+) calculated value: 596.2365. measured value: 596.2375.
Embodiment 12
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-cyanic acid benzyl ester (compound 12)
Adopt synthetic logical method, use 4-cyanic acid benzyl bromine as raw material, yield: 39%, faint yellow solid, m.p.69.4-71.0 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.42 (br s, 2H, piperidines-H), 1.56 (br s, 4H, piperidines-H), 2.01 (br s, 2H, CH
2), 2.51 (m, 6H, NCH
2, piperidines-H), 3.87 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.18 (m, 4H, piperazine-H, OCH
2), 4.44 (br s, 2H, piperazine-H), 4.72 (s, 2H, CH
2S), 7.22 (s, 2H, quinazoline 5-H, 8-H), 7.62 (d, J=8.4Hz, 2H, phenyl 2-H, 6-H), 7.80 (d, J=8.4Hz, 2H, phenyl 3-H, 5-H), 8.54 (s, 1H, quinazoline 2-H) .ESI-HRMS m/z:C
30H
37N
6O
2S
2([M+H]
+) calculated value: 577.2419. measured value: 577.2421.
Embodiment 13
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-nitrobenzyl ester (compound 13)
Adopt synthetic logical method, use 4-nitrobenzyl bromine as raw material, yield: 31%, yellow solid, m.p.83.5-85.0 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.44 (br s, 2H, piperidines-H), 1.60 (br s, 4H, piperidines-H), 2.06 (br s, 2H, CH
2), 2.50 (br s, 2H, NCH
2, with the DMSO peak overlapping), 2.67 (br s, 4H, piperidines-H), 3.88 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.17 (br s, 2H, piperazine-H), 4.20 (t, J=6.0Hz, 2H, OCH
2), 4.44 (br s, 2H, piperazine-H), 4.78 (s, 2H, CH
2S), 7.23 (s, 2H, quinazoline 5-H, 8-H), 7.69 (d, J=7.8Hz, 2H, phenyl 2-H, 6-H), 8.19 (d, J=7.8Hz, 2H, phenyl 3-H, 5-H), 8.54 (s, 1H, quinazoline 2-H) .ESI-HRMSm/z:C
29H
37N
6O
4S
2([M+H]
+) calculated value: 597.2318. measured value: 597.2326.
Embodiment 14
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid cyclohexyl methyl ester (compound 14)
Adopt synthetic logical method, using the brooethyl cyclohexane give is raw material, yield: 36%, and faint yellow solid, m.p.57.3-58.5 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 0.99-1.23 (m, 5H, cyclohexyl-H), 1.43 (br s, 2H, piperidines-H), 1.59 (m, 6H, piperidines-H, cyclohexyl-H), 1.68 (d, J=12Hz, 2H, cyclohexyl-H), 1.80 (d, J=12Hz, 2H, cyclohexyl-H), 2.04 (br s, 2H, CH
2), 2.50 (br s, 2H, NCH
2, with the DMSO peak overlapping), 2.61 (br s, 4H, piperidines-H), 3.22 (d, J=6.6Hz, 2H, CH
2S), 3.87 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.18 (br s, 2H, piperazine-H), 4.19 (t, J=6.0Hz, 2H, OCH
2), 4.43 (br s, 2H, piperazine-H), 7.22 (s, 1H, quinazoline 5-H), 7.23 (s, 1H, quinazoline 8-H), 8.54 (s, 1H, quinazoline 2-H) .ESI-HRMS m/z:C
29H
44N
5O
2S
2([M+H]
+) calculated value: 558.2936. measured value: 558.2946.
Embodiment 15
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio pyridine carboxylic acid-2-ylmethyl ester (compound 15)
Adopt synthetic logical method, application 2-chloromethyl pyridine hydrochloride is as raw material, yield: 30%, and faint yellow solid, m.p.41.3-43.0 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.41 (br s, 2H, piperidines-H), 1.54 (m, 4H, piperidines-H), 1.98 (m, 2H, CH
2), 2.50 (br s, 6H, NCH
2, piperidines-H is with the DMSO peak overlapping), 3.88 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.18 (br s, 2H, piperazine-H), 4.18 (t, J=6.0Hz, 2H, OCH
2), 4.44 (br s, 2H, piperazine-H), 4.70 (s, 2H, CH
2S), 7.22 (s, 1H, quinazoline 5-H), 7.23 (s, 1H, quinazoline 8-H); (7.29 dd, J=7.2,5.4Hz, 1H, pyridine 4-H), 7.51 (d, J=7.2Hz; 1H, pyridine 6-H), 7.76 (td, J=7.2,1.8Hz, 1H, pyridine 5-H); (8.52 d, J=7.2Hz, 1H, pyridine 3-H), 8.53 (s, 1H, quinazoline 2-H) .ESI-HRMS m/z:C
28H
37N
6O
2S
2([M+H]
+) calculated value: 553.2419. measured value: 553,2414.
Embodiment 16
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio pyridine carboxylic acid-3-ylmethyl ester (compound 16)
Adopt synthetic logical method, use the 3-chloromethyl pyridine hydrochloride as raw material, yield: 32%, faint yellow solid, m.p.68.2-69.4 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.44 (br s, 2H, piperidines-H), 1.60 (br s, 4H, piperidines-H), 2.05 (br s, 2H, CH
2), 2.50 (br s, 6H, piperidines-H, NCH
2, with the DMSO peak overlapping), 3.87 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.15 (br s, 2H, piperazine-H), 4.19 (t, J=6.0Hz, 2H, OCH
2), 4.44 (br s, 2H, piperazine-H), 4.64 (s, 2H, CH
2S), 7.23 (s, 2H, quinazoline 5-H, 8-H), 7.36 (dd, J=7.8,4.8Hz1H; Pyridine 5-H), 7.83 (d, J=7.8Hz, 1H, pyridine 6-H), 8.47 (d, J=4.8Hz, 1H; Pyridine 4-H), 8.53 (s, 1H, quinazoline 2-H), 8.63 (s, 1H, pyridine 2-H) .ESI-HRMS m/z:C
28H
37N
6O
2S
2([M+H]
+) calculated value: 553.2419. measured value: 553.2391.
Embodiment 17
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio pyridine carboxylic acid-4-ylmethyl ester (compound 17)
Adopt synthetic logical method, use the 4-chloromethyl pyridine hydrochloride as raw material, yield: 54%, faint yellow solid, m.p.35.7-38.0 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.40 (br s, 2H, piperidines-H), 1.54 (br s, 4H, piperidines-H), 1.99 (m, 2H, CH
2), 2.47 (br s, 4H, piperidines-H), 2.52 (br s, 2H, NCH
2), 3.88 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.18 (br s, 2H, piperazine-H), 4.18 (t, J=6.0Hz, 2H, OCH
2), 4.44 (br s, 2H, piperazine-H), 4.65 (s, 2H, CH
2S), 7.22 (s, 2H, quinazoline 5-H, 8-H), 7.42 (d, J=4.8Hz, 2H, pyridine 2-H, 6-H), 8.51 (d, J=4.8Hz, 2H, pyridine 3-H, 5-H), 8.54 (s, 1H, quinazoline 2-H) .ESI-HRMS m/z:C
28H
37N
6O
2S
2([M+H]
+) calculated value: 553.2419. measured value: 553.2418.
Embodiment 18
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-(2-methylthiazol-4-yl) methyl ester (compound 18)
Adopt synthetic logical method, use 4-chloromethyl-2-methylthiazol hydrochloride as raw material, yield: 52%, faint yellow solid, m.p.63.7-65.0 ℃.
1H NMR (600MHz, DMSO-d
6) δ: 1.42 (br s, 2H, piperidines-H), 1.55 (br s, 4H, piperidines-H), 1.99 (t, J=6.0Hz, 2H, CH
2), 2.50 (piperidines-H is with the DMSO peak overlapping for br s, 4H), 2.54 (br s, 2H, NCH
2), 2.63 (s, 3H, CH
3), 3.87 (br s, 4H, piperazine-H), 3.93 (s, 3H, OCH
3), 4.15 (br s, 2H, piperazine-H), 4.19 (t, J=6.0Hz, 2H, OCH
2), 4.43 (br s, 2H, piperazine-H), 4.62 (s, 2H, CH
2S), 7.22 (2s, 2H, quinazoline 5-H, 8-H), 7.44 (s, 1H, thiazole-H), 8.53 (s, 1H, quinazoline 2-H) .ESI-HRMSm/z:C
27H
37N
6O
2S
3([M+H]
+) calculated value: 573.2140. measured value: 573.2124.
Embodiment 19
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.
Embodiment 20
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.
Test Example
Antiproliferative activity
Adopt mtt assay to measure the 503nhibiting concentration (IC of formula I compound to people's lung cancer A549, mammary cancer MCF-7, colorectal carcinoma HCT-116 cell proliferation
50), the result sees table 1.With 5 FU 5 fluorouracil (5-FU) and Sutent (Sunitinib) as positive control.
Table 1. formula I compound is to the antiproliferative activity of A549, MCF-7 and HCT-116 cell
The result shows that the compound of embodiment according to the invention has significant inhibition effect to people's lung cancer A549, mammary cancer MCF-7, colorectal carcinoma HCT-116 cell proliferation.
In sum; More than being merely preferred embodiment of the present invention, is not to be used to limit protection scope of the present invention, therefore; All any modifications of within spirit of the present invention and principle, being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. suc as formula the quinazoline shown in (I)-4-piperazine dithio formate compound:
Wherein, Y is-(CH
2)
n-; Here, n is 1,2,3 or 4;
Z is aryl or substituted aryl, heteroaryl or substituted heteroaryl or C3-C7 naphthenic base or substituted C3-C7 naphthenic base.
2. compound according to claim 1, wherein, n is 1.
3. compound according to claim 1, wherein, Z is aryl or substituted aryl, described aryl is a phenyl or naphthyl; Said substituted aryl is substituted phenyl or substituted naphthyl, is meant that the optional position is randomly replaced by one or more halogen, cyanic acid, nitro, carboxyl, hydroxyl, C1-C4 alkyl or C1-C4 alkoxyl group on the phenyl or naphthyl.
4. compound according to claim 3, wherein, Z is phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 3-methoxyphenyl, 4-bromo phenyl, 4-chlorophenyl, 4-fluoro phenyl, 2; 4-phenyl-difluoride base, 3; 4-phenyl-difluoride base, 2,3,4; 5,6-phenyl-pentafluoride base, 4-carboxyl phenyl, 4-cyano-phenyl or 4-nitrophenyl.
5. compound according to claim 1; Wherein, Z is heteroaryl or substituted heteroaryl, and described heteroaryl is furyl, thienyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, tetrazyl, thiazolyl 、 oxazolyl 、 isoxazolyl 、 oxadiazole base, thiadiazolyl group, isothiazolyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, benzothiazolyl, indyl or indazolyl; Said substituted heteroaryl is meant on the optional position of heteroaryl and is randomly replaced by one or more halogen, cyanic acid, nitro, carboxyl, hydroxyl, C1-C4 alkyl or C1-C4 alkoxyl group.
6. compound according to claim 1, wherein, Z is Trimetylene base, pentamethylene base or cyclohexyl.
7. be selected from a kind of compound in the following compounds:
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid benzyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-methyl-benzyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-methoxy-benzyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-3-methyl-benzyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-bromobenzyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-chlorine benzyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-luorobenzyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-2,4-difluorobenzyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-3,4-difluorobenzyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-2,3,4,5,6-PFBBR ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-carboxyl benzyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-cyanic acid benzyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-4-nitrobenzyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid cyclohexyl methyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio pyridine carboxylic acid-2-ylmethyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio pyridine carboxylic acid-3-ylmethyl ester;
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio pyridine carboxylic acid-4-ylmethyl ester; Or
4-(6-methoxyl group-7-(3-(piperidines-1-yl) propoxy-) quinazoline-4-yl) piperazine-1-dithio formic acid-(2-methylthiazol-4-yl) methyl ester.
8. the preparation method of the said compound of each claim in the claim 1 to 7 comprises the steps:
Formula (IX) compound, formula (II) compound and dithiocarbonic anhydride reaction obtain formula (I) compound,
Wherein, in formula (I) compound, formula (II) compound definition of Z and Y as defined in the claim of being quoted from;
X is a chlorine or bromine in formula (II) compound.
9. pharmaceutical composition that comprises each said compound in the claim 1 to 7.
10. each said compound or the said pharmaceutical composition of claim 9 application in the preparation antitumor drug in the claim 1 to 7.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850283A (en) * | 2012-10-18 | 2013-01-02 | 郑州大学 | Triazolyl-containing amino-dithio formic ether compound as well as preparation method and application of compound |
| CN104402799A (en) * | 2014-12-08 | 2015-03-11 | 河南慧锦药业有限公司 | N-(3-methyl chlorine) piperidine refining method |
-
2012
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Non-Patent Citations (2)
| Title |
|---|
| ANJALI PANDEY ET AL.: "Identification of orally active，potent，and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family", 《J. MED. CHEM.》 * |
| MATSUNO ET AL.: "Potent and selective inhibitors of PDGF receptor phosphorylation.2.Synthesis,structure activity relationship,improvement of aqueous solubility,and biological effects of 4-[4-(N-Substituted(thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives", 《J.MED.CHEM.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850283A (en) * | 2012-10-18 | 2013-01-02 | 郑州大学 | Triazolyl-containing amino-dithio formic ether compound as well as preparation method and application of compound |
| CN104402799A (en) * | 2014-12-08 | 2015-03-11 | 河南慧锦药业有限公司 | N-(3-methyl chlorine) piperidine refining method |
| CN104402799B (en) * | 2014-12-08 | 2017-01-04 | 河南慧锦药业有限公司 | A kind of N-(3-chloropropyl) piperidines process for purification |
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