CN107226789A - Dithiocarbamates compound, its preparation method and the purposes in antineoplastic is prepared - Google Patents

Dithiocarbamates compound, its preparation method and the purposes in antineoplastic is prepared Download PDF

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CN107226789A
CN107226789A CN201710321371.3A CN201710321371A CN107226789A CN 107226789 A CN107226789 A CN 107226789A CN 201710321371 A CN201710321371 A CN 201710321371A CN 107226789 A CN107226789 A CN 107226789A
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dhn
dihydronaphthalene
dioxies
methyl
isophthalic acids
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CN107226789B (en
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尹玉新
宁显玲
齐海龙
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Peking University
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/14—Dithiocarbamic acids; Derivatives thereof
    • C07C333/18—Esters of dithiocarbamic acids
    • C07C333/20—Esters of dithiocarbamic acids having nitrogen atoms of dithiocarbamate groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/14—Dithiocarbamic acids; Derivatives thereof
    • C07C333/18—Esters of dithiocarbamic acids
    • C07C333/22—Esters of dithiocarbamic acids having nitrogen atoms of dithiocarbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07—ORGANIC CHEMISTRY
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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    • C07—ORGANIC CHEMISTRY
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues

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Abstract

The invention discloses a series of dithiocarbamates compounds, its preparation method and the purposes in antineoplastic is prepared.The present invention therefrom has found a kind of PKM2 inhibitor of new construction type, and a series of dithiocarbamates compound for having synthesized structures with shown in formula I is designed according to the inhibitor by carrying out screening active ingredients to micromolecular compound storehouse.Tested by enzymatic activity, it was demonstrated that such compound is all significantly better than current existing PKM2 inhibitor to PKM2 inhibitory activity and selectivity.Pyruvate kinase M2 and M2 hypotype and MCF 7, the lethal effect test of tetra- kinds of tumor cell lines of HCT116, Hela, H1299 are carried out respectively to the compound in the present invention, active testing proves that such compound has the significant effect for suppressing tumor cell proliferation.

Description

Dithiocarbamates compound, its preparation method and antitumor preparing Purposes in medicine
Technical field
The present invention relates to novel amino dithiocarbonic acid esters compound, its officinal salt, the medicine containing the compound Compositions.Prepared the invention further relates to such compound with the effect of selectivity antagonism pyruvate kinase M2 hypotypes, induction Purposes in the antineoplastic of apoptosis of tumor cells.Also relate to the preparation method of these class compounds.The invention belongs to Technical field of medicine synthesis.
Background technology
Antineoplastic research is always one of hot fields of whole world drug research.At present, effective antitumour medicine Thing is a lot, but the low antineoplastic of good drug efficacy, toxic side effect is seldom.Therefore, current antineoplastic research will be solved Key issue be the antineoplastic for finding that good effect, toxic side effect are low.It had been metabolized using tumour cell and normal cell Difference in journey, optionally intervenes the key link in tumour cell metabolic process, it is possible to reaches and neither damages normal thin Born of the same parents, can suppress the purpose of growth of tumour cell again.
Glucose metabolism is the important energy-provision way of body, and it mainly has two kinds of forms --- anerobic glycolysis and aerobic oxygen Change.Glycolysis refers to that under the conditions of oxygen-deficient breakdown of glucose is the process of pyruvic acid or lactic acid, and with a small amount of ATP Generation.And under aerobic conditions, pyruvic acid can enter the further oxidation Decomposition generation CO of tricarboxylic acid cycle2And H2O, is produced more ATP, the process be referred to as sugar aerobic oxidation.Normal cell, under conditions of oxygen is sufficient, glucose, which passes through, foster oxidation, Sufficient ATP is produced, only in the case of oxygen-deficient, just carries out glycolysis to produce lactic acid and less ATP.And tumour No matter whether sufficient oxygen is for cell, and glucose sugar is all by glycolytic pathway, and last metabolism of pyruvate is produced on a small quantity into lactic acid ATP.Abnormal carbohydrate metabolism is a key character of tumour cell, and this phenomenon is in 1920s by German biologist Otto Warburg have found, therefore referred to as Warburg effects (Warburg effect) (Warburg, O.On the origin of cancer cells,Science,1956,123,309-314)。
Although having found that Warburg effects early in early stage in 20th century, how this effect produces, to tumour The problems such as what meaning generation development have is unclear always.The fast development studied recently as tumor metabolic, scientists Meaning of the Warburg effects to tumour is slowly disclosed, i.e., it provides material base for the propagation of tumour cell. (Matthew,G.Understanding the Warburg Effect:The Metabolic Requirements of Cell Proliferation.Science,2009,324,1029-1033).And a very crucial factor in the process, Exactly it is catalyzed key enzyme-pyruvate kinase of glycolysis final step.In tumour cell, the M2 hypotypes of pyruvate kinase are notable Height expression, exactly it is guarded at last outpost of the tax office of glycolysis, controls the trend of glucose sugar carbon source, and energy is being provided to cell Propagation while amount to tumour cell provides material base.2005, Mazurek, PKM2 is sub- in the tumour cell that S has found Type expression significantly increases (Mazurek, S.；Boschek,C.B.Pyruvate kinase type M2and its role in Tumor growth and spreading.Semin.Cancer Biol., 2005,15,300-308), this phenomenon is caused The great attention of people.Increasing research shows that PKM2 high expression is related to Warburg effects, promotes tumour thin Growth (Ferguson E.C, the Rathmell J.C.New roles for pyruvate kinase M2 of born of the same parents:working out the Warburg effect.Trends Biochem Sci,2008,33,359-362).Pyruvate kinase has 4 kinds of Asias Type, i.e. PKL, PKR, PKM1 and PKM2 hypotype.PKL hypospecificities are expressed in red blood cell, and PKR subtype expressions are in liver and kidney； In normal cell tissue, most mature tissue is all expression PKM1 hypotypes, and PKM2 hypotypes are only in embryo formation stage table Reach；However, PKM2 hypotypes high normal hypotype expressed and slowly instead of basic stitch in tumour cell.
Suppress PKM2 so as to tumour produce inhibitory action mechanism nude mice into knurl experiment in be confirmed, this into Fruit is published on the Nature magazines of 2008.(Christofk,H.R.；Vander Heiden,M.G.The M2splice isoform of pyruvate kinase is important for cancer metabolism and tumour Growth.Nature.2008,452,230-233), therefore, PKM2 is considered as that a very valuable antineoplastic is new Target spot.Antineoplastic research is carried out based on the target spot, it is possible to find the efficient, anti-cancer agent of low toxicity, solved anti-at present Key issue in tumour medicine research.
The breakthrough that Study on Molecular Mechanism of the PKM2 in tumour cell metabolic process is obtained, causes pharmaceutical chemistry Family high interest, in recent years using PKM2 as the anti-cancer agent of target spot research start to be taken seriously., Spoden etc. in 2008 Some aptamer peptides are developed, are formed for suppressing PKM2, these aptamers are proved to be able to suppress under low glucose state Cell breeds (Spoden, G.A.；Mazurek,S.；Morandell,D.；Bacher,N.；Ausserlechner,M.J.； Jansen-Durr,P.；Eigenbrodt,E.；Zwerschke,W.Isotype-specific inhibitors of the glycolytic key regulator pyruvate kinase subtype M2moderately decelerate tumor cell proliferation.Int J Cancer2008,123,312-321).2010, Matthew etc. passed through height Throughtput screening technologies obtain three PKM2 micromolecular inhibitors, and experiment confirms that they can effectively suppress H1299 tumour cells and split Solve activity (the Vander Heiden, M.G. of PKM2 in liquid；Christofk,H.R.；Schuman,E.；Subtelny,A.O.； Sharfi,H.；Harlow,E.E.；Xian,J.；Cantley,L.C.Identification of small molecule inhibitors of pyruvate kinase M2.Biochem Pharmacol2010,79,1118-1124).2011, It is thin that the research such as Chen finds that natural products alkannin (Shikonin) and the like can substantially suppress A549 and MCF-7 tumours Glycolysis (Chen, the J. of born of the same parents；Xie,J.；Jiang,Z.；Wang,B.；Wang,Y.；Hu,X.Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase- M2Oncogene 2011,30,4297-4306)。
Although having had now been found that several PKM2 inhibitor, activity is low, and relatively other pyruvate kinase hypotypes Selectivity it is undesirable.Therefore, we carry out screening active ingredients to micromolecular compound storehouse, therefrom find a kind of new construction type PKM2 inhibitor, and a series of compound has been synthesized according to inhibitor design.Tested by enzymatic activity, it was demonstrated that such chemical combination Thing is all significantly better than current existing PKM2 inhibitor to PKM2 inhibitory activity and selectivity.
Compound in the present invention has been carried out respectively pyruvate kinase M2 and M2 hypotype and MCF-7, HCT116, Hela, The lethal effect test of tetra- kinds of tumor cell lines of H1299.Active testing proves that such compound has significant suppression tumour thin The effect of born of the same parents' propagation.
The content of the invention
It is new with the antitumor of selectivity antagonism pyruvate kinase M2 hypotypes effect it is an object of the invention to provide a class Compound, and these compounds preparation method and purposes.
In order to achieve the above object, present invention employs following technological means：
A kind of dithiocarbamates compound or its pharmaceutically acceptable salt of the present invention, with formula I institutes The structure shown：
Wherein,
N is 0-3 integer；
R is the substituent of the optional position on phenyl ring, and R is selected from hydrogen, C1-4Alkyl, C1-4Alkoxy, halogen, C1-4Halo The group that alkyl, hydroxyl, cyano group, sulfydryl, nitro and amino are constituted；
R ' and R " meets one of following two kinds of situations：(1) R ' and R " is each independently selected from hydrogen, alkyl, haloalkyl, ring The group that alkyl, alkenyl, alkynyl, aryl, aralkyl are constituted；Or the common shape of N atoms that (2) R ' and R " is connected together with the two Into 5-6 circle heterocycles, the heterocycle is selected from substituted or non-substituted following group：Morpholinyl, thiomorpholine base, thiazolidinyl, oxazoles Base, isoxazolyls, imidazolidinyl, piperidyl, piperazinyl, pyrrolidinyl；The heterocycle is optionally taken by one or more substituents Dai Shi, the substituent is each independently selected from the group being made up of alkyl, acyl group, alkenyl, alkynyl, phenyl and benzyl；
R " ' is selected from hydrogen, C1-4Alkyl, C1-4Alkoxy, halogen, C1-4Haloalkyl, hydroxyl, cyano group, sulfydryl, nitro, amino The group constituted.
In the present invention, it is preferred to, in formula I：
N is 0 or 1；
R is selected from hydrogen；
R ' and R " meets one of following two kinds of situations：(1) R ' and R " be each independently selected from hydrogen, methyl, ethyl, propyl group, Butyl, ethoxy, pi-allyl, cyclohexyl, C1-4The substituted or non-substituted piperazinyl of alkyl, C1-4The substituted or non-substituted piperazine of alkyl Piperidinyl, C1-4Alkyl substituted or non-substituted benzyl and C1-4The substituted or non-substituted pyridine alkyl of alkyl；Or (2) R ' and R " Morpholinyl, thiomorpholine base, 2,6- dimethylated morpholinyls, thiazolidinyl, methyl piperazine are collectively forming together with the two N atom connected Piperazine base, isopropyl piperazinyl, acetylpiperazinyl, Phenylpiperazinyl, benzyl diethylenediamine base, piperidyl or pyrrolidinyl；
R " ' is selected from methyl, hydrogen, diethyl thiocarbamoyl sulfidomethyl, dipropyl thiocarbamoyl sulfidomethyl, morpholine -4- Thiocarbamoyl sulfidomethyl, piperidines -1- thiocarbamoyls sulfidomethyl, dihydroxy ethyl thiocarbamoyl sulfidomethyl, dimethyl thio Carbamyl sulfidomethyl, pyrrolidines -4- thiocarbamoyls sulfidomethyl, thiazolidine -4- thiocarbamoyls sulfidomethyl, diallyl amino The group that thiocarbamoyl sulfidomethyl, thiomorpholine -4- thiocarbamoyl sulfidomethyls are constituted.
In the present invention, it is preferred to, described dithiocarbamates compound or its pharmaceutically acceptable salt, The group constituted selected from following compound：
Diethylamino dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Dipropylamino dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Dibutylamino dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Double dihydroxy ethyl aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Diallyl aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Morpholine -4- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Thiomorpholine -4- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
2,6- thebaine -4- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Thiazolidine -3- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Pyrrolidines -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Piperidines -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
4- methyl piperazine -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
4- isopropyl piperazine -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
4- Acetylpiperazine -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Cyclohexylmethylamino dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Methylamino dithiocarbamate formic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
(4- methyl piperazines -1)-dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
2- diethyllaminoethyl dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Piperidines -1- dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Benzyl dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Pyridine -3- methyl dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Pyridine -2- methyl dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Pyridine -4- methyl dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
4- phenylpiperazine -1- dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
4- benzyl diethylenediamine -1- dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Diethylamino dithiocarbonic acid -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Morpholine -4- aminodithioformic acids -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Piperidines -1- aminodithioformic acids -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
4- phenylpiperazine -1- aminodithioformic acids -- 1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Dipropylamino dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- esters；
Morpholine -4- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- esters；
Piperidines -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- esters；
4- Acetylpiperazine -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- esters；
Diethylamino dithiocarbonic acid -3- diethyl thiocarbamoyl sulfidomethyl -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- Methyl esters；
Dipropylamino dithiocarbonic acid -3- dipropyl thiocarbamoyl sulfidomethyl -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- Methyl esters；
Morpholine -4- aminodithioformic acid -3- morpholine -4- thiocarbamoyl sulfidomethyl -1,4- dioxy-DHN 1,4 dihydronaphthalenes - 2- methyl esters；
Piperidines -1- aminodithioformic acid -3- piperidines -1- thiocarbamoyl sulfidomethyl -1,4- dioxy-DHN 1,4 dihydronaphthalenes - 2- methyl esters；
Dihydroxy ethyl aminodithioformic acid -3- dihydroxy ethyl thiocarbamoyl sulfidomethyl -1,4- dioxy -1,4- dihydros Naphthalene -2- methyl esters；
Dimethylamino dithiocarbonic acid -3- dimethyl thio carbamyl sulfidomethyl -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- Methyl esters；
Pyrrolidines -4- aminodithioformic acid -3- pyrrolidines -4- thiocarbamoyl sulfidomethyl -1,4- dioxy -1,4- dihydros Naphthalene -2- methyl esters；
Thiazolidine -4- aminodithioformic acid -3- thiazolidine -4- thiocarbamoyl sulfidomethyl -1,4- dioxy -1,4- dihydros Naphthalene -2- methyl esters；
Diallyl aminodithioformic acid -3- diallyl aminothio carbamyl sulfidomethyl -1,4- dioxies -1,4- two Hydrogen naphthalene -2- methyl esters；
Thiomorpholine -4- aminodithioformic acid -3- thiomorpholine -4- thiocarbamoyl sulfidomethyl -1,4- dioxy -1,4- dihydros Naphthalene -2- methyl esters.
Further, the invention also provides the dithiocarbamates compound described in preparation or its pharmaceutically Acceptable salt method, comprises the following steps：
Using menadione as raw material, occur nucleophilic addition and substitution reaction generation 2- with formaldehyde and hydrogen chloride in acetate solvate Chloromethyl -3- methylnaphthoquinones, i.e. compound 1,2- chloromethyl -3- methylnaphthoquinones are anti-from carbon disulfide and different amine in a solvent Target compound 2-26 should be generated；Using AIBN as initiator, bromo-reaction generation 2- bromomethyl naphthalenes occur for menadione and NBS Quinone, i.e. compound 27,2- bromomethyls naphthoquinones generate target compound 28- from carbon disulfide and different amine reactions in a solvent 31；Menadione directly reacts generation target compound 32-35 from carbon disulfide and different amine in a solvent；Using naphthoquinones as original Material, occurs nucleophilic addition and substitution reaction generation 2,3- dichloromethyl naphthoquinones with formaldehyde and hydrogen chloride in acetate solvate, that is, changes Compound 36,2,3- dichloromethyls naphthoquinones generates target compound 37-46 from carbon disulfide and different amine reactions in a solvent；
Further, the invention also provides described dithiocarbamates compound or its can pharmaceutically connect Purposes of the salt received in antineoplastic is prepared.Described compound or its pharmaceutically acceptable salt have selection to PKM2 Property suppress effect.
Wherein, it is preferred that described tumour includes colon cancer, breast cancer, cervical cancer cell and lung cancer.
Further, the invention also provides a kind of pharmaceutical composition for being used to treat tumour, it contains described ammonia Base dithiocarbonic acid esters compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or excipient.
The present invention pharmaceutical composition can be administered alone also with other antineoplastic drug combinations.
Described pharmaceutical composition can be oral drugs, spray, rectal application, nasal cavity applied medicine, cheek medication or injection Agent.The pharmaceutical composition of the present invention can be applied using following any-mode：Orally, spraying suction, rectal application, nasal cavity are used Medicine, cheek medication, local application, non-bowel medication, such as subcutaneous, vein, intramuscular, intraperitoneal, intrathecal, intracardiac room, in breastbone or Intravenous administration mode.
When oral medication, the compounds of this invention can be made into any oral acceptable dosage form, include but is not limited to Tablet, capsule, the aqueous solution or water slurry.Wherein, the carrier that tablet is used may include filler, lubricant, disintegrant, bonding Agent.Filler may include but be not limited to starch, pregelatinized starch, dextrin, Icing Sugar, lactose, mannitol, microcrystalline cellulose.Lubrication Agent includes but is not limited to stearic acid, calcium stearate, magnesium stearate, talcum powder, oxidation vegetable oil, polyethylene glycol, dodecyl sulphur Sour sodium, superfine silica gel powder, talcum powder.Disintegrant may include but be not limited to Ac-Di-Sol, PVPP, starch and Its derivative, low-substituted hydroxypropyl cellulose,
Gas-producing disintegrant.Adhesive may include but be not limited to hydroxypropyl cellulose, PVP, starch slurry, dextrin, Icing Sugar, Syrup, rubber cement, cellulose and its derivates.The diluent that capsule preparations are used generally comprises lactose and dried corn starch.Water Suspended emulsion preparation is then to be used in mixed way active component with suitable suspending agent, and suspending agent may include but be not limited to wetting agent, wadding Solidifying agent, deflocculant.Optionally, some sweeteners, aromatic or colouring agent can also be added in above oral dosage form.
Embodiment
In order to which the present invention is expanded on further, a series of embodiments are given below.These embodiments be entirely it is illustrative, it Only be used for the present invention is specifically described, be not construed as limitation of the present invention.
The preparation method of compound as shown in table 1 below is sets forth in embodiment 1-46：
The compound number of table 1 and its structural formula
Embodiment 1：The preparation (1) of 2- chloromethyl -3- methyl-1,4-naphthaquinones
Menadione (1g, 5.81mmol) is dissolved in glacial acetic acid (10ml), 36% formalin (3ml) is added, Hydrogen chloride gas, stirring reaction 30min are passed through under condition of ice bath, until solution becomes red, stirring at normal temperature reaction is stayed overnight.Solution It is changed into dark brown, reaction solution is poured into frozen water, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying uses silicon Glue column separating purification (petrol ether/ethyl acetate elution) obtains yellow solid 1,960mg, yield 75.0%,1H NMR (400MHz,CDCl3)δ8.13-8.18(m,2H,ArH),7.76-7.78(m,2H,ArH),4.64(s,2H,CH2S),2.35(s, 3H, C=CCH3).
Embodiment 2：Diethylamino dithiocarbonic acid -3- methyl isophthalic acids, the preparation of 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters (2)
Diethylamine (123 μ L, 1.2mmol) is dissolved in acetonitrile (10ml), carbon disulfide (72 μ L, 1.2mmol) is added, Stirring at normal temperature reacts 30min, and 2- chloromethyl -3- methyl isophthalic acids are added portionwise, and 4- naphthoquinones (220mg, 1mmol), stirring at normal temperature is reacted, TLC detection raw material points disappear, and terminating reaction, decompression is spin-dried for solvent, adds a small amount of water, is extracted with ethyl acetate, and merges ester layer, satisfies And brine It, anhydrous sodium sulfate drying, obtain yellow solid with silica gel column separating purification (petrol ether/ethyl acetate elution) 2,298mg, yield 89.6%, mp 155-156 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.14(m,2H,ArH),7.73- 7.74(m,2H,ArH),4.65(s,2H,CH2S),4.06(q,2H,NCH2),3.73(q,2H,NCH2), 2.37 (s, 3H, C= CCH3),1.30(t,6H,2CH2CH3).13C NMR(100MHz,CDCl3)δ194.49,184.81,183.95,146.42, 141.66,133.67,133.63,132.19,131.92,126.49,49.92,46.80,33.85,13.70,12.53, 11.57.HR-MS(ESI+)m/z:334.0936[M+H]+.Found:334.0932[M+H]+.
Embodiment 3：Dipropylamino dithiocarbonic acid -3- methyl isophthalic acids, the preparation of 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters (3)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and di-n-propylamine are reactant Obtain yellow solid 3, yield 86.0%, mp 80-81 DEG C1H NMR(400MHz,CDCl3)δ8.10-8.14(m,2H,ArH), 7.72-7.74(m,2H,ArH),4.63(s,2H,CH2S),3.93(t,2H,NCH2),3.61(t,2H,NCH2),2.35(s,3H, C=CCH3),1.70-1.82(m,4H,2CH2CH3),0.92-0.98(m,6H,2CH2CH3).13C NMR(100MHz,CDCl3)δ 195.02,184.79,183.89,146.48,141.64,133.62,132.19,131.93,126.49,57.25,54.43, 33.92,20.70,19.62,13.66,11.18.HR-MS(ESI+)m/z:362.1249[M+H]+.Found:362.1244[M+ H]+.
Embodiment 4：Dibutylamino dithiocarbonic acid -3- methyl isophthalic acids, the preparation of 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters (4)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and dibutyl amine are reactant Obtain yellow solid 4, yield 90.5%, yellow, viscous liquid.1H NMR(400MHz,CDCl3)δ8.11-8.15(m,2H, ArH),7.73-7.75(m,2H,ArH),4.63(s,2H,CH2S),3.98(t,2H,NCH2),3.64(t,2H,NCH2),2.36 (s, 3H, C=CCH3),1.67-1.75(m,4H,2CH2CH2CH3),1.32-1.41(m,4H,2CH2CH2CH3),0.93-1.00 (m,6H,2CH2CH2CH3).13C NMR(100MHz,CDCl3)δ194.80,184.81,183.88,146.48,141.67, 133.60,132.21,131.97,126.48,55.46,52.60,33.93,29.69,29.38,26.36,20.12,13.81, 13.65.HR-MS(ESI+)m/z:390.1562[M+H]+.Found:390.1558[M+H]+.
Embodiment 5：Double dihydroxy ethyl aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Prepare (5)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and diethanolamine are anti- Thing is answered to obtain yellow solid 5, yield 82.4%, mp 91-92 DEG C1H NMR(400MHz,CDCl3)δ8.10-8.12(m,2H, ArH),7.73-7.75(m,2H,ArH),4.61(s,2H,CH2S),3.98-4.33(m,8H,2NCH2CH2),2.78(s,2H, 2OH), 2.35 (s, 3H, C=CCH3).13C NMR(100MHz,CDCl3)δ197.91,184.62,183.85,146.68, 141.64,133.78,133.72,132.13,131.83,126.56,126.50,60.65,59.35,57.57,57.52, 34.19,13.69.HR-MS(ESI+)m/z:366.0834[M+H]+.Found:366.0830[M+H]+.
Embodiment 6：Diallyl aminodithioformic acid -3- methyl isophthalic acids, the system of 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Standby (6)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and diallylamine are anti- Thing is answered to obtain yellow solid 6, yield 75.0%, mp 95-96 DEG C1H NMR(400MHz,CDCl3)δ8.10-8.12(m,2H, ), ArH 7.72-7.75 (m, 2H, ArH), 5.81-5.91 (m, 2H, 2CH=CH2), 5.20-5.28 (m, 4H, 2CH=CH2), 4.68(m,2H,NCH2),4.65(s,2H,CH2S),4.31(m,2H,NCH2), 2.35 (s, 3H, C=CCH3).13C NMR (100MHz,CDCl3)δ196.95,184.72,183.83,146.51,141.44,133.65,133.62,132.19, 131.92,130.98,130.92,130.31,126.48,118.74,56.86,53.71,34.25,13.65.HR-MS(ESI+) m/z:358.0936[M+H]+.Found:358.0934[M+H]+.
Embodiment 7：Morpholine -4- aminodithioformic acid -3- methyl isophthalic acids, the preparation of 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters (7)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and morpholine obtain for reactant To yellow solid 7, yield 86.4%, mp 132-133 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.14(m,2H,ArH), 7.74-7.76(m,2H,ArH),4.68(s,2H,CH2S),4.32(m,2H,NCH2),3.99(m,2H,NCH2),3.78(m,4H, CH2CH2), 2.38 (s, 3H, C=CCH3).13C NMR(100MHz,CDCl3)δ196.44,184.71,183.93,146.54, 141.26,133.76,133.71,132.15,131.86,126.56,126.50,66.26,66.17,53.63,33.70, 13.74.HR-MS(ESI+)m/z:348.0728[M+H]+.Found:348.0727[M+H]+.
Embodiment 8：Thiomorpholine -4- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Prepare (8)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and thiomorpholine are reactant Obtain yellow solid 8, yield 88.4%, mp 157-158 DEG C1H NMR(400MHz,CDCl3)δ8.12-8.13(m,2H, ArH),7.73-7.75(m,2H,ArH),4.67(s,2H,CH2S),4.55(t,2H,NCH2),4.36(t,2H,NCH2),2.77 (s,4H,CH2SCH2), 2.37 (s, 3H, C=CCH3).13C NMR(100MHz,CDCl3)δ195.78,184.68,183.91, 146.54,141.27,133.74,133.69,132.16,131.87,126.54,126.49,60.19,54.19,33.92, 27.27,13.71.HR-MS(ESI+)m/z:364.0500[M+H]+.Found:364.1151[M+H]+.
Embodiment 9：2,6- thebaine -4- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- The preparation (9) of methyl esters
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and thebaine are anti- Thing is answered to obtain yellow solid 9, yield 76.5%, mp 141-142 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.14(m,2H, ArH),7.73-7.76(m,2H,ArH),5.48(m,1H,NCH2CH),4.68(s,2H,CH2S),4.42(m,1H,NCH2CH), 3.67(t,2H,NCH2),2.83(t,2H,NCH2), 2.37 (s, 3H, C=CCH3),1.25(d,3H,CHCH3),1.24(d,3H, CHCH3).13C NMR(100MHz,CDCl3)δ195.87,184.70,183.97,146.52,141.33,133.75,133.69, 132.16,131.86,126.55,126.49,71.33,71.30,33.65,18.56,13.71.HR-MS(ESI+)m/z: 376.1041[M+H]+.Found:376.1039[M+H]+.
Embodiment 10：Thiazolidine -3- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Prepare (10)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and thiazolidine are reactant Obtain yellow solid 10, yield 76.3%, mp 148-149 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.14(m,2H, ArH),7.73-7.76(m,2H,ArH),5.07(s,1H,NCH2S),4.70(s,1H,NCH2S),4.67(s,2H,CH2S), 4.35(t,1H,NCH2CH2S),3.98(t,1H,NCH2CH2S),3.21(t,1H,NCH2CH2S),3.14(t,1H,NCH2CH2S), 2.38 (s, 3H, C=CCH3).13C NMR(100MHz,CDCl3)δ192.87,184.80,183.98,146.43,141.25, 133.78,133.71,132.16,131.83,126.56,126.49,56.61,52.58,33.82,31.18,13.78.HR-MS (ESI+)m/z:350.0343[M+H]+.Found:350.0339[M+H]+.
Embodiment 11：Pyrrolidines -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Prepare (11)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and pyrrolidines are reactant Obtain yellow solid 11, yield 91.0%, mp 171-172 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.12(m,2H, ArH),7.72-7.74(m,2H,ArH),4.68(s,2H,CH2S),3.97(t,2H,NCH2),3.64(t,2H,NCH2),2.38 (s, 3H, C=CCH3),2.05-2.12(m,2H,CH2CH2CH2CH2),1.97-2.03(m,2H,CH2CH2CH2CH2).13C NMR (100MHz,CDCl3)δ191.67,184.80,184.02,146.18,141.82,133.64,133.60,132.20, 131.92,126.48,126.45,55.37,50.52,33.19,26.11,24.25,13.72.HR-MS(ESI+)m/z: 332.0779[M+H]+.Found:332.0777[M+H]+.
Embodiment 12：Piperidines -1- aminodithioformic acid -3- methyl isophthalic acids, the system of 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Standby (12)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and piperidines obtain for reactant To yellow solid 12, yield 88.0%, mp 146-147 DEG C1H NMR(400MHz,CDCl3)δ8.10-8.12(m,2H,ArH), 7.72-7.74(m,2H,ArH),4.66(s,2H,CH2S),4.25(m,4H,CH2NCH2), 2.37 (s, 3H, C=CCH3),1.72 (m,6H,CH2CH2CH2).13C NMR(100MHz,CDCl3)δ194.53,192.77,184.77,183.94,146.38, 141.68,133.63,133.60,132.20,131.94,126.47,53.47,51.41,33.90,25.74,24.22, 13.66.HR-MS(ESI+)m/z:346.0936[M+H]+.Found:346.0932[M+H]+.
Embodiment 13：4- methyl piperazine -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- first The preparation (13) of ester
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and N methyl piperazine are anti- Thing is answered to obtain yellow solid 13, yield 97.2%, mp 124-125 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.12(m, 2H,ArH),7.72-7.75(m,2H,ArH),4.66(s,2H,CH2), S 4.37 (m, 2H, S=CNCH2), 3.96 (m, 2H, S= CNCH2),2.52(m,4H,CH2NCH2),2.37(s,3H,NCH3), 2.35 (s, 3H, C=CCH3).13C NMR(100MHz, CDCl3)δ195.86,184.72,183.93,146.47,141.41,133.70,133.66,132.17,131.89,126.52, 126.48,54.34,45.56,33.86,13.71.HR-MS(ESI+)m/z:361.1045[M+H]+.Found:361.1035[M+ H]+.
Embodiment 14：4- isopropyl piperazine -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- The preparation (14) of methyl esters
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and N- isopropyl piperazines are Reactant obtains yellow solid 14, yield 75.7%, mp 157-158 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.12(m, 2H,ArH),7.72-7.75(m,2H,ArH),4.66(s,2H,CH2), S 4.37 (m, 2H, S=CNCH2), 3.93 (m, 2H, S= CNCH2),2.76(m,1H,NCH),2.61(m,4H,CH2NCH2),2.37(s,3H,NCH3),1.07(s,3H,CHCH3),1.06 (s,3H,CHCH3).13C NMR(100MHz,CDCl3)δ195.35,184.75,183.94,146.45,141.48,133.69, 133.64,132.18,131.90,126.51,54.35,48.13,33.78,18.39,13.71.HR-MS(ESI+)m/z: 389.1358[M+H]+.Found:389.1348[M+H]+.
Embodiment 15：4- Acetylpiperazine -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- The preparation (15) of methyl esters
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and N- Acetylpiperazines are Reactant obtains yellow solid 15, yield 92.8%, mp 157-158 DEG C1H NMR(400MHz,CDCl3)δ8.10-8.12(m, 2H,ArH),7.73-7.75(m,2H,ArH),4.66(s,2H,CH2S),4.12-4.18(m,4H,CH2NCH2),3.75(t,2H, S=CNCH2), 3.62 (t, 2H, S=CNCH2), 2.36 (s, 3H, O=CCH3), 2.15 (s, 3H, C=CCH3).13C NMR (100MHz,CDCl3)δ196.75,184.64,183.90,169.30,146.59,141.06,133.81,133.74, 132.12,131.82,126.56,126.50,45.20,40.56,33.91,21.36,13.75.HR-MS(ESI+)m/z: 389.0994[M+H]+.Found:389.0991[M+H]+.
Embodiment 16：Cyclohexylmethylamino dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Prepare (16)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and N-methylcyclohexylamine are Reactant obtains yellow solid 16, yield 75.0%, mp 128-129 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.12(m, 2H,ArH),7.72-7.74(m,2H,ArH),4.66(s,2H,CH2S),3.17-3.42(d,3H,NCH3), 2.36 (s, 3H, C= CCH3),1.11-1.87(m,11H,NCHCH2CH2CH2CH2CH2).13C NMR(100MHz,CDCl3)δ196.02,184.75, 183.90,146.53,146.50,141.60,133.63,133.60,132.21,131.96,126.48,62.92,62.12, 37.75,33.91,33.69,30.22,29.42,25.47,25.17,13.65.HR-MS(ESI+)m/z:374.1249[M+H]+ .Found:374.1247[M+H]+.
Embodiment 17：Methylamino dithiocarbamate formic acid -3- methyl isophthalic acids, the preparation (17) of 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and methylamine obtain for reactant To yellow solid 17, yield 90.7%, mp 106-107 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.13(m,2H,ArH), 8.04 (s, 1H, NH), 7.75-7.77 (m, 2H, ArH), 4.40 (s, 2H, CH2S),3.29(s,3H,NCH3),2.33(s,3H,C =CCH3).13C NMR(100MHz,CDCl3)δ196.22,185.22,184.47,146.40,141.73,134.19, 133.81,132.10,131.60,126.71,126.62,34.03,31.09,13.63.HR-MS(ESI+)m/z:292.0466 [M+H]+.Found:292.0457[M+H]+.
Embodiment 18：(4- methyl piperazines -1)-dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Preparation (18)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and 4- methyl piperazine -1- amine Yellow solid 18, yield 95.9%, mp 162-163 DEG C are obtained for reactant1H NMR(400MHz,CDCl3)δ11.11(s, 1H, NH), 8.00-8.01 (m, 2H, ArH), 7.85-7.87 (m, 2H, ArH), 4.30 (s, 2H, CH2S),2.69-2.79(m, 8H, 2NCH2CH2), 2.20 (s, 3H, C=CCH3),2.14(d,3H,NCH3).13C NMR(100MHz,DMSO)δ199.97, 183.85,179.14,144.78,143.38,136.90,135.12,134.92,127.65,124.81,122.46,122.40, 54.30,53.41,53.33,45.50,13.06.HR-MS(ESI+)m/z:376.1153[M+H]+.Found:374.1143[M+ H]+.
Embodiment 19：2- diethyllaminoethyl dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Prepare (19)
Use the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and 2- diethyllaminoethyls Amine is that reactant obtains yellow solid 19, yield 73.3%, mp149-150 DEG C of1H NMR(400MHz,DMSO)δ10.41(s, 1H, NH), 8.01-8.03 (m, 2H, ArH), 7.85-7.88 (m, 2H, ArH), 4.94 (s, 2H, CH2S),3.99(m,2H, NHCH2),3.31(m,2H,NHCH2CH2),3.30(q,4H,CH3CH2NCH2CH3), 2.23 (s, 3H, C=CCH3), 1.22 (t, 6H,2CH2CH2).13C NMR(100MHz,DMSO)δ197.34,184.60,183.74,145.89,141.16,134.68, 134.60,132.14,131.79,126.58,126.46,48.31,47.19,41.62,31.35,13.80,8.88.HR-MS (ESI+)m/z:377.1357[M+H]+.Found:377.1348[M+H]+.
Embodiment 20：Piperidines -1- dithiocarbonic acid -3- methyl isophthalic acids, the preparation of 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters (20)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and piperidines -1- amine are reaction Thing obtains yellow solid 20, yield 90.9%, mp 166-167 DEG C1H NMR(400MHz,CDCl3) δ 8.19 (s, 1H, NH), 8.10-8.12(m,2H,ArH),7.72-7.74(m,2H,ArH),4.51(s,2H,CH2S),3.18(m,4H,CH2NCH2), 2.34 (s, 3H, C=CCH3), 1.68 (m, 6H, CH2CH2CH2).13C NMR(100MHz,CDCl3)δ201.01,184.80, 183.88,146.34,142.05,133.61,132.17,131.94,126.48,56.06,30.51,25.22,22.87, 13.59.HR-MS(ESI+)m/z:361.1044[M+H]+.Found:361.1031[M+H]+.
Embodiment 21：Benzyl dithiocarbonic acid -3- methyl isophthalic acids, the preparation (21) of 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and benzylamine obtain for reactant To yellow solid 21, yield 84.8%, mp 113-114 DEG C1H NMR(400MHz,CDCl3)δ8.01-8.12(m,3H,PhH), 7.73-7.76(m,2H,ArH),7.33-7.38(m,5H,ArH,NH),4.95(d,2H,CH2NH),4.44(s,2H,CH2S), 2.34 (s, 3H, C=CCH3).13C NMR(100MHz,CDCl3)δ195.66,184.82,184.51,146.32,141.60, 135.93,134.08,133.74,132.09,131.56,128.88,128.46,128.14,126.64,126.60,51.35, 31.19,13.65.HR-MS(ESI+)m/z:368.078[M+H]+.Found:368.077[M+H]+.
Embodiment 22：Pyridine -3- methyl dithiocarbonic acid -3- methyl isophthalic acids, the system of 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Standby (22)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and pyridine -3- methyl amines are Reactant obtains yellow solid 22, yield 76.1%, mp 140-141 DEG C1H NMR(400MHz,CDCl3)1HNMR(400MHz, CDCl3)δ10.58(t,1H,NH),8.48-8.54(m,2H,PyH),7.99-8.02(m,2H,ArH),7.84-8.86(m,2H, ArH),7.71-7.73(d,1H,PyH),7.37-7.40(m,1H,PyH),4.86(d,2H,CH2NH),4.49(s,2H,CH2S), 2.21 (s, 3H, C=CCH3).13C NMR(100MHz,CDCl3)δ196.82,184.60,183.79,149.57,148.95, 145.79,141.40,136.08,134.64,134.56,133.24,132.13,131.77,126.56,126.44,124.03, 47.94,31.34,13.81.HR-MS(ESI+)m/z:369.0731[M+H]+.Found:369.0722[M+H]+.
Embodiment 23：Pyridine -2- methyl dithiocarbonic acid -3- methyl isophthalic acids, the system of 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Standby (23)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and pyridine -2- methyl amines are Reactant obtains yellow solid 23, yield 72.5%, mp 149-150 DEG C1H NMR(400MHz,CDCl3)δ8.54(d,1H, NH),8.09-8.12(m,2H,ArH),7.73-7.75(m,2H,ArH),7.25-7.73(m,4H,PyH),5.02(d,2H, CH2NH),4.62(s,2H,CH2), S 2.38 (s, 3H, C=CCH3).13C NMR(100MHz,CDCl3)δ196.13,184.75, 184.20,153.96,148.76,146.00,141.70,137.11,133.81,133.69,132.13,131.80,126.55, 126.52,122.85,122.22,51.27,31.67,13.72.HR-MS(ESI+)m/z:369.0731[M+H]+.Found: 369.0719[M+H]+.
Embodiment 24：Pyridine -4- methyl dithiocarbonic acid -3- methyl isophthalic acids, the system of 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Standby (24)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and pyridine -4- methyl amines are Reactant obtains yellow solid 24, yield 78.5%, mp 131-132 DEG C1H NMR(400MHz,CDCl3)δ8.68(d,1H, NH),8.55-8.57(m,2H,ArH),8.11-8.13(m,2H,PyH),7.72-7.77(m,2H,ArH),7.28(s,2H, PyH),5.01(d,2H,CH2NH),4.43(s,2H,CH2), S 2.33 (s, 3H, C=CCH3).13C NMR(100MHz,CDCl3)δ 196.96,185.11,184.37,149.99,146.59,145.39,141.42,134.27,133.86,132.07,131.49, 126.74,126.56,122.74,49.34,31.22,13.65.HR-MS(ESI+)m/z:369.0731[M+H]+.Found: 369.0722[M+H]+.
Embodiment 25：4- phenylpiperazine -1- dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Prepare (25)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and 4- phenylpiperazine -1- amine Yellow solid 25, yield 96.4%. are obtained for reactant1H NMR(400MHz,CDCl3)δ8.12-8.13(m,2H,ArH), 7.74-7.76 (m, 2H, ArH), 7.28-7.33 (m, 2H, PhH), 6.94-6.96 (m, 3H, PhH), 4.69 (s, 2H, CH2S), 4.11-4.51(m,4H,2NCH2),3.33(s,4H,2NCH2), 2.39 (s, 3H, CH=CHCH3).13C NMR(100MHz, CDCl3)δ196.09,184.71,183.95,146.52,141.34,133.74,133.68,132.18,131.88,129.36, 126.55,126.50,120.82,116.45,48.87,33.85,13.74.HR-MS(ESI+)m/z:423.1201[M+H]+ .Found:423.1192[M+H]+.
Embodiment 26：4- benzyl diethylenediamine -1- dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Prepare (26)
Using the synthetic method of as above compound 2, with 2- chloromethyl -3- methyl isophthalic acids, 4- naphthoquinones and 4- benzyl diethylenediamine -1- amine Yellow solid 26, yield 96.3%. are obtained for reactant1H NMR(400MHz,CDCl3)δ8.11-8.12(m,2H,ArH), 7.72-7.75(m,2H,ArH),7.29-7.35(m,5H,PhH),4.66(s,2H,CH2S),3.94-4.38(m,4H,2NCH2), 3.56(s,2H,CH2Ph),2.56(s,4H,2NCH2), 2.36 (s, 3H, CH=CHCH3).13C NMR(100MHz,CDCl3)δ 195.63,184.72,183.92,146.48,141.42,133.69,132.17,131.89,129.13,128.42,127.46, 126.51,62.46,52.34,33.84,13.70.HR-MS(ESI+)m/z:437.1357[M+H]+.Found:437.1351[M+ H]+.
Embodiment 27：The preparation (27) of 2- bromomethyl -1,4- naphthoquinones
Menadione (1g, 5.9mmol) is dissolved in acetic anhydride (15ml), initiator A IBN (0.05g, 0.3mmol) is added, It is heated to reflux, NBS (1.05g, 5.9mmol) is added portionwise, flows back 40min.Reaction solution is poured into frozen water and stirred, ethyl acetate Extraction, saturated common salt water washing, anhydrous sodium sulfate drying is obtained with silica gel column separating purification (petrol ether/ethyl acetate elution) Yellow solid 27,910mg, yield 62.8%.1H NMR(400MHz,CDCl3)δ8.10-8.18(m,2H,ArH),7.70-7.81 (m, 2H, ArH), 7.13 (s, 1H, C=CH), 4.42 (s, 2H, CH2Br).
Embodiment 28：The preparation (28) of diethylamino dithiocarbonic acid -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters
Diethylamine (30 μ L, 0.29mmol) is dissolved in dichloromethane (10ml), addition carbon disulfide (18 μ L, 0.3mmol), stirring at normal temperature reaction 30min, is added portionwise 2- bromomethyls -1,4-naphthoquinone (72.5mg, 0.29mmol), normal temperature is stirred Reaction is mixed, TLC detection raw material points disappear, and terminating reaction, decompression is spin-dried for solvent, adds a small amount of water, is extracted with ethyl acetate, and merges Ester layer, saturated common salt water washing, anhydrous sodium sulfate drying is obtained with silica gel column separating purification (petrol ether/ethyl acetate elution) Yellow solid 28,65mg, yield 75.3%, mp 118-119 DEG C1H NMR(400MHz,CDCl3)δ8.07-8.14(m,2H, ), ArH 7.75-7.79 (m, 2H, ArH), 7.23 (s, 1H, C=CH), 4.59 (s, 2H, CH2S),4.03(q,2H,NCH2),3.78 (q,2H,NCH2),1.27-1.34(m,6H,2CH2CH3).13C NMR(100MHz,CDCl3)δ193.65,185.11,184.76, 146.42,135.88,133.90,133.72,132.21,132.08,126.63,126.20,50.14,46.84,34.42, 12.63,11.54.HR-MS(ESI+)m/z:320.0779[M+H]+.Found:320.0770[M+H]+.
Embodiment 29：The preparation (29) of morpholine -4- aminodithioformic acids -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters
Using the synthetic method of as above compound 18, yellow is obtained using 2- bromomethyls -1,4-naphthoquinone and morpholine as reactant Solid 29, yield 68.9%, mp 137-138 DEG C1H NMR(400MHz,CDCl3)δ8.07-8.15(m,2H,ArH),7.75- 7.78 (m, 2H, ArH), 7.23 (s, 1H, C=CH), 4.61 (s, 2H, CH2S),4.27(m,2H,OCH2),4.01(m,2H, OCH2),3.78(m,4H,CH2NCH2).13C NMR(100MHz,CDCl3)δ195.65,184.97,184.66,145.92, 136.06,133.97,133.77,132.19,132.03,126.64,126.24,66.25,66.17,34.23,29.67, 22.68.HR-MS(ESI+)m/z:334.0572[M+H]+.Found:334.0567[M+H]+.
Embodiment 30：The preparation (30) of piperidines -1- aminodithioformic acids -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters
Using the synthetic method of as above compound 18, yellow is obtained using 2- bromomethyls -1,4-naphthoquinone and piperidines as reactant Solid 30, yield 70.9%, mp 122-123 DEG C1H NMR(400MHz,CDCl3)δ8.07-8.14(m,2H,ArH),7.74- 7.77 (m, 2H, ArH), 7.23 (s, 1H, C=CH), 4.59 (s, 2H, CH2S),4.03(m,2H,CH2NCH2),3.78(m,2H, CH2NCH2),1.27-1.34(m,6H,CH2CH2CH2).13C NMR(100MHz,CDCl3)δ193.65,185.60,184.78, 146.41,135.92,133.90,133.71,132.20,132.08,126.63,126.20,54.62,53.58,34.44, 25.97,25.48,24.21.HR-MS(ESI+)m/z:332.0779[M+H]+.Found:332.0770[M+H]+.
Embodiment 31：The system of 4- phenylpiperazine -1- aminodithioformic acids -- 1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters Standby (31)
Using the synthetic method of as above compound 18, obtained using 2- bromomethyls -1,4-naphthoquinone and N- phenylpiperazines as reactant To yellow solid 31, yield 72.7%, mp 144-145 DEG C1H NMR(400MHz,CDCl3)δ8.08-8.16(m,2H,ArH), 7.75-7.78 (m, 2H, ArH), 6.93-7.33 (m, 6H, PhH, C=CH), 4.63 (s, 2H, CH2S),4.49(m,2H,NCH2), 4.15(m,2H,NCH2),3.33(m,4H,CH2NCH2).HR-MS(ESI+)m/z:409.1045[M+H]+.Found:409.1037 [M+H]+.
Embodiment 32：Dipropylamino dithiocarbonic acid -3- methyl isophthalic acids, the preparation of 4- dioxies-DHN 1,4 dihydronaphthalene -2- esters (32)
Di-n-propylamine (273 μ L, 2mmol) is dissolved in acetonitrile (10ml), carbon disulfide (121 μ L, 2mmol) is added, often Warm stirring reaction 30min, is added portionwise menadione (172mg, 1mmol), and stirring at normal temperature reaction, TLC detection product points no longer increase Many, terminating reaction, decompression is spin-dried for solvent, adds a small amount of water, is extracted with ethyl acetate, and merges ester layer, saturated common salt water washing, nothing Aqueous sodium persulfate is dried, and yellow solid 32,226mg, yield are obtained with silica gel column separating purification (petrol ether/ethyl acetate elution) 129-130 DEG C of of 65.1%, mp1H NMR(400MHz,CDCl3)δ8.12-8.16(m,2H,ArH),7.73-7.76(m,2H, ArH),3.80-3.89(m,4H,CH2NCH2), 2.40 (s, 3H, C=CCH3),1.97(m,2H,CH2CH3),1.80(m,2H, CH2CH3),1.08(m,3H,CH2CH3),0.95(m,3H,CH2CH3).13C NMR(100MHz,CDCl3)δ191.34,184.09, 180.30,151.16,142.25,133.80,133.50,132.15,127.20,126.24,57.37,56.19,21.28, 19.71,15.95,11.28,11.19.HR-MS(ESI+)m/z:348.1092[M+H]+.Found:348.1088[M+H]+.
Embodiment 33：Morpholine -4- aminodithioformic acid -3- methyl isophthalic acids, the preparation of 4- dioxies-DHN 1,4 dihydronaphthalene -2- esters (33)
Using the synthetic method of as above compound 32, yellow solid 33, yield are obtained using menadione and morpholine as reactant 140-141 DEG C of of 54.2%, mp1H NMR(400MHz,CDCl3)δ8.13-8.18(m,2H,ArH),7.75-7.78(m,2H, ArH),4.15-4.27(m,4H,CH2OCH2),3.86-3.87(m,4H,CH2NCH2), 2.41 (s, 3H, C=CCH3).13C NMR (100MHz,CDCl3)δ192.39,183.85,180.10,152.18,141.55,133.94,132.91,132.11, 127.24,126.76,66.26,66.22,51.96,51.07,16.06.HR-MS(ESI+)m/z:334.0572[M+H]+ .Found:334.0568[M+H]+.
Embodiment 34：Piperidines -1- aminodithioformic acid -3- methyl isophthalic acids, the preparation of 4- dioxies-DHN 1,4 dihydronaphthalene -2- esters (34)
Using the synthetic method of as above compound 32, yellow solid 34, yield are obtained using menadione and piperidines as reactant 139-140 DEG C of of 65.4%, mp1H NMR(400MHz,CDCl3)δ8.13-8.17(m,2H,ArH),7.74-7.76(m,2H, ArH),4.21(m,2H,NCH2),4.08(m,2H,NCH2), 2.41 (s, 3H, C=CCH3),1.77-1.87(m,6H, CH2CH2CH2).13C NMR(100MHz,CDCl3)δ190.63,184.07,180.36,151.21,141.96,133.83, 133.53,133.10,132.14,127.22,126.66,53.34,52.44,26.37,25.28,24.03,15.94.HR-MS (ESI+)m/z:332.0779[M+H]+.Found:332.0775[M+H]+.
Embodiment 35：4- Acetylpiperazine -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- The preparation (35) of ester
Using the synthetic method of as above compound 32, yellow solid 35, yield are obtained using menadione and morpholine as reactant 119-120 DEG C of of 69.5%, mp1H NMR(400MHz,CDCl3)δ8.11-8.18(m,2H,ArH),7.75-7.78(m,2H, ArH),4.18-4.30(m,4H,CH2NCH2),3.70-3.88(m,4H,CH2NCH2), 2.41 (s, 3H, C=CCH3),2.19(s, 3H, O=CCH3).13C NMR(100MHz,CDCl3)δ183.79,180.02,169.38,152.39,141.42,133.96, 132.82,132.09,127.24,126.80,50.78,40.69,29.69,21.37,16.10.HR-MS(ESI+)m/z: 375.0837[M+H]+.Found:375.0833[M+H]+.
Embodiment 36：The preparation (36) of 2,3- dichloride methyl -1,4- naphthoquinones
Naphthoquinones (1g, 6.33mmol) is dissolved in glacial acetic acid (10ml), 36% formalin (3ml), ice is added Hydrogen chloride gas, stirring reaction 30min are passed through under the conditions of bath, until solution becomes red, stirring at normal temperature reaction is stayed overnight.Will reaction Liquid is poured into frozen water, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying, with silica gel column separating purification (oil Ether/ethyl acetate elution) obtain yellow solid 36,1.1g, yield 68.9%.1H NMR(400MHz,CDCl3)δ8.18-8.20 (m,2H,ArH),7.81-7.83(m,2H,ArH),4.72(s,4H,2CH2Cl).
Embodiment 37：Diethylamino dithiocarbonic acid -3- diethyl thiocarbamoyl sulfidomethyl -1,4- dioxies -1,4- The preparation (37) of dihydronaphthalene -2- methyl esters
Diethylamine (206 μ L, 2.0mmol) is dissolved in acetonitrile (15ml), addition carbon disulfide (120 μ L, 2.0mmol), stirring at normal temperature reaction 30min, is added portionwise 2,3- dichloromethyls -1,4-naphthoquinone (254mg, 1mmol), normal temperature is stirred Mix reaction 24h, TLC detection product point no longer to increase, terminating reaction, decompression is spin-dried for solvent, adds a small amount of water, with ethyl acetate is extracted Take, merging ester layer, saturated common salt water washing, anhydrous sodium sulfate drying, with silica gel column separating purification, (petrol ether/ethyl acetate is washed It is de-) obtain yellow solid 37,453mg, yield 94.3%, mp130-131 DEG C of1H NMR(400MHz,CDCl3)δ8.12-8.14 (m,2H,ArH),7.74-7.76(m,2H,ArH),4.83(s,4H,2CH2S),4.03(q,4H,2NCH2),3.72(m,4H, 2NCH2),1.29(m,12H,4CH3).13C NMR(100MHz,CDCl3)δ194.15,183.87,144.02,133.84, 132.06,126.66,49.89,46.84,34.02,12.60,11.57.HR-MS(ESI+)m/z:481.1112[M+H]+, 503.0931[M+Na]+.Found:481.1111[M+H]+,503.0934[M+Na]+.
Embodiment 38：Dipropylamino dithiocarbonic acid -3- dipropyl thiocarbamoyl sulfidomethyl -1,4- dioxies -1,4- The preparation (38) of dihydronaphthalene -2- methyl esters
Using the synthetic method of as above compound 37, obtained with 2,3- dichloromethyls -1,4-naphthoquinone and di-n-propylamine for reactant To yellow solid 38, yield 92.9%, mp 111-112 DEG C1H NMR(400MHz,CDCl3)δ8.12-8.14(m,2H,ArH), 7.73-7.76(m,2H,ArH),4.80(s,4H,2CH2S),3.91(q,4H,2NCH2),3.60(m,4H,2NCH2),1.73- 1.79(m,8H,4CH2CH3),0.93-0.95(m,12H,4CH3).13C NMR(100MHz,CDCl3)δ194.67,183.78, 144.06,133.81,132.08,126.66,57.25,54.50,34.06,20.75,19.61,11.22.HR-MS(ESI+)m/ z:537.1738[M+H]+.Found:537.1728[M+H]+,559.1567[M+Na]+.
Embodiment 39：Morpholine -4- aminodithioformic acid -3- morpholine -4- thiocarbamoyl sulfidomethyl -1,4- dioxy -1, The preparation (39) of 4- dihydronaphthalene -2- methyl esters
Using the synthetic method of as above compound 37, obtained with 2,3- dichloromethyls -1,4-naphthoquinone and morpholine for reactant Yellow solid 39, yield 78.4%, mp 153-154 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.13(m,2H,ArH), 7.75-7.77(m,2H,ArH),4.89(s,4H,2CH2S),3.99-4.28(m,8H,4OCH2),3.76(s,8H,4NCH2).13C NMR(100MHz,CDCl3)δ196.10,183.92,143.72,134.00,131.95,126.70,66.28,66.20, 33.96.HR-MS(ESI+)m/z:509.0697[M+H]+.Found:509.0686[M+H]+.
Embodiment 40：Piperidines -1- aminodithioformic acid -3- piperidines -1- thiocarbamoyl sulfidomethyl -1,4- dioxy -1, The preparation (40) of 4- dihydronaphthalene -2- methyl esters
Using the synthetic method of as above compound 37, obtained with 2,3- dichloromethyls -1,4-naphthoquinone and piperidines for reactant Yellow solid 40, yield 84.2%, mp 142-143 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.13(m,2H,ArH), 7.73-7.75(m,2H,ArH),4.86(s,4H,2CH2S),4.29(q,4H,2NCH2),3.87(q,4H,2NCH2),1.70(m, 12H,2CH2CH2CH2).13C NMR(100MHz,CDCl3)δ194.21,183.95,143.97,133.84,132.05, 126.65,34.11,24.25.HR-MS(ESI+)m/z:505.1112[M+H]+,527.0931[M+Na]+.Found: 505.1100[M+H]+,527.0903[M+Na]+.
Embodiment 41：Dihydroxy ethyl aminodithioformic acid -3- dihydroxy ethyl thiocarbamoyl sulfidomethyl -1,4- dioxies - The preparation (41) of DHN 1,4 dihydronaphthalene -2- methyl esters
It is reaction with 2,3- dichloromethyls -1,4-naphthoquinone and diethanolamine using the synthetic method of as above compound 37 Thing obtains yellow solid 41, yield 64.2%,1H NMR(400MHz,CDCl3)δ8.03-8.05(m,2H,ArH),7.88-7.91 (m,2H,ArH),4.89-5.04(m,4H,2CH2S),3.84-4.12(m,8H,4NCH2),3.63-3.73(m,8H,4HOCH2) .HR-MS(ESI+)m/z:545.0908[M+H]+.Found:545.0918[M+H]+.
Embodiment 42：Dimethylamino dithiocarbonic acid -3- dimethyl thio carbamyl sulfidomethyl -1,4- dioxies -1,4- The preparation (42) of dihydronaphthalene -2- methyl esters
Using the synthetic method of as above compound 37, with 2,3- dichloromethyls -1,4-naphthoquinone and dimethyl amine for reactant Obtain yellow solid 42, yield 92.0%, mp 157-158 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.13(m,2H, ArH),7.74-7.76(m,2H,ArH),4.83(s,4H,2CH2S),3.56(s,3H,NCH3),3.36(s,3H,NCH3).13C NMR(100MHz,CDCl3)δ195.73,183.91,143.82,133.90,132.00,126.67,45.74,41.54, 34.05.HR-MS(ESI+)m/z:425.0486[M+H]+,447.0305[M+Na]+.Found:425.0487[M+H]+, 447.0304[M+Na]+.
Embodiment 43：Pyrrolidines -4- aminodithioformic acid -3- pyrrolidines -4- thiocarbamoyl sulfidomethyls -1,4- two The preparation (43) of oxygen-DHN 1,4 dihydronaphthalene -2- methyl esters
Using the synthetic method of as above compound 37, obtained with 2,3- dichloromethyls -1,4-naphthoquinone and pyrrolidines for reactant To yellow solid 43, yield 88.2%, mp 150-151 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.13(m,2H,ArH), 7.73-7.75(m,2H,ArH),4.88(s,4H,2CH2S),3.95(q,4H,2NCH2),3.64(q,4H,2NCH2),1.96- 2.09(m,8H,2CH2CH2).13C NMR(100MHz,CDCl3)δ191.33,184.00,143.87,133.85,132.04, 126.64,55.34,50.61,33.49,26.18,24.29.HR-MS(ESI+)m/z:477.0799[M+H]+,499.0618[M+ Na]+.Found:477.0791[M+H]+,499.0626[M+Na]+.
Embodiment 44：Thiazolidine -4- aminodithioformic acid -3- thiazolidine -4- thiocarbamoyl sulfidomethyls -1,4- two The preparation (44) of oxygen-DHN 1,4 dihydronaphthalene -2- methyl esters
Using the synthetic method of as above compound 37, obtained with 2,3- dichloromethyls -1,4-naphthoquinone and thiazolidine for reactant To yellow solid 44, yield 88.8%, mp 158-159 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.14(m,2H,ArH), 7.75-7.77(m,2H,ArH),5.04(s,4H,2NCH2S),4.86(s,4H,2CH2S),3.96(q,4H,2NCH2CH2), 3.21(q,4H,2NCH2CH2S).13C NMR(100MHz,CDCl3)δ192.47,183.92,143.55,134.04,131.92, 126.72,56.63,52.66,34.15,31.24,29.06.HR-MS(ESI+)m/z:512.9927[M+H]+,534.9747[M+ Na]+.Found:512.9944[M+H]+,534.9720[M+Na]+.
Embodiment 45：Diallyl aminodithioformic acid -3- diallyl aminothio carbamyl sulfidomethyls -1,4- two The preparation (45) of oxygen-DHN 1,4 dihydronaphthalene -2- methyl esters
It is reaction with 2,3- dichloromethyls -1,4-naphthoquinone and diallylamine using the synthetic method of as above compound 37 Thing obtains yellow, viscous liquid 45, yield 83.3%.1H NMR(400MHz,CDCl3)δ8.11-8.14(m,2H,ArH), 7.74-7.76 (m, 2H, ArH), 5.80-5.91 (m, 4H, 4CH=CH2), 5.27 (d, 2H, CH=CH2), 5.25 (d, 2H, CH= CH2), 5.24 (d, 2H, CH=CH2), 5.20 (d, 2H, CH=CH2),4.83(s,4H,4CH2S),4.66(d,4H,2NCH2), 4.30(d,4H,2NCH2).13C NMR(100MHz,CDCl3)δ196.56,183.79,143.87,133.89,132.00, 131.03,130.34,126.68,118.85,118.67,56.85,53.75,34.41.HR-MS(ESI+)m/z:529.1112 [M+H]+.Found:529.1113[M+H]+.
Embodiment 46：Thiomorpholine -4- aminodithioformic acid -3- thiomorpholine -4- thiocarbamoyl sulfidomethyls -1,4- two The preparation (46) of oxygen-DHN 1,4 dihydronaphthalene -2- methyl esters
Using the synthetic method of as above compound 37, obtained with 2,3- dichloromethyls -1,4-naphthoquinone and thiomorpholine for reactant To yellow solid 46, yield 90.7%, mp 146-147 DEG C1H NMR(400MHz,CDCl3)δ8.11-8.13(m,2H,ArH), 7.74-7.77(m,2H,ArH),4.66(s,4H,2CH2S),4.57-4.58(m,4H,2NCH2),4.26-4.29(m,4H, 2NCH2),2.76(s,8H,4CH2S).13C NMR(100MHz,CDCl3)δ195.33,183.88,143.77,134.02, 131.93,126.72,34.16,27.28.HR-MS(ESI+)m/z:541.0240[M+H]+,563.0060[M+Na]+.Found: 541.0343[M+H]+,563.0178[M+Na]+.
Embodiment 47：PKM2 enzyme inhibition activity evaluations are carried out to synthesized formula compound I
1st, experimental method：
Adding the μ L compounds of 40 μ L buffer+5 μ L FBP (final concentration 2.5mM)+1 into the every hole of 96 orifice plates, (DMSO is molten Liquid)+PKM2 enzymes, it is incubated at room temperature after 15min and adds stock solution (the μ L of 30 μ L buffer+5 μ L PEP (final concentration 0.5mM)+5 The μ LLDH (final concentration 1unit) of+5 μ L NADH (final concentration 0.12mM) of ADP (final concentration 4mM)+5), pass through fluorescence microplate reader immediately Detect change in fluorescence amount (excitation wavelength：340nm, launch wavelength 460nm), record slope.
Blank group and control group are set.Blank group：Buffer replaces PKM2 enzymes；Control group：DMSO replaces compound, other Reagent is constant.
Inhibiting rate=(Lt-L)/(Lb- L) * 100%
Wherein, L is dosing group slope, LtFor control group slope, LbFor blank group slope.
According to slope, IC is calculated50Value.
2nd, result
Partial target compound and positive drug alkannin are as shown in table 2 below to PKM2 inhibitory action：
Table 2：The inhibitory action of partial target compound and positive drug alkannin to PKM2
Compound of Formula I has the effect for significantly inhibiting PKM2, most of target chemical combination it can be seen from data in chart The effect of thing is significantly stronger than positive control drug alkannin, and the wherein activity of compound 40 is the most notable.
Embodiment 48：PKM1 enzyme selectivity evaluations are carried out to synthesized formula compound I
1st, experimental method：
Adding the μ L compounds of 40 μ L buffer+5 μ L FBP (final concentration 2.5mM)+1 into the every hole of 96 orifice plates, (DMSO is molten Liquid)+PKM1 enzymes, it is incubated at room temperature after 15min and adds stock solution (the μ L of 30 μ L buffer+5 μ L PEP (final concentration 0.5mM)+5 The μ LLDH (final concentration 1unit) of+5 μ L NADH (final concentration 0.12mM) of ADP (final concentration 4mM)+5), pass through fluorescence microplate reader immediately Detect change in fluorescence amount (excitation wavelength：340nm, launch wavelength 460nm), record slope.
Blank group and control group are set.Blank group：Buffer replaces PKM1 enzymes；Control group：DMSO replaces compound, other Reagent is constant.
Inhibiting rate=(Lt-L)/(Lb- L) * 100%
Wherein, L is dosing group slope, LtFor control group slope, LbFor blank group slope.
According to slope, IC is calculated50Value.
2nd, result
Partial target compound and alkannin are as shown in table 3 below to PKM1 inhibitory action：
Table 3：The inhibitory action of partial target compound and alkannin to PKM1
Representative target compound is significantly lower than PKM2, explanation to PKM1 inhibitory action it can be seen from data above Formula compound I is selective to PKM2, and selectivity is better than alkannin.
Embodiment 49：CDCC evaluation is carried out to synthesized formula compound I
1st, experimental method：
Cell line：HCT116 colon cancer cells, MCF7 breast cancer cells, Hela cervical cancer cells, H1299 lung carcinoma cells
Screening technique：Mtt assay
Action time：48h
2nd, result
Cell toxicant test result is as shown in table 4 below：
Table 4：Cell toxicant test result (IC50It is worth unit μM .L-1) ("-" is represented and do not detected)
Compound of Formula I is to HCT116 colon cancer cells, MCF7 breast cancer cells, Hela it can be seen from data above Cervical cancer cell and H1299 lung carcinoma cells have significant lethal effect.The killing to Partial tumors cell of compound of Formula I Effect is better than alkannin, and the wherein activity of compound 2,7,8,12,22,24,37,40,42,43,44,46 is the most notable.

Claims (10)

1. dithiocarbamates compound or its pharmaceutically acceptable salt, it is characterised in that with shown in formula I Structure：
Wherein,
N is 0-3 integer；
R is the substituent of the optional position on phenyl ring, and R is selected from hydrogen, C1-4Alkyl, C1-4Alkoxy, halogen, C1-4Haloalkyl, The group that hydroxyl, cyano group, sulfydryl, nitro and amino are constituted；
R ' and R " meets one of following two kinds of situations：(1) R ' and R " is each independently selected from hydrogen, alkyl, haloalkyl, cycloalkanes The group that base, alkenyl, alkynyl, aryl, aralkyl are constituted；Or (2) R ' and R " is collectively forming together with the two N atom connected 5-6 circle heterocycles, the heterocycle is selected from substituted or non-substituted following group：Morpholinyl, thiomorpholine base, thiazolidinyl, oxazolyls, Isoxazolyl, imidazolidinyl, piperidyl, piperazinyl, pyrrolidinyl；The heterocycle is optionally substituted by one or more substituents When, the substituent is each independently selected from the group being made up of alkyl, acyl group, alkenyl, alkynyl, phenyl and benzyl；
R " ' is selected from hydrogen, C1-4Alkyl, C1-4Alkoxy, halogen, C1-4Haloalkyl, hydroxyl, cyano group, sulfydryl, nitro and amino The group constituted.
2. dithiocarbamates compound as claimed in claim 1 or its pharmaceutically acceptable salt, its feature exist In in formula I：
Wherein,
N is 0 or 1；
R is selected from hydrogen；
R ' and R " meets one of following two kinds of situations：(1) R ' and R " be each independently selected from hydrogen, methyl, ethyl, propyl group, butyl, Ethoxy, pi-allyl, cyclohexyl, C1-4The substituted or non-substituted piperazinyl of alkyl, C1-4The substituted or non-substituted piperidyl of alkyl, C1-4Alkyl substituted or non-substituted benzyl and C1-4The substituted or non-substituted pyridine alkyl of alkyl；Or (2) R ' and R " together with The two N atom connected is collectively forming morpholinyl, thiomorpholine base, 2,6- dimethylated morpholinyls, thiazolidinyl, methyl piperazine Base, isopropyl piperazinyl, acetylpiperazinyl, Phenylpiperazinyl, benzyl diethylenediamine base, piperidyl or pyrrolidinyl；
It is thio that R " ' is selected from methyl, hydrogen, diethyl thiocarbamoyl sulfidomethyl, dipropyl thiocarbamoyl sulfidomethyl, morpholine -4- Carbamyl sulfidomethyl, piperidines -1- thiocarbamoyls sulfidomethyl, dihydroxy ethyl thiocarbamoyl sulfidomethyl, dimethyl thio ammonia first Acyl sulfidomethyl, pyrrolidines -4- thiocarbamoyls sulfidomethyl, thiazolidine -4- thiocarbamoyls sulfidomethyl, diallyl aminothio The group that carbamyl sulfidomethyl, thiomorpholine -4- thiocarbamoyl sulfidomethyls are constituted.
3. dithiocarbamates compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, its feature It is, the group constituted selected from following compound：
Diethylamino dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Dipropylamino dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Dibutylamino dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Double dihydroxy ethyl aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Diallyl aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Morpholine -4- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Thiomorpholine -4- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
2,6- thebaine -4- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Thiazolidine -3- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Pyrrolidines -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Piperidines -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
4- methyl piperazine -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
4- isopropyl piperazine -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
4- Acetylpiperazine -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Cyclohexylmethylamino dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Methylamino dithiocarbamate formic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
(4- methyl piperazines -1)-dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
2- diethyllaminoethyl dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Piperidines -1- dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Benzyl dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Pyridine -3- methyl dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Pyridine -2- methyl dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Pyridine -4- methyl dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
4- phenylpiperazine -1- dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
4- benzyl diethylenediamine -1- dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Diethylamino dithiocarbonic acid -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Morpholine -4- aminodithioformic acids -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Piperidines -1- aminodithioformic acids -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
4- phenylpiperazine -1- aminodithioformic acids -- 1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Dipropylamino dithiocarbonic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- esters；
Morpholine -4- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- esters；
Piperidines -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- esters；
4- Acetylpiperazine -1- aminodithioformic acid -3- methyl isophthalic acids, 4- dioxies-DHN 1,4 dihydronaphthalene -2- esters；
Diethylamino dithiocarbonic acid -3- diethyl thiocarbamoyl sulfidomethyl -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Dipropylamino dithiocarbonic acid -3- dipropyl thiocarbamoyl sulfidomethyl -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Morpholine -4- aminodithioformic acid -3- morpholine -4- thiocarbamoyl sulfidomethyl -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- first Ester；
Piperidines -1- aminodithioformic acid -3- piperidines -1- thiocarbamoyl sulfidomethyl -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- first Ester；
Dihydroxy ethyl aminodithioformic acid -3- dihydroxy ethyl thiocarbamoyl sulfidomethyl -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- Methyl esters；
Dimethylamino dithiocarbonic acid -3- dimethyl thio carbamyl sulfidomethyl -1,4- dioxies-DHN 1,4 dihydronaphthalene -2- methyl esters；
Pyrrolidines -4- aminodithioformic acid -3- pyrrolidines -4- thiocarbamoyl sulfidomethyl -1,4- dioxy-DHN 1,4 dihydronaphthalenes - 2- methyl esters；
Thiazolidine -4- aminodithioformic acid -3- thiazolidine -4- thiocarbamoyl sulfidomethyl -1,4- dioxy-DHN 1,4 dihydronaphthalenes - 2- methyl esters；
Diallyl aminodithioformic acid -3- diallyl aminothio carbamyl sulfidomethyl -1,4- dioxy -1,4- dihydros Naphthalene -2- methyl esters；
Thiomorpholine -4- aminodithioformic acid -3- thiomorpholine -4- thiocarbamoyl sulfidomethyl -1,4- dioxy-DHN 1,4 dihydronaphthalenes - 2- methyl esters.
4. prepare the dithiocarbamates compound or its pharmaceutically acceptable salt described in claim any one of 1-3 Method, it is characterised in that comprise the following steps：
Using menadione as raw material, occur nucleophilic addition and substitution reaction generation 2- chloromethanes with formaldehyde and hydrogen chloride in acetate solvate Base -3- methylnaphthoquinones, i.e. compound 1,2- chloromethyl -3- methylnaphthoquinones react from carbon disulfide and different amine in a solvent gives birth to Into target compound 2-26；Using AIBN as initiator, bromo-reaction generation 2- bromomethyl naphthoquinones occurs for menadione and NBS, i.e., Compound 27,2- bromomethyls naphthoquinones generates target compound 28-31 from carbon disulfide and different amine reactions in a solvent；First naphthalene Quinone directly reacts generation target compound 32-35 from carbon disulfide and different amine in a solvent；Using naphthoquinones as raw material, in acetic acid With formaldehyde and hydrogen chloride generation nucleophilic addition and substitution reaction generation 2,3- dichloromethyl naphthoquinones, i.e. compound 36 in solvent, 2, 3- dichloromethyls naphthoquinones generates target compound 37-46 from carbon disulfide and different amine reactions in a solvent；
Wherein, R ' and R " definition is with any one of claim 1-3.
5. the dithiocarbamates compound or its pharmaceutically acceptable salt described in claim any one of 1-3 are in system Purposes in standby antineoplastic.
6. purposes as claimed in claim 5, it is characterised in that described compound or its pharmaceutically acceptable salt are to PKM2 Effect with selective depression.
7. purposes as claimed in claim 5, it is characterised in that described tumour includes colon cancer, breast cancer, cervical cancer cell And lung cancer.
8. a kind of pharmaceutical composition for being used to treat tumour, it is characterised in that contain the amino described in claim any one of 1-3 Dithiocarbonic acid esters compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or excipient.
9. pharmaceutical composition as claimed in claim 8, it is characterised in that also including other antineoplastics.
10. pharmaceutical composition as claimed in claim 8 or 9, it is characterised in that described pharmaceutical composition is oral drugs, spray Mist agent, rectal application, nasal cavity applied medicine, cheek medication or injection.
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