CN105085350A - Dithiocarbamic acid allyl ester compound, preparation method and uses thereof - Google Patents
Dithiocarbamic acid allyl ester compound, preparation method and uses thereof Download PDFInfo
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- CN105085350A CN105085350A CN201410157717.7A CN201410157717A CN105085350A CN 105085350 A CN105085350 A CN 105085350A CN 201410157717 A CN201410157717 A CN 201410157717A CN 105085350 A CN105085350 A CN 105085350A
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- dithiocarbonic acid
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- 0 *C(*)=C(CSCN(*)*)C(*)=O Chemical compound *C(*)=C(CSCN(*)*)C(*)=O 0.000 description 1
- GUHZRDPEKLKAMX-UHFFFAOYSA-N CC(CSC(N(C)C)=S)C(c(cc1)ccc1F)=O Chemical compound CC(CSC(N(C)C)=S)C(c(cc1)ccc1F)=O GUHZRDPEKLKAMX-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention relates to a compound represented by a general formula (I) or a pharmaceutically acceptable salt or solvate thereof, a preparation method of the compound, and uses of the compound in preparation of antitumor drugs. The formula I is defined in the specification.
Description
Technical field
The present invention relates to a kind of compound with anti-tumor activity.Specifically, the present invention relates to general formula (I) compound and preparation method thereof, also relate to the purposes of general formula (I) compound at anti-tumor aspect.
Background technology
Dithiocarbamates compound has biological activity widely, particularly anti-tumor activity.The people such as such as Li Run great waves disclose the general formula of this compounds in Chinese invention patent application CN200410054686.9:
Wherein, R
2be selected from-(CH
2)
n-R
3,-CH
2-R
4,-(CH
2)
m-COR
5or-(CH
2)
m-COCO
2r
6.
The present inventor, through a large amount of experimental studies, constantly optimizes and transforms on the basis of above-mentioned general formula, has found that a class has the novel amino dithiocarbonic acid allyl ester compounds of anti-tumor activity.
Summary of the invention
In a first aspect of the present invention, provide and there is the compound shown in general formula (I) or its pharmacy acceptable salt or solvate:
Wherein,
R
1for phenyl or comprise a heteroatomic 5-6 unit heteroaryl, described heteroatoms is selected from N, S and O, above-mentioned phenyl and heteroaryl optionally replace by one or more substituting group, described substituting group is selected from the group be made up of alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group and methylene-dioxy independently of one another;
R
2and R
3meet one of following two kinds of situations: (1) R
2and R
3be selected from independently of one another by hydrogen, alkyl, benzyl, the group that aryl forms, abovementioned alkyl, benzyl, aryl optionally replace by one or more substituting group, described substituting group is selected from independently of one another by alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl, arylalkyl, heteroaryl, heterocyclic radical, alkoxyl group, cycloalkyloxy, aryloxy, alkyl sulfenyl, cycloalkylsulfanyl, artyl sulfo, alkoxy carbonyl, aryloxycarbonyl, acyl group, Thioacyl, acyloxy, amide group, urea groups, sulfinyl, alkyl sulphonyl, aryl sulfonyl, haloalkyl, carbamyl, halogen, cyano group, isocyano-, nitro, nitroso-group, thiocyanogen, isothiocyano, hydrazide group, sulfanyl, the group that sulfo group and silyl form, or (2) R
2and R
35-6 unit heterocyclic radical is jointly formed together with the two atom N connected, described heterocyclic radical optionally additionally comprises the heteroatoms that is selected from N, S and O except above-mentioned atom N, described heterocyclyl replace by one or more substituting group, described substituting group is selected from the group be made up of alkyl, alkoxy carbonyl and phenyl independently of one another,
R
4and R
5independently selected from by hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl, arylalkyl, heteroaryl, heterocyclic radical, alkoxyl group, cycloalkyloxy, aryloxy, alkyl sulfenyl, cycloalkylsulfanyl, artyl sulfo, alkoxy carbonyl, aryloxycarbonyl, sulfamyl, acyl group, Thioacyl, acyloxy, amide group, urea groups, sulfinyl, alkyl sulphonyl, aryl sulfonyl, amino, haloalkyl, carbamyl, halogen, cyano group, isocyano-, nitro, nitroso-group, thiocyanogen, isothiocyano, hydrazide group, sulfanyl, the group that sulfo group and silyl form, abovementioned alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl, arylalkyl, heteroaryl, heterocyclic radical, alkoxyl group, cycloalkyloxy, aryloxy, alkyl sulfenyl, cycloalkylsulfanyl, artyl sulfo, alkoxy carbonyl, aryloxycarbonyl, sulfamyl, acyl group, Thioacyl, acyloxy, amide group, urea groups, sulfinyl, alkyl sulphonyl, aryl sulfonyl, amino, haloalkyl optionally replace by one or more substituting group, described substituting group is selected from independently of one another by alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl, arylalkyl, heteroaryl, heterocyclic radical, alkoxyl group, cycloalkyloxy, aryloxy, alkyl sulfenyl, cycloalkylsulfanyl, artyl sulfo, alkoxy carbonyl, aryloxycarbonyl, sulfamyl, acyl group, Thioacyl, acyloxy, amide group, urea groups, sulfinyl, alkyl sulphonyl, aryl sulfonyl, amino, haloalkyl, carbamyl, halogen, cyano group, isocyano-, nitro, nitroso-group, thiocyanogen, isothiocyano, hydrazide group, sulfanyl, the group that sulfo group and silyl form.
In the preferred implementation of first aspect present invention, R
1be selected from the group be made up of phenyl, furyl, thienyl and pyrryl, described phenyl, furyl, thienyl and pyrryl optionally replace by one or more substituting group, described substituting group is selected from independently of one another by C
1-4alkyl, C
1-4the group that alkoxyl group, halogen, hydroxyl, nitro, cyano group and methylene-dioxy form.
In the preferred implementation of first aspect present invention, R
2and R
3meet one of following two kinds of situations: (1) R
2and R
3be selected from independently of one another by C
1-4the group that alkyl and benzyl form; Or (2) R
2and R
3jointly form Pyrrolidine base, piperidyl, morpholinyl or piperazinyl together with the two atom N connected, described Pyrrolidine base, piperidyl, morpholinyl or piperazinyl optionally replace by one or more substituting group, described substituting group is selected from C independently of one another
1-4alkyl, C
1-4the group that alkoxy carbonyl and phenyl form.
In the preferred implementation of first aspect present invention, R
4and R
5be hydrogen.
In the preferred implementation of first aspect present invention, described compound is the particular compound described in Examples below 1-31.
In a second aspect of the present invention, provide a kind of pharmaceutical composition, described pharmaceutical composition comprises: compound described in first aspect present invention or its pharmacy acceptable salt or solvate; And pharmaceutically acceptable carrier.
In a third aspect of the present invention, prepare the method for above-mentioned general formula (I) compound, the method comprises the steps:
(1) in the presence of acid, formula (a) compound, paraformaldehyde, formula (b) compound and dimethylamine hydrochloride are reacted, then by pH regulator to alkalescence, obtain the reaction system containing formula (c) compound;
(2) in the presence of an inorganic base, by the described reaction system that obtains in step (1) and CS
2react with formula (d) compound, obtain the compound shown in general formula (I);
Wherein, R
1, R
2, R
3, R
4, R
5all as in above-mentioned general formula (I) define.
In the preferred implementation of third aspect present invention, described step (1) reacts 6-18h, preferably 12h under reflux, and described acid is acetic acid; And/or in described step (2), by described mineral alkali, formula (d) compound and CS
2mixture after stirring is added dropwise to described reaction system, and described mineral alkali is salt of wormwood.
In a fourth aspect of the present invention, provide above-mentioned general formula (I) compound or its pharmacy acceptable salt or solvate for the preparation of the purposes in anti-tumor drug.
In the preferred implementation of fourth aspect present invention, described tumour is selected from the group be made up of lung cancer, mammary cancer, liver cancer, cancer of the stomach, cervical cancer, colorectal carcinoma.
Embodiment
The term " alkyl " used in the present invention refers to and is only made up of carbon atom and hydrogen atom and does not have the group of degree of unsaturation (such as double bond, triple bond or ring), and it covers various possible rotamerism group and stereoisomerism group.This group is connected with the rest part of molecule by singly-bound.As the limiting examples of alkyl, the group of following straight or branched can be enumerated: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl and other seven kinds of isomer thereof, n-hexyl and other 16 kinds of isomer, n-heptyl and various isomer, n-octyl and various isomer thereof, n-nonyl and various isomer, positive decyl and various isomer thereof.
The term " cycloalkyl " used in the present invention refers to that the saturated non-aromatic ring system be made up of at least 3 carbon atoms, this ring system can be monocycle, dicyclo, many rings, also can be condensed ring, bridged ring, volution.As the limiting examples of cycloalkyl, following group can be enumerated: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl; And condensed ring, bridged ring or the spiro-cyclic groups to be formed by common edge and public carbon atom by two or more above-mentioned monocycle.
The group that the term " thiazolinyl " used in the present invention is formed when referring to that (except methyl) exists one or more double bond in abovementioned alkyl group.
The group that the term " cycloalkenyl group " used in the present invention is formed when referring to and there is one or more double bond in above-mentioned group of naphthene base.
The group that the term " alkynyl " used in the present invention is formed when referring to that (except methyl) exists one or more three key in abovementioned alkyl group.
The term " alkoxyl group " used in the present invention refers to that Sauerstoffatom is connected with abovementioned alkyl and is connected to the group of molecule rest part by this Sauerstoffatom with singly-bound, and it covers various possible rotamerism group and stereoisomerism group.As the limiting examples of alkoxyl group, the group of following straight or branched can be enumerated: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy and other seven kinds of isomer thereof, positive hexyloxy and other 16 kinds of isomer thereof, positive heptan oxygen base and various isomer, n-octyloxy and various isomer thereof, positive ninth of the ten Heavenly Stems oxygen base and various isomer, n-decyloxy and various isomer thereof.
The term " aryl " used in the present invention refers to the aromatic ring be made up of at least 6 carbon atoms, and this ring system can be monocycle, dicyclo, many rings, and wherein dicyclo and many rings can be formed by singly-bound mode of connection or the mode that condenses by monocycle.As the limiting examples of aryl, following group can be enumerated: phenyl, naphthyl, anthryl, phenanthryl, indenyl, pyrenyl, perylene base, Azulene base, pentalenyl, heptalenyl, acenaphthenyl, fluorenyl, that thiazolinyl non-, fluoranthenyl, acephenanthrylenyl, benzo acenaphthenyl, triphenylenyl,
base, naphthacenyl, Pi base, pentaphene base, pentacenyl, neighbours' phenylene, hexaphene base, hexacenyl, cool base, trinaphthylenyl, heptaphene base, heptaphenyl, pyranthrenyl, ovalenyl, xenyl, binaphthylyl.
The term " heteroaryl " used in the present invention refers to have one or more heteroatomic 5-14 unit heteroaromatic ring system independently selected from N, O or S, this ring system can be monocycle, dicyclo, many rings, and wherein dicyclo and many rings can be formed by singly-bound mode of connection or the mode that condenses by monocycle.As the limiting examples of heteroaryl, following group: oxazolyl can be enumerated, isoxazolyl, imidazolyl, furyl, indyl, pseudoindoyl, pyrryl, triazolyl, triazinyl, tetrazyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, benzimidazolyl-, benzothienyl, benzopyranyl, carbazyl, quinolyl, isoquinolyl, quinazolyl, cinnolines base, naphthyridinyl, pteridyl, purine radicals, quinoxalinyl, thiadiazolyl group, indolizinyl, acridyl, phenazinyl, phthalazinyl, tonka bean camphor base, Pyrazolopyridine base, pyrido pyridazinyl, pyrrolopyridinyl, imidazopyridyl, pyrazolo pyridazine base, and the group to be formed by singly-bound mode of connection or the mode that condenses by above-mentioned heteroaryl.
The term " heterocyclic radical " used in the present invention refers to the non-aromatic 3-15 unit ring system be made up of carbon atom and the heteroatoms being independently selected from N, O or S, this ring system can be monocycle, dicyclo or many rings, also can be condensed ring, bridged ring, volution, and can optionally comprise one or more double bond.As the limiting examples of heterocyclic radical, following group can be enumerated: azepine
base, acridyl, benzodioxole group, benzo dioxacyclohexyl, chromanyl, dioxolanyl, dioxy phosphorus heterocycle amyl group, Decahydroisoquinolinpreparation base, indanyl, indoline base, isoindoline base, isochroman base, isothiazole alkyl, isoxazole alkyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2-oxopiperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azepine
base, octahydro indyl, octahydro pseudoindoyl, perhydroazepine
base, piperazinyl, 4-piperidone base, piperidyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydro isoquinolyl, tetrahydrofuran base, THP trtrahydropyranyl, Pyrrolidine base, thiazolinyl, thiazolidyl, thio-morpholinyl, thiomorpholino sulfoxide and thio-morpholinyl sulfone.
The term " arylalkyl " used in the present invention refers to the alkyl that one or more hydrogen atom is independently replaced by aryl, and wherein said aryl and alkyl are as hereinbefore defined.
The term " heteroarylalkyl " used in the present invention refers to the alkyl that one or more hydrogen atom is independently replaced by heteroaryl, and wherein said heteroaryl and alkyl are as hereinbefore defined.
The term " halogen " used in the present invention or " halo " refer to fluorine, chlorine, bromine or iodine.
Pharmaceutical composition in the present invention contains compound described in first aspect present invention as activeconstituents.In addition, this pharmaceutical composition also can comprise pharmaceutically acceptable carrier, include but not limited to: water, salts solution, alcohol, polyoxyethylene glycol, polyhydroxy-ethoxylated Viscotrol C, peanut oil, sweet oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesiumcarbonate, sugar, cyclodextrin, amylose starch, Magnesium Stearate, talcum, gelatin, agar, pectin, gum arabic, stearic acid or the low alkyl oxide of Mierocrystalline cellulose, silicic acid, lipid acid, fatty acid amine, glycerine monofatty ester and two glyceryl ester, the sour ether of tetramethylolmethane fat, polyoxyethylene, Walocel MT 20.000PV and polyvinylpyrrolidone.This pharmaceutical composition also can comprise one or more pharmaceutically acceptable auxiliarys, wetting agent, emulsifying agent, suspension agent, sanitas, osmotic pressure regulator, buffer reagent, sweeting agent, correctives, tinting material or above-mentioned arbitrary combination.
Pharmaceutical composition of the present invention can make any type of preparation, such as capsule, tablet, aerosol, solution, suspension agent, sugar-coat agent, lozenge, syrup, emulsion, ointment, paste, injection, powder, granule, paste, sustained release dosage, foaming agent.According to route of administration, medicine of the present invention can make drug-delivery preparation, intramuscular administration preparation, intranasal formulation, dosing eyes preparation, epidural administration preparation or local administration preparation in oral Preparation, nasal administration preparation, formulation for pulmonary delivery, buccal preparation, transdermal formulations, intradermal administration preparation, percutaneous drug administration preparation, Parenteral formulations, rectal administration preparation, reservoir type drug-delivery preparation, preparation for intravenous administration, urethra.
" cancer " in the present invention comprises various cancer as known in the art, includes but not limited to: lung cancer, liver cancer, cancer of the stomach, cervical cancer, colorectal carcinoma, mammary cancer, leukemia, non-small cell carcinoma, prostate cancer or tired melanoma, the cancer of the brain, skin carcinoma, osteocarcinoma, lymphatic cancer, nasopharyngeal carcinoma, laryngocarcinoma, esophagus cancer, duodenal cancer, carcinoma of small intestine, large bowel cancer, carcinoma of the pancreas, kidney, genital cancer, thyroid carcinoma.
Embodiment
Next, by embodiment, the present invention will be described in detail further, but the present invention is not limited only to these embodiments.
In general, compound of the present invention synthesizes by the following method.
Be dissolved in acetic acid by paraformaldehyde, dimethylamine hydrochloride, formula (b) compound, formula (a) compound, reflux under 120 ° of C 12h.Question response system is cooled to room temperature, revolves the acetic acid steamed in removing system, adds 25mL water, stirs and residue is dissolved, and regulates pH to 8-9, be designated as reaction system I with Anhydrous potassium carbonate, for subsequent use.Separately get a reaction vessel, add formula (d) compound, Anhydrous potassium carbonate, suitable solvent (water or acetone) successively respectively, after stirring fully mixing, add dithiocarbonic anhydride, after continuing stirring reaction 30min-2h, dropwise add in reaction system I for subsequent use.After adding, continue reaction 1h, terminate reaction.Target product is obtained through suitable purification step.
Embodiment 1: the synthesis of dimethylamino dithiocarbonic acid-2-benzoyl allyl ester
Paraformaldehyde (0.30g counts 10mmol by free formaldehyde), dimethylamine hydrochloride (0.82g, 10mmol), methyl phenyl ketone (0.60g, 5mmol) are dissolved in 25mL acetic acid, back flow reaction 12h at 120 DEG C.Question response system is cooled to room temperature, revolves the acetic acid steamed in removing system, adds 25mL water, stirs and residue is dissolved, and regulates pH to 8-9, be designated as reaction system I with Anhydrous potassium carbonate, for subsequent use.Separately get a reaction vessel, add dimethylamine hydrochloride (0.24g respectively successively, 3mmol), Anhydrous potassium carbonate (0.828g, 6mmol), water 15ml, after stirring makes dimethylamine hydrochloride and salt of wormwood dissolve, reaction 10min adds dithiocarbonic anhydride (0.19g, 0.25mmol), after continuing stirring reaction 30min, dropwise add in reaction system I for subsequent use.After adding, continue reaction 1h, terminate reaction.
Be extracted with ethyl acetate three times (10ml × 3), merge organic phase, wash twice (15mL × 2) with saturated sodium-chloride water solution, organic phase anhydrous sodium sulfate drying, filter, mix sample by proper silica gel, (eluent is sherwood oil to silica gel column chromatography separating purification: ethyl acetate=20:1, v/v), pale yellow oily liquid body 0.29g is obtained.
1HNMR(400M,CDCl
3):δ=7.73-7.75(m,2H),7.51-7.55(m,1H),7.41-7.44(m,2H),6.31(s,1H),5.78(s,1H),4.40(s,2H),3.55(s,3H),3.35(s,3H)
13CNMR(101MHz,CDCl
3):δ=196.81,196.27,142.81,137.26,132.23,129.44,129.04,028.08,45.38,41.30,37.81.
Ultimate analysis: C
12h
15nOS
2, theoretical value: C, 55.83, H, 5.71; N, 5.28; Measured value: C, 59.08; H, 5.83, N, 5.11.
Embodiment 2: the synthesis of dimethylamino dithiocarbonic acid-2-(4-anisoyl) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 4-methoxyacetophenone, obtains yellow oil.
1HNMR(400MHz,CDCl
3)δ7.80(d,J=8.8Hz,2H),6.92(d,J=8.8Hz,2H),6.20(s,1H),5.71(s,1H),4.39(s,2H),3.86(s,3H),3.54(s,3H),3.35(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.42,195.62,163.28,142.96,132.07,129.89,127.12,113.53,55.49,45.48,41.46,38.96.
HRMS:C
14h
17nO
2s
2+ H
+, theoretical value: 296.07735; FTMS (ESI
+, [M+H]
+) measured value: 296.07806.
Embodiment 3: the synthesis of dimethylamino dithiocarbonic acid-2-(2-anisoyl) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 2-methoxyacetophenone, obtains yellow oil.
1HNMR(400MHz,CDCl
3)δ=7.39(t,J=7.9Hz,1H),7.25(d,J=7.4Hz,1H),6.95(dd,J=15.0,7.8Hz,2H),6.32(s,1H),5.76(s,1H),4.40(s,2H),3.77(s,3H),3.54(s,3H),3.37(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.95,196.87,157.20,144.35,131.71,130.85,129.23,128.35,120.20,110.50,55.72,45.52,41.46,36.91.
HRMS:C
14h
17nO
2s
2+ H+, theoretical value: 296.07735; FTMS (ESI
+, [M+H]
+) measured value: 296.07816.
Embodiment 4: the synthesis of dimethylamino dithiocarbonic acid-2-(4-hydroxy benzoyl) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 4-hydroxyacetophenone, obtains faint yellow solid.
1HNMR(400MHz,CDCl
3)δ=7.74(d,J=8.7Hz,2H),6.91(d,J=8.5Hz,2H),6.22(s,1H),5.74(s,1H),4.40(d,J=8.9Hz,2H),3.55(d,J=11.5Hz,3H),3.34(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.92,196.43,161.07,142.82,132.62,129.21,127.96,115.43,45.55,41.58,38.93.
HRMS:C
13h
15nO
2s
2+ H
+, theoretical value: 282.06170; FTMS (ESI
+, [M+H]
+) measured value: 282.06225.
Embodiment 5: the synthesis of dimethylamino dithiocarbonic acid-2-(4-methyl benzoyl) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 4-methyl acetophenone, obtains faint yellow solid.
1HNMR(400MHz,CDCl
3)δ=7.65(d,J=8.1Hz,2H),7.21(d,J=8.0Hz,2H),6.25(s,1H),5.74(s,1H),4.37(s,2H),3.52(s,3H),3.32(s,3H),2.38(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.63,196.36,143.23,142.94,134.64,129.83,128.96,128.42,45.43,41.49,38.16,21.66.
HRMS:C
14h
17nOS
2+ H
+, theoretical value: 280.08243; FTMS (ESI
+, [M+H]
+) measured value: 280.08312.
Embodiment 6: the synthesis of dimethylamino dithiocarbonic acid-2-(3-methyl benzoyl) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 3-methyl acetophenone, obtains faint yellow solid.
1HNMR(400MHz,CDCl
3)δ=7.60–7.46(m,2H),7.32(dt,J=14.9,7.6Hz,2H),6.31(s,1H),5.79(s,1H),4.41(s,2H),3.55(s,3H),3.36(s,3H),2.39(s,3H).
13CNMR(101MHz,CDCl3)δ=197.14,196.49,143.01,138.09,137.44,133.16,129.93,129.17,128.07,126.90,45.55,41.49,38.02,21.36.
HRMS:C
14h
17nOS
2+ H
+, theoretical value: 280.08243; FTMS (ESI
+, [M+H]
+) measured value: 280.08321
Embodiment 7: the synthesis of dimethylamino dithiocarbonic acid-2-(3,4-methylene-dioxy benzoyl) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 3,4-methylene-dioxy methyl phenyl ketone, obtains faint yellow solid.
1HNMR(400MHz,CDCl
3)δ=7.38(dd,J=8.1,1.7Hz,1H),7.29(d,J=1.6Hz,1H),6.82(d,J=8.1Hz,1H),6.18(s,1H),6.03(s,2H),5.70(s,1H),4.36(s,2H),3.54(s,3H),3.34(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.36,195.20,151.57,147.86,142.89,131.63,127.15,126.29,109.47,107.68,101.82,45.48,41.47,38.46.
HRMS:C
14h
15nO
3s
2+ H
+, theoretical value: 310.05661; FTMS (ESI
+, [M+H]
+) measured value: 310.05646.
Embodiment 8: the synthesis of dimethylamino dithiocarbonic acid-2-(4-nitro benzoyl) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 4-nitro-acetophenone, obtains brown solid.
1HNMR(400MHz,CDCl
3)δ=8.29(d,J=8.5Hz,2H),7.88(d,J=8.5Hz,2H),6.44(s,1H),5.79(s,1H),4.38(s,2H),3.57(s,3H),3.39(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.00,195.27,149.78,143.17,142.72,130.61,130.40,123.47,45.63,41.45,37.13.
HRMS:C
13h
14n
2o
3s
2+ H+, theoretical value: 311.05186; FTMS (ESI
+, [M+H]
+) measured value 311.05138.
Embodiment 9: the synthesis of dimethylamino dithiocarbonic acid-2-(3-nitro benzoyl) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 3-nitro-acetophenone, obtains dark brown solid.
1HNMR(400MHz,CDCl
3)δ=8.57(dd,J=12.4,1.6Hz,1H),8.49–8.34(m,1H),8.09(dd,J=11.2,4.5Hz,1H),7.67(td,J=8.0,4.0Hz,1H),6.49–6.32(m,1H),5.80(d,J=6.3Hz,1H),4.40(d,J=14.8Hz,2H),3.57(d,J=10.5Hz,3H),3.39(d,J=6.0Hz,3H).
13CNMR(101MHz,CDCl
3)δ=195.89,194.59,148.07,142.95,135.16,130.01,129.58,129.55,126.65,124.31,45.63,41.53,37.34.
HRMS:C
13h
14n
2o
3s
2+ H
+, theoretical value: 311.05186; FTMS (ESI
+, [M+H]
+) measured value: 311.05203
Embodiment 10: the synthesis of dimethylamino dithiocarbonic acid-2-(2-nitro benzoyl) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 2-nitro-acetophenone, obtains dark brown solid.
1HNMR(400MHz,CDCl
3)δ=8.15(d,J=8.2Hz,1H),7.73(t,J=7.4Hz,1H),7.63(t,J=7.7Hz,1H),7.42(d,J=7.4Hz,1H),6.35(s,1H),5.55(s,1H),4.43(s,2H),3.54(s,3H),3.40(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.42,193.88,146.51,143.87,135.35,134.10,13.068,028.95,124.46,45.65,41.57,36.23.
HRMS:C
13h
14n
2o
3s
2+ H+, theoretical value: 311.05186; FTMS (ESI+, [M+H]+) measured value: 311.05101
Embodiment 11: the synthesis of dimethylamino dithiocarbonic acid-2-(4-fluoro benzoyl) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 4-fluoro acetophenone, obtains colourless oil liquid.
1HNMR(400MHz,CDCl
3)δ=7.79(dd,J=8.7,5.5Hz,2H),7.10(t,J=8.6Hz,2H),6.27(s,1H),5.73(s,1H),4.37(s,2H),3.54(s,3H),3.35(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.21,195.46,166.59,164.07,142.95,133.58,135.55,132.27,132.18,128.52,115.48,115.27,45.52,41.47,37.94.
HRMS:C
13h
14fNOS
2+ H
+, theoretical value: 284.05736; FTMS (ESI
+, [M+H]
+) measured value: 284.05691
Embodiment 12: the synthesis of dimethylamino dithiocarbonic acid-2-(3-fluoro benzoyl) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 3-fluoro acetophenone, obtains colourless oil liquid.
1HNMR(400MHz,CDCl
3)δ=7.49(d,J=7.7Hz,1H),7.45–7.35(m,2H),7.19(td,J=8.0,2.2Hz,1H),6.29(s,1H),5.75(s,1H),4.33(s,2H),3.50(s,3H),3.32(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.04,195.45,163.56,161.10,142.81,139.45,139.38,130.02,129.94,129.45,125.38,125.35,119.43,119.22,116.33,116.11,45.51,41.46,37.68.
HRMS:C
13h
14fNOS
2+ H
+, theoretical value: 284.05736; FTMS (ESI
+, [M+H]
+) measured value: 284.05714
Embodiment 13: the synthesis of dimethylamino dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 4-chloro-acetophenone, obtains faint yellow solid.
1HNMR(400MHz,CDCl
3)δ=7.64(d,J=8.4Hz,2H),7.34(d,J=8.3Hz,2H),6.24(s,1H),5.69(s,1H),4.30(s,2H),3.47(s,3H),3.29(s,3H).
13CNMR(101MHz,CDCl
3)δ=195.58,195.58,142.86,138.68,135.63,131.04,128.95,128.55,45.53,41.50,37.76.
HRMS:C
13h
14clNOS
2+ H
+, theoretical value: 300.02781; FTMS (ESI
+, [M+H]
+) measured value: 300.02776
Embodiment 14: the synthesis of dimethylamino dithiocarbonic acid-2-(2-chlorobenzene formacyl) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 2-chloro-acetophenone, obtains pale yellow oily liquid body.
1HNMR(400MHz,CDCl
3)δ=7.33(dt,J=8.1,4.8Hz,2H),7.29–7.20(m,2H),6.41(s,1H),5.70(s,1H),4.37(s,2H),3.49(s,3H),3.33(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.31,195.68,143.36,137.94,132.96,131.08,131.04,129.98,129.92,126.49,45.56,41.49,36.29.
HRMS:C
13h
14clNOS
2+ H
+, theoretical value: 300.02781; FTMS (ESI
+, [M+H]
+) measured value: 300.02732
Embodiment 15: the synthesis of dimethylamino dithiocarbonic acid-2-(3,4-dichloro-benzoyl base) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 3,4-dichloroacetophenone, obtains faint yellow solid.
1HNMR(400MHz,CDCl
3)δ=7.79(s,1H),7.55(d,J=8.2Hz,1H),7.48(d,J=8.1Hz,1H),6.30(s,1H),5.73(s,1H),4.31(s,2H),3.51(s,3H),3.33(s,3H).
13CNMR(101MHz,CDCl
3)δ=195.88,194.41,142.75,136.97,136.82,132.97,131.33,130.40,129.37,128.87,45.58,41.53,37.53.
HRMS:C
13h
13nCl
2oS
2+ H
+, theoretical value: 333.98884; FTMS (ESI
+, [M+H]
+) measured value: 333.98844
Embodiment 16: the synthesis of dimethylamino dithiocarbonic acid-2-(4-cyanobenzoyl) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 4-cyano-acetophenone, obtains beige solid.
1HNMR(400MHz,CDCl
3)δ=7.84(d,J=8.3Hz,2H),7.75(d,J=8.4Hz,2H),6.42(s,1H),5.77(s,1H),4.39(s,2H),3.57(s,3H),3.39(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.09,195.48,143.04,141.09,132.10,130.25,121.91,117.98,115.61,45.60,41.51,37.26.
HRMS:C
14h
14n
2oS
2+ H
+, theoretical value: 291.06203; FTMS (ESI
+, [M+H]
+) measured value: 291.06171
Embodiment 17: the synthesis of dimethylamino dithiocarbonic acid-2-(furans-2-formyl radical) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 2-acetofuran, obtains yellow oil.
1HNMR(400MHz,CDCl
3)δ=7.65(s,1H),7.20(d,J=3.4Hz,1H),6.54(dd,J=3.3,1.5Hz,1H),6.26(s,1H),6.22(s,1H),4.39(s,2H),3.54(s,3H),3.35(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.38,182.39,151.82,147.14,142.57,121.72,120.27,112.07,45.53,42.45,38.07.
HRMS:C
11h
13nO
2s
2+ H
+, theoretical value: 256.04605; FTMS (ESI
+, [M+H]
+) measured value: 256.04592
Embodiment 18: the synthesis of dimethylamino dithiocarbonic acid-2-(thiophene-2-formyl radical) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 2-acetyl thiophene, obtains yellow oil.
1HNMR(400MHz,CDCl
3)δ=7.64(t,J=4.3Hz,2H),7.09(dd,J=4.8,3.9Hz,1H),6.16(s,1H),5.95(s,1H),4.34(s,2H),3.50(s,3H),3.31(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.08,188.18,143.06,142.95,134.34,127.99,126.74,45.54,41.45,38.34.
HRMS:C
11h
13nOS
32+H
+, theoretical value: 272.02320; FTMS (ESI
+, [M+H]
+) measured value: 272.02316
Embodiment 19: the synthesis of dimethylamino dithiocarbonic acid-2-(pyrroles-2-formyl radical) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 2-acetyl-pyrrole, obtains white solid.
1HNMR(400MHz,CDCl
3)δ=9.85(s,1H),7.05(s,1H),6.83(s,1H),6.21(s,1H),6.01(s,1H),5.96(s,1H),4.33(s,2H),3.47(s,3H),3.26(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.59,184.78,142.73,130.84,125.68,125.55,118.92,110.82,45.47,41.42,38.73
HRMS:C
11h
14n
2oS
2+ H
+, theoretical value: 255.06218; FTMS (ESI
+, [M+H]
+) measured value: 255.06203
Embodiment 20: the synthesis of dimethylamino dithiocarbonic acid-2-(pyridine-3-formyl radical) allyl ester
According to similar method in embodiment 1, methyl phenyl ketone is replaced with 3-acetylpyridine, obtains brown oil.
1HNMR(400MHz,CDCl
3)δ=8.94(d,J=1.6Hz,1H),8.77(dd,J=4.8,1.6Hz,1H),8.05(dt,J=7.9,1.9Hz,1H),7.40(dd,J=7.8,4.9Hz,1H),6.42(s,1H),5.82(s,1H),4.41(s,2H),3.56(s,3H),3.38(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.12,195.27,152.81,150.49,143.22,136.88,133.03,130.05,123.25,45.59,41.49,37.39.
HRMS:C
12h
14n
2oS
2+ H
+, theoretical value: 267.06203; FTMS (ESI
+, [M+H]
+) measured value: 267.0625
Embodiment 21: the synthesis of Diethylamina Dithiomothyle acid-2-(4-chlorobenzene formacyl) allyl ester
Paraformaldehyde (0.30g counts 10mmol by free formaldehyde), dimethylamine hydrochloride (0.82g, 10mmol), 4-chloro-acetophenone (0.60g, 5mmol) are dissolved in 25mL acetic acid, back flow reaction 12h at 120 DEG C.Question response system is cooled to room temperature, revolves the acetic acid steamed in removing system, adds 25mL water, stirs and residue is dissolved, and regulates pH to 8-9, be designated as reaction system I with Anhydrous potassium carbonate, for subsequent use.Separately get a reaction vessel, add diethylamine (0.219g, 3mmol), Anhydrous potassium carbonate (0.828g, 6mmol), acetone 15ml respectively successively, after stirring fully mixing, add dithiocarbonic anhydride (0.19g, 0.25mmol).After continuing stirring reaction 2h, revolve the acetone steamed in removing system, add after suitable quantity of water makes resistates fully dissolve, elimination insoluble substance, gained dropwise adds in reaction system I for subsequent use.After adding, continue reaction 1h, terminate reaction.Be extracted with ethyl acetate three times (10ml × 3), merge organic phase, wash twice (15mL × 2) with saturated sodium-chloride water solution, organic phase anhydrous sodium sulfate drying, filter, mix sample by proper silica gel, (eluent is sherwood oil to silica gel column chromatography separating purification: ethyl acetate=20:1, v/v), pale yellow oil 0.40g is obtained.
1HNMR(400MHz,CDCl
3)δ=7.72(d,J=8.5Hz,2H),7.41(d,J=8.5Hz,2H),6.30(s,1H),5.74(s,1H),4.40(s,2H),4.04(q,J=6.9Hz,2H),3.74(dd,J=13.7,6.6Hz,2H),1.27(dd,J=11.3,6.7Hz,6H).
13CNMR(101MHz,CDCl
3)δ=195.87,194.53,143.01,138.83,135.74,131.07,128.77,128.58,49.73,46.79,37.36,12.55,11.59.
HRMS:C
15h
18clNOS
2+ H
+, theoretical value: 328.05911; FTMS (ESI
+, [M+H]
+) measured value: 328.05901
The synthesis of embodiment 22: two n-propylamine base dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester
According to similar method in embodiment 21, diethylamine is replaced with di-n-propylamine, obtains yellow oily liquid.
1HNMR(400MHz,CDCl
3)δ=7.73(d,J=8.5Hz,2H),7.43(d,J=8.5Hz,2H),6.30(s,1H),5.75(s,1H),4.40(s,2H),3.97–3.87(m,2H),3.66–3.58(m,2H),1.84–1.66(m,4H),0.95(q,J=7.1Hz,6H).
13CNMR(101MHz,CDCl
3)δ=195.96,195.13,143.00,138.85,135.76,131.09,128.79,128.58,57.02,54.35,37.42,20.74,19.64,11.21.
HRMS:C
17h
22clNOS
2+ H
+, theoretical value: 356.09041; FTMS (ESI
+, [M+H]
+) measured value: 356.09011
The synthesis of embodiment 23: two n-butyl amine base dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester
According to similar method in embodiment 21, diethylamine is replaced with Di-n-Butyl Amine, obtains yellow oil.
1HNMR(400MHz,CDCl
3)δ=7.73(d,J=8.4Hz,2H),7.42(d,J=8.4Hz,2H),6.29(s,1H),5.74(s,1H),4.40(s,2H),3.99–3.94(m,2H),3.67–3.61(m,2H),1.74–1.64(m,4H),1.39–1.32(m,4H),0.95(dt,J=20.6,7.4Hz,10H).
13CNMR(101MHz,CDCl
3)δ=195.94,194.86,143.02,138.86,135.77,131.09,128.63,128.57,55.23,55.51,37.43,29.42,28.38,20.13,20.06,13.86,13.70.
HRMS:C
19h
26clNOS
2+ H
+, theoretical value: 384.12171; FTMS (ESI+, [M+H]+) measured value: 384.12271
Embodiment 24: the synthesis of tetrahydro pyrrolidine-N-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester
According to similar method in embodiment 21, diethylamine is replaced with tetrahydro pyrrolidine, obtains faint yellow solid.
1HNMR(400MHz,CDCl
3)δ=7.73(d,J=8.5Hz,2H),7.43(d,J=8.5Hz,2H),6.36(s,1H),5.77(s,1H),4.42(s,2H),3.96(t,J=6.9Hz,2H),3.66(t,J=6.8Hz,2H),2.14–2.05(m,2H),2.04–1.95(m,2H).
13CNMR(101MHz,CDCl
3)δ=195.83,191.93,143.15,138.82,135.72,131.07,129.01,128.58,55.23,50.62,36.71,26.08,24.28.
HRMS:C
15h
26clNOS
2+ H
+, theoretical value: 326.04346; FTMS (ESI
+, [M+H]
+) measured value: 326.04354
Embodiment 25:(R) synthesis of-proline methyl ester-N-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester
According to similar method in embodiment 21, diethylamine is replaced with R-proline methyl ester, obtains yellow oil.
1HNMR(400MHz,CDCl
3)δ=7.78–7.64(m,2H),7.41(d,J=8.4Hz,2H),6.29(d,J=9.6Hz,1H),5.73(d,J=9.5Hz,1H),4.91(ddd,J=10.3,8.7,2.2Hz,1H),4.45–4.29(m,2H),4.23–3.82(m,1H),4.02–3.67(m,1H),3.70(d,J=35.3Hz,4H),2.42–1.84(m,4H).
13CNMR(101MHz,CDCl
3)δ=195.78,195.69,194.30,193.44,170.99,170.59,142.59,138.83,135.69,131.09,129.18,128.92,128.59,128.56,66.37,62.57,55.45,52.68,52.40,50.92,37.02,36.94,31.50,29.16,24.57,22.34.
HRMS:C
17h
18clNOS
2+ H
+, theoretical value: 384.04894; FTMS (ESI
+, [M+H]
+) measured value: 384.04987
Embodiment 26:(S) synthesis of-proline methyl ester-N-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester
According to similar method in embodiment 21, diethylamine is replaced with S-proline methyl ester, obtains yellow oil.
1HNMR(400MHz,CDCl
3)δ=7.78–7.64(m,2H),7.41(d,J=8.4Hz,2H),6.29(d,J=9.6Hz,1H),5.73(d,J=9.5Hz,1H),4.91(ddd,J=10.3,8.7,2.2Hz,1H),4.45–4.29(m,2H),4.23–3.82(m,1H),4.02–3.67(m,1H),3.70(d,J=35.3Hz,4H),2.42–1.84(m,4H).
13CNMR(101MHz,CDCl
3)δ=195.78,195.69,194.30,193.44,170.99,170.59,142.59,138.83,135.69,131.09,129.18,128.92,128.59,128.56,66.37,62.57,55.45,52.68,52.40,50.92,37.02,36.94,31.50,29.16,24.57,22.34.
HRMS:C
17h
18clNOS
2+ H
+, theoretical value: 384.04894; FTMS (ESI
+, [M+H]
+) measured value: 384.04907
Embodiment 27: the synthesis of piperidines-N-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester
According to similar method in embodiment 21, diethylamine is replaced with piperidines, obtains faint yellow solid.
1HNMR(400MHz,CDCl3)δ=7.73(d,J=8.6Hz,2H),7.44–7.39(m,2H),6.31(s,1H),5.75(s,1H),4.42(s,2H),4.30(s,2H),3.89(s,2H),1.71(s,6H).
13CNMR(101MHz,CDCl3)δ=195.85,194.63,143.08,138.84,135.74,131.09,128.77,128.57,53.73-52.59,37.40,26.25-25.41,24.26.
HRMS:C
16h
18clNOS
2+ H
+, theoretical value: 340.05911; FTMS (ESI
+, [M+H]
+) measured value: 340.08939
Embodiment 28: the synthesis of morpholine-4-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester
According to similar method in embodiment 21, diethylamine is replaced with morpholine, obtains white solid.
1HNMR(400MHz,CDCl
3)δ=7.72(d,J=8.5Hz,2H),7.43(d,J=8.5Hz,2H),6.33(s,1H),5.79(s,1H),4.44(s,2H),4.15(m,4H),3.77(s,4H).
13CNMR(101MHz,CDCl
3)δ=196.67,195.68,142.71,138.95,135.61,131.06,129.25,128.63,66.77-65.59,52.10-50.16,37.24.
HRMS:C
15h
16clNOS
2+ H
+, theoretical value: 342.03837; FTMS (ESI
+, [M+H]
+) measured value: 342.03795
Embodiment 29:(2R, 6S) synthesis of-thebaine-N-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester
According to similar method in embodiment 21, diethylamine is replaced with (2R, 6S)-thebaine, obtains pale yellow oil.
1HNMR(400MHz,CDCl
3)δ=7.72(d,J=8.4Hz,2H),7.43(d,J=8.3Hz,2H),6.33(s,1H),5.79(s,1H),4.50(s,2H),3.75(t,J=6.4Hz,1H),3.65(s,2H),3.50(t,J=6.4Hz,1H),2.82(d,J=45.2Hz,2H),1.25(s,3H),1.23(s,3H).
13CNMR(101MHz,CDCl
3)δ=196.12,195.70,142.75,138.93,135.62,131.05,129.56,128.62,71.79-70.87,56.66-55.80,37.49,18.59.
HRMS:C
17h
21clNOS
2+ H
+, theoretical value: 370.06967; FTMS (ESI
+, [M+H]
+) measured value: 370.07033
The synthesis of embodiment 30:N-phenyl-Piperazine-N-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester
According to similar method in embodiment 21, diethylamine is replaced with N-phenylpiperazine, obtains yellow-green colour oily matter.
1HNMR(400MHz,CDCl
3)δ=7.74(d,J=8.5Hz,2H),7.44(t,J=6.8Hz,2H),7.30(dd,J=13.8,6.1Hz,2H),6.94(t,J=7.3Hz,3H),6.35(s,1H),5.80(s,1H),4.46(s,2H),4.34(t,J=68.8Hz,4H),3.68-3.61(m,4H).
13CNMR(101MHz,CDCl
3)δ=196.25,195.71,150.23,142.80,138.94135.65,131.07,129.35,129.12,128.64,120.62,116.33,48.77,37.39.
HRMS:C
21h
21clNOS
2+ H
+, theoretical value: 417.08566; FTMS (ESI
+, [M+H]
+) measured value: 417.08677
The synthesis of embodiment 31:N-methylbenzylamine-N-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester
According to similar method in embodiment 21, diethylamine is replaced with N-methylbenzylamine, obtains white solid.
1HNMR(400MHz,CDCl3)δ=7.75(d,J=7.5Hz,2H),7.44(d,J=8.4Hz,2H),7.41–7.23(m,5H),6.35(d,J=19.4Hz,1H),5.79(d,J=16.0Hz,1H),5.20(d,J=156.1Hz,2H),4.46(s,2H),3.54–3.16(m,3H).
HRMS:C
19h
18clNOS
2+ H
+, theoretical value: 376.05911; FTMS (ESI
+, [M+H]
+) measured value: 376.05941
Test example
Adopt attached cell mtt assay to measure the activity of the compound in the embodiment of the present invention, concrete steps are as described below.
Vitro culture human lung carcinoma cell line H460 and Breast cancer lines MDA-MB-231, Growth of Cells is to logarithmic growth after date, and collecting cell, centrifugal 5 minutes of 1000rpm, abandoning supernatant, suspends with appropriate substratum, adjustment cell concn to 3 × 10
4/ ml.By cell suspension inoculation in 96 porocyte culture plates, every hole 100 μ l, put into cell culture incubator (37 DEG C, 5%CO
2) in cultivate after 24h, add medicine to be measured (from 10
-4~ 10
2selected eight concentration in μM, for not being: 1 × 10
-4μM, 1 × 10
-3μM, 1 × 10
-2μM, 1 × 10
-1μM, 1 μM, 10 μMs, 1 × 10
1.5μM, 1 × 10
2μM).It is 0.5% that negative control group adds DMSO(final concentration), all establish 3 multiple holes for each group.After cultivating 72h in incubator, every hole adds the MTT20 μ l of 5mg/ml, places 3h in 37 DEG C.Every hole adds 150 μ lDMSO, and 37 DEG C of shaking table vibrations 5min, 492nm/620nm survey absorbancy (OD).PrismGraphpad statistical software is used to calculate IC50 value.Acquired results is summarized in following table 1.
Table 1
Adopt and similar method mentioned above, further study the antitumor action of particular compound for HepG2 cell lines, human gastric carcinoma cell line BGC 823, human cervical carcinoma cell lines Hela and human colon cancer cell strain HCT116 of the embodiment of the present invention.Experimental result shows, 31 particular compound of the embodiment of the present invention all have killing action good equally for above-mentioned cell strain.Only for embodiment 1 compound of 10 μMs, its killing action for each cell strain is as shown in table 2 below.
Table 2
Claims (10)
1. the compound shown in general formula (I) or its pharmacy acceptable salt or solvate:
Wherein,
R
1for phenyl or comprise a heteroatomic 5-6 unit heteroaryl, described heteroatoms is selected from N, S and O, above-mentioned phenyl and heteroaryl optionally replace by one or more substituting group, described substituting group is selected from the group be made up of alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group and methylene-dioxy independently of one another;
R
2and R
3meet one of following two kinds of situations: (1) R
2and R
3be selected from independently of one another by hydrogen, alkyl, benzyl, the group that aryl forms, abovementioned alkyl, benzyl, aryl optionally replace by one or more substituting group, described substituting group is selected from independently of one another by alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl, arylalkyl, heteroaryl, heterocyclic radical, alkoxyl group, cycloalkyloxy, aryloxy, alkyl sulfenyl, cycloalkylsulfanyl, artyl sulfo, alkoxy carbonyl, aryloxycarbonyl, acyl group, Thioacyl, acyloxy, amide group, urea groups, sulfinyl, alkyl sulphonyl, aryl sulfonyl, haloalkyl, carbamyl, halogen, cyano group, isocyano-, nitro, nitroso-group, thiocyanogen, isothiocyano, hydrazide group, sulfanyl, the group that sulfo group and silyl form, or (2) R
2and R
35-6 unit heterocyclic radical is jointly formed together with the two atom N connected, described heterocyclic radical optionally additionally comprises the heteroatoms that is selected from N, S and O except above-mentioned atom N, described heterocyclyl replace by one or more substituting group, described substituting group is selected from the group be made up of alkyl, alkoxy carbonyl and phenyl independently of one another,
R
4and R
5independently selected from by hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl, arylalkyl, heteroaryl, heterocyclic radical, alkoxyl group, cycloalkyloxy, aryloxy, alkyl sulfenyl, cycloalkylsulfanyl, artyl sulfo, alkoxy carbonyl, aryloxycarbonyl, sulfamyl, acyl group, Thioacyl, acyloxy, amide group, urea groups, sulfinyl, alkyl sulphonyl, aryl sulfonyl, amino, haloalkyl, carbamyl, halogen, cyano group, isocyano-, nitro, nitroso-group, thiocyanogen, isothiocyano, hydrazide group, sulfanyl, the group that sulfo group and silyl form, abovementioned alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl, arylalkyl, heteroaryl, heterocyclic radical, alkoxyl group, cycloalkyloxy, aryloxy, alkyl sulfenyl, cycloalkylsulfanyl, artyl sulfo, alkoxy carbonyl, aryloxycarbonyl, sulfamyl, acyl group, Thioacyl, acyloxy, amide group, urea groups, sulfinyl, alkyl sulphonyl, aryl sulfonyl, amino, haloalkyl optionally replace by one or more substituting group, described substituting group is selected from independently of one another by alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl, arylalkyl, heteroaryl, heterocyclic radical, alkoxyl group, cycloalkyloxy, aryloxy, alkyl sulfenyl, cycloalkylsulfanyl, artyl sulfo, alkoxy carbonyl, aryloxycarbonyl, sulfamyl, acyl group, Thioacyl, acyloxy, amide group, urea groups, sulfinyl, alkyl sulphonyl, aryl sulfonyl, amino, haloalkyl, carbamyl, halogen, cyano group, isocyano-, nitro, nitroso-group, thiocyanogen, isothiocyano, hydrazide group, sulfanyl, the group that sulfo group and silyl form.
2. compound as claimed in claim 1 or its pharmacy acceptable salt or solvate, wherein, R
1be selected from the group be made up of phenyl, furyl, thienyl and pyrryl, described phenyl, furyl, thienyl and pyrryl optionally replace by one or more substituting group, described substituting group is selected from independently of one another by C
1-4alkyl, C
1-4the group that alkoxyl group, halogen, hydroxyl, nitro, cyano group and methylene-dioxy form.
3. compound as claimed in claim 1 or 2 or its pharmacy acceptable salt or solvate, wherein, R
2and R
3meet one of following two kinds of situations: (1) R
2and R
3be selected from independently of one another by C
1-4the group that alkyl and benzyl form; Or (2) R
2and R
3jointly form Pyrrolidine base, piperidyl, morpholinyl or piperazinyl together with the two atom N connected, described Pyrrolidine base, piperidyl, morpholinyl or piperazinyl optionally replace by one or more substituting group, described substituting group is selected from C independently of one another
1-4alkyl, C
1-4the group that alkoxy carbonyl and phenyl form.
4. the compound according to any one of claim 1-3 or its pharmacy acceptable salt or solvate, wherein, R
4and R
5be hydrogen.
5. compound as claimed in claim 1 or its pharmacy acceptable salt or solvate, described compound is selected from the group be made up of following compound:
Dimethylamino dithiocarbonic acid-2-benzoyl allyl ester;
Dimethylamino dithiocarbonic acid-2-(4-anisoyl) allyl ester;
Dimethylamino dithiocarbonic acid-2-(2-anisoyl) allyl ester;
Dimethylamino dithiocarbonic acid-2-(4-hydroxy benzoyl) allyl ester;
Dimethylamino dithiocarbonic acid-2-(4-methyl benzoyl) allyl ester;
Dimethylamino dithiocarbonic acid-2-(3-methyl benzoyl) allyl ester;
Dimethylamino dithiocarbonic acid-2-(3,4-methylene-dioxy benzoyl) allyl ester;
Dimethylamino dithiocarbonic acid-2-(4-nitro benzoyl) allyl ester;
Dimethylamino dithiocarbonic acid-2-(3-nitro benzoyl) allyl ester;
Dimethylamino dithiocarbonic acid-2-(2-nitro benzoyl) allyl ester;
Dimethylamino dithiocarbonic acid-2-(4-fluoro benzoyl) allyl ester;
Dimethylamino dithiocarbonic acid-2-(3-fluoro benzoyl) allyl ester;
Dimethylamino dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester;
Dimethylamino dithiocarbonic acid-2-(2-chlorobenzene formacyl) allyl ester;
Dimethylamino dithiocarbonic acid-2-(3,4-dichloro-benzoyl base) allyl ester;
Dimethylamino dithiocarbonic acid-2-(4-cyanobenzoyl) allyl ester;
Dimethylamino dithiocarbonic acid-2-(furans-2-formyl radical) allyl ester;
Dimethylamino dithiocarbonic acid-2-(thiophene-2-formyl radical) allyl ester;
Dimethylamino dithiocarbonic acid-2-(pyrroles-2-formyl radical) allyl ester;
Dimethylamino dithiocarbonic acid-2-(pyridine-3-formyl radical) allyl ester;
Diethylamina Dithiomothyle acid-2-(4-chlorobenzene formacyl) allyl ester;
Two n-propylamine base dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl esters;
Two n-butyl amine base dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl esters;
Tetrahydro pyrrolidine-N-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester;
(R)-proline methyl ester-N-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester;
(S)-proline methyl ester-N-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester;
Piperidines-N-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester;
Morpholine-4-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester;
(2R, 6S)-thebaine-N-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester; N-phenyl-Piperazine-N-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester; And N-methylbenzylamine-N-dithiocarbonic acid-2-(4-chlorobenzene formacyl) allyl ester.
6. a pharmaceutical composition, described pharmaceutical composition comprises: compound according to any one of claim 1-5 or its pharmacy acceptable salt or solvate; And pharmaceutically acceptable carrier.
7. prepare the method for compound according to any one of claim 1-5, described method comprises the steps:
(1) in the presence of acid, formula (a) compound, paraformaldehyde, formula (b) compound and dimethylamine hydrochloride are reacted, then by pH regulator to alkalescence, obtain the reaction system containing formula (c) compound;
(2) in the presence of an inorganic base, by the described reaction system that obtains in step (1) and CS
2react with formula (d) compound, obtain the compound shown in general formula (I).
8. method as claimed in claim 7, wherein, described step (1) reacts 6-18h, preferably 12h under reflux, and described acid is acetic acid; And/or in described step (2), by described mineral alkali, formula (d) compound and CS
2mixture after stirring is added dropwise to described reaction system, and described mineral alkali is salt of wormwood.
9. the compound according to any one of claim 1-5 and pharmacy acceptable salt thereof or solvate are for the preparation of the purposes in anti-tumor drug.
10. purposes as claimed in claim 9, described tumour is selected from the group be made up of lung cancer, mammary cancer, liver cancer, cancer of the stomach, cervical cancer and colorectal carcinoma.
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Citations (5)
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US3723494A (en) * | 1971-03-24 | 1973-03-27 | American Cyanamid Co | Dithiocarbamate ester bactericides and fungicides |
US4011230A (en) * | 1973-01-12 | 1977-03-08 | American Cyanamid Company | Dithiocarbamate ester bactericides and fungicides |
CN1727332A (en) * | 2004-07-27 | 2006-02-01 | 北京大学 | Compound in category of aryl methylamino dithio formic ether, preparation method and application |
CN102180845A (en) * | 2011-03-29 | 2011-09-14 | 郑州大学 | Butenolide structure-containing benzyl amino dithio formiate compounds, and preparation method and application thereof |
CN102234271A (en) * | 2010-04-21 | 2011-11-09 | 北京大学 | Aryl (alkyl) amino dithio formate compounds, and preparation method and application thereof |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3723494A (en) * | 1971-03-24 | 1973-03-27 | American Cyanamid Co | Dithiocarbamate ester bactericides and fungicides |
US4011230A (en) * | 1973-01-12 | 1977-03-08 | American Cyanamid Company | Dithiocarbamate ester bactericides and fungicides |
CN1727332A (en) * | 2004-07-27 | 2006-02-01 | 北京大学 | Compound in category of aryl methylamino dithio formic ether, preparation method and application |
CN102234271A (en) * | 2010-04-21 | 2011-11-09 | 北京大学 | Aryl (alkyl) amino dithio formate compounds, and preparation method and application thereof |
CN102180845A (en) * | 2011-03-29 | 2011-09-14 | 郑州大学 | Butenolide structure-containing benzyl amino dithio formiate compounds, and preparation method and application thereof |
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