CN106146487A - Pyridylmethyl dithiocarbonic acid hetero-aromatic ring alkyl esters compound and its production and use - Google Patents
Pyridylmethyl dithiocarbonic acid hetero-aromatic ring alkyl esters compound and its production and use Download PDFInfo
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- CN106146487A CN106146487A CN201510204696.4A CN201510204696A CN106146487A CN 106146487 A CN106146487 A CN 106146487A CN 201510204696 A CN201510204696 A CN 201510204696A CN 106146487 A CN106146487 A CN 106146487A
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- 0 CCC[C@@]1[C@@](C)(C[C@@](C)*C2CC2)CC(C)(C)C1 Chemical compound CCC[C@@]1[C@@](C)(C[C@@](C)*C2CC2)CC(C)(C)C1 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Nc1ccccc1 Chemical compound Nc1ccccc1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The present invention relates to logical compound shown in formula (I) or its pharmaceutically acceptable salt or solvate, further relate to the preparation method of above-claimed cpd and in preparation purposes in terms of anti-tumor drug.
Description
Technical field
The present invention relates to a kind of compound with anti-tumor activity.Specifically, the present invention relates to logical formula (I) compound and preparation method thereof, further relate to the logical formula (I) compound purposes at anti-tumor aspect.
Background technology
Dithiocarbamates compound has biological activity widely, particularly anti-tumor activity.Such as Li Run great waves et al. disclose the formula of this compounds in Chinese invention patent application CN200410054686.9:
Wherein, R2Selected from-(CH2)n-R3、-CH2-R4、-(CH2)m-COR5Or-(CH2)m-COCO2R6。
The present inventor, through substantial amounts of experimentation, constantly optimizes on the basis of above-mentioned formula and transforms, it was found that a class has the novel amino dithiocarbonic acid ethyl ester compound of anti-tumor activity.
Summary of the invention
In a first aspect of the present invention, it is provided that logical compound shown in formula (I) or its pharmaceutically acceptable salt or solvate:
Wherein, n is the integer of 1-4；
Y1、Y2、Y3、Y4And Y5In at least two be the hetero atom selected from O, N and S, remaining is C atom, and Y1It is not O or S；
R1Representing the substituent group being optionally present on pyridine ring, p represents substituent R1Quantity, for the integer of 0-4, the above-mentioned substituent R being optionally present1For alkoxyl；
R represents the substituent group being optionally present on five yuan of hetero-aromatic rings; m represents the quantity of substituent R; integer for 0-3; the above-mentioned substituent R being optionally present is independently selected from the group being made up of aryl, heteroaryl, benzo, alkoxyl, cycloalkyloxy, aryloxy, alkyl sulfenyl, cycloalkylsulfanyl, artyl sulfo, acyl group, Thioacyl, acyloxy, haloalkyl, nitro, nitroso-group, sulfanyl and silicyl, and the one or more group R being optionally independently selected from lower group2It is further substituted with: alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical, cycloheteroalkylalkyl, alkoxyl, cycloalkyloxy, aryloxy, alkyl sulfenyl, cycloalkylsulfanyl, artyl sulfo, alkoxy carbonyl, aryloxycarbonyl, acyl group, Thioacyl, acyloxy, amide groups, urea groups, sulfinyl, alkyl sulphonyl, aryl sulfonyl, haloalkyl, carbamyl, halogen, cyano group, isocyano group, nitro, nitroso-group, thiocyanogen, isothiocyano, hydrazide group, sulfanyl, the group that sulfo group and silicyl are formed.
In a preferred embodiment, what the definition of logical formula (I) met in condition defined below (1) to (6) is one or more:
(1) n be the integer of 1-3, preferably n be 1 or 2；
(2) substituent R being optionally present1For C1-C4Alkoxyl, preferably methoxyl group；
(3) p be the integer of 0-3, preferably p be the integer of 0-2, more preferably p be 0 or 1；
(4) m be the integer of 0-2, more preferably m be 0 or 1；
(5)It is connected to 2 of pyridine ring, 3 or 4；And/or
(6)Y1、Y2、Y3、Y4And Y5The five yuan of hetero-aromatic rings constituted contain 2-4 the hetero atom selected from O, N and S, the most described five yuan of hetero-aromatic rings contain 1-4 atom N and 0-1 O or S atom, and the most described five yuan of hetero-aromatic rings are selected from the group being made up of azoles, isoxazole, imidazoles, thiazole, triazole, diazole, thiadiazoles and tetrazolium.
In a preferred embodiment, the substituent R being optionally present is selected from the group being made up of phenyl, benzo and the heteroaryl that comprises 5-12 annular atoms, and the one or more group R being optionally independently selected from lower group2It is further substituted with: C1-C4Alkyl, C1-C4Alkoxyl, C1-C4Haloalkyl, C1-C4Halogenated alkoxy, halogen, nitro.
In a preferred embodiment, the described heteroaryl of 5-12 annular atoms that comprises is selected from by oxazolyl, isoxazolyl, imidazole radicals, furyl, indyl, isoindolyl, pyrrole radicals, triazolyl, triazine radical, tetrazole radical, thienyl, thiazolyl, isothiazolyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl group, benzimidazolyl, benzothienyl, benzopyranyl, carbazyl, quinolyl, isoquinolyl, quinazolyl, cinnolines base, naphthyridinyl, pteridyl, purine radicals, quinolyl, thiadiazolyl group, indolizinyl, acridinyl, phenazinyl, phthalazinyl, coumarin base, Pyrazolopyridine base, pyrido pyridazinyl, pyrrolopyridinyl, imidazopyridyl, pyrazolo pyridazine base.
In a preferred embodiment, the one or more group R2It is independently selected from fluorine, chlorine, bromine, iodine, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy, nitro.
In a second aspect of the present invention, it is provided that a kind of pharmaceutical composition, described pharmaceutical composition comprises: compound described in first aspect present invention or its pharmaceutically acceptable salt or solvate；And pharmaceutically acceptable carrier.
In a third aspect of the present invention, it is provided that the method for compound described in preparation first aspect present invention, described method includes the following coupling reaction that raw material A, Carbon bisulfide and raw material B occurred in the presence of organic base, preferred triethylamine:
The most each substituent group such as first aspect present invention is defined, and X represents halogen atom.
In a fourth aspect of the present invention, it is provided that compound described in first aspect present invention and pharmaceutically acceptable salt thereof or solvate are in preparation purposes in terms of anti-tumor drug.
In a preferred embodiment, described tumor is selected from the group being made up of pulmonary carcinoma, breast carcinoma, hepatocarcinoma, gastric cancer, cervical cancer, colon cancer and epithelial cancer.
Detailed description of the invention
The term " alkyl " used in the present invention refers to only be made up of carbon atom and hydrogen atom and do not have the group of degree of unsaturation (such as double bond, three keys or ring), and it covers various possible geometrical isomerism group and stereoisomerism group.This group is connected with the remainder of molecule by singly-bound.As the limiting examples of alkyl, the group of following straight or branched can be enumerated: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl and other seven kinds of isomers thereof, n-hexyl and other 16 kinds of isomers, n-heptyl and various isomer, n-octyl and various isomer thereof, n-nonyl and various isomer thereof, positive decyl and various isomer thereof.
The term " cycloalkyl " used in the present invention refers to that the saturated non-aromatic ring system that is made up of at least 3 carbon atoms, this ring system can be monocycles, dicyclo, multi-ring, it is also possible to be condensed ring, bridged ring, volution.As the limiting examples of cycloalkyl, following group can be enumerated: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl；And condensed ring, bridged ring or the spiro-cyclic groups formed by common edge and public carbon atom by two or more above-mentioned monocycles.
The term " thiazolinyl " used in the present invention refers to there is the group formed in the case of one or more double bond in abovementioned alkyl group (in addition to methyl).
The term " cycloalkenyl group " used in the present invention refers to there is the group formed in the case of one or more double bond in above-mentioned group of naphthene base.
The term " alkynyl " used in the present invention refers to there is the group formed in the case of one or more three key in abovementioned alkyl group (in addition to methyl).
The term " alkoxyl " used in the present invention refers to that oxygen atom is connected with abovementioned alkyl and is connected to the group of molecule remainder by this oxygen atom with singly-bound, and it covers various possible geometrical isomerism group and stereoisomerism group.As the limiting examples of alkoxyl, the group of following straight or branched can be enumerated: methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy and other seven kinds of isomers thereof, positive hexyloxy and other 16 kinds of isomers thereof, epoxide in positive heptan and various isomer, n-octyloxy and various isomer thereof, positive nonyl epoxide and various isomer, n-decyloxy and various isomer thereof.
The term " aryl " used in the present invention refers to that the aromatic ring that is made up of at least 6 carbon atoms, this ring system can be monocycles, dicyclo, multi-ring, wherein dicyclo and multi-ring can be formed by singly-bound connected mode or the mode that condenses by monocycle.As the limiting examples of aryl, following group can be enumerated: phenyl, naphthyl, anthryl, phenanthryl, indenyl, pyrenyl, base, base, pentalenyl, heptalenyl, acenaphthenyl, fluorenyl, that thiazolinyl non-, fluoranthenyl, acephenanthrylenyl, benzo acenaphthenyl, triphenylenyl,Base, naphthacenyl, base, pentaphene base, pentacenyl, neighbours' phenylene, hexaphene base, hexacenyl, cool base, trinaphthylenyl, heptaphene base, heptaphenyl, pyranthrenyl, ovalenyl, xenyl, binaphthyl.
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, multi-ring, wherein dicyclo and multi-ring can be formed by singly-bound connected mode or the mode that condenses by monocycle.Limiting examples as heteroaryl, following group can be enumerated: oxazolyl, isoxazolyl, imidazole radicals, furyl, indyl, isoindolyl, pyrrole radicals, triazolyl, triazine radical, tetrazole radical, thienyl, thiazolyl, isothiazolyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl group, benzimidazolyl, benzothienyl, benzopyranyl, carbazyl, quinolyl, isoquinolyl, quinazolyl, cinnolines base, naphthyridinyl, pteridyl, purine radicals, quinolyl, thiadiazolyl group, indolizinyl, acridinyl, phenazinyl, phthalazinyl, coumarin base, Pyrazolopyridine base, pyrido pyridazinyl, pyrrolopyridinyl, imidazopyridyl, pyrazolo pyridazine base；And the group formed by singly-bound connected mode or the mode that condenses by above-mentioned heteroaryl.
The term " heterocyclic radical " used in the present invention refers to by carbon atom and the non-aromatic 3-15 unit ring system that is independently selected from that the hetero atom of N, O or S forms, this ring system can be monocycle, dicyclo or multi-ring, can also 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: azepineBase, acridinyl, 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, oxazoline base, oxazolidinyl, di azoly, 2-oxopiperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azepineBase, octahydro indyl, octahydro isoindolyl, perhydroazepineBase, piperazinyl, 4-piperidone base, piperidyl, phenothiazinyl, phenazinyl, quininuclidinyl, tetrahydro isoquinolyl, tetrahydrofuran base, THP trtrahydropyranyl, nafoxidine base, thiazolinyl, thiazolidinyl, thio-morpholinyl, thiomorpholino sulfoxide and thio-morpholinyl sulfone.
The term " aryl alkyl " 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 " heteroaryl alkyl " 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 " or " halo " that use in the present invention refer to fluorine, chlorine, bromine or iodine.
The term " benzo " used in the present invention refers to that phenyl ring is fused to the situation of two adjacent carbon atoms of the cyclic group being replaced with two adjacent carbon atoms.
When being been described by substituent group in the present invention, " optionally " vocabulary used shows that substituent group can exist, it is also possible to do not exist.Such as, " substituent group being optionally present on five yuan of hetero-aromatic rings " represents that these five yuan of hetero-aromatic rings both can be substituted, it is also possible to be unsubstituted.
Pharmaceutical composition in the present invention contains the compound described in first aspect present invention as active component.In addition, this pharmaceutical composition also can comprise pharmaceutically acceptable carrier, include but not limited to: water, saline solution, alcohol, Polyethylene Glycol, polyhydroxy-ethoxylated Oleum Ricini, Oleum Arachidis hypogaeae semen, olive oil, gelatin, lactose, Gypsum Fibrosum powder, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, Talcum, gelatin, agar, pectin, arabic gum, stearic acid or the low alkyl ether of cellulose, silicic acid, fatty acid, fatty acid amine, glycerine monofatty ester and two glyceride, tetramethylolmethane fat acid ether, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.This pharmaceutical composition also can comprise one or more pharmaceutically acceptable adjuvant, wetting agent, emulsifying agent, suspending agent, preservative, osmotic pressure regulator, buffer agent, sweeting agent, correctives, coloring agent or above-mentioned combination in any.
The pharmaceutical composition of the present invention can make any type of preparation, such as capsule, tablet, aerosol, solution, suspending agent, sugar-coat agent, lozenge, syrup, Emulsion, ointment, unguentum, injection, powder, granule, paste, slow releasing agent, foam.According to route of administration, the medicine of the present invention can make drug-delivery preparation in oral Preparation, nasal administration preparation, formulation for pulmonary delivery, buccal preparation, transdermal formulations, intradermal administration preparation, percutaneous drug administration preparation, Parenteral formulations, rectally preparation, reservoir type drug-delivery preparation, preparation for intravenous administration, urethra, intramuscular administration preparation, intranasal formulation, dosing eyes preparation, epidural administration preparation or local administration preparation.
" cancer " in the present invention includes various cancer as known in the art, includes but not limited to: pulmonary carcinoma, hepatocarcinoma, gastric cancer, cervical cancer, colon cancer, breast carcinoma, leukemia, non-small cell carcinoma, carcinoma of prostate or tired melanoma, the brain cancer, skin carcinoma, osteocarcinoma, lymphatic cancer, nasopharyngeal carcinoma, laryngeal carcinoma, esophageal carcinoma, duodenal carcinoma, carcinoma of small intestine, colorectal cancer, cancer of pancreas, renal carcinoma, genital cancer, thyroid carcinoma.
Embodiment
It follows that illustrated the present invention in further detail by embodiment, but the present invention is not limited only to these embodiments.
In an exemplary embodiment, the compound of the present invention is synthesized by following universal method, and the most each substituent group is as defined in logical formula (I), and X represents halogen atom, and organic base is triethylamine (TEA).
Those skilled in the art are after reading herein, it is possible to be readily ascertained by the condition needed for this type of coupling reaction.In an exemplary compou nd synthesis, the process of above-mentioned coupling reaction is as described below.
The synthesis of [synthesis example] 3-pyridylmethyl dithiocarbonic acid-(3-hydroxyl) propyl ester
By 3-pyridyl-methanamine (108mg, 1mmol), triethylamine (100mg, 1mmol) add in 10ml water, after stirring 5 minutes under room temperature, be added dropwise over Carbon bisulfide (91mg, 1.2mmol), after stirring 5 minutes under room temperature, add 3-bromopropyl alcohol (138mg, 1mmol), react 2 hours, extracting by ethyl acetate (15mL × 3), merge organic facies, anhydrous sodium sulfate is dried, filter, concentrating, silica gel column chromatography separates, and obtains white solid 191mg, yield 79%, fusing point: 70-71 DEG C.
In above-mentioned synthesis example and following example, all source chemicals are commercially available chemical pure or analytical reagent, the most treated direct use.Other related experiment instrument condition is as follows:
Column chromatography: Haiyang Chemical Plant, Qingdao's silica gel 200-300 mesh.
Melting point apparatus: X-4 type micro-meldometer.
Mass spectrograph: APEX IV type Fourier transform high resolution mass spectrum.
Nuclear magnetic resonance analyser: Bruker-400MHz
Colour developing: iodine, ultraviolet.
Embodiment 1:3-pyridylmethyl dithiocarbonic acid (2-(5-phenyl-1,3,4-thiadiazoles-2-base)) ethyl ester
The preparation of N '-(3-chlorine propiono) benzoyl hydrazine: by benzoyl hydrazine (0.68g; 5mmol) it is dissolved in 50mL TEA, is stirred at room temperature down, be added dropwise over chlorpromazine chloride (0.76g; ethyl acetate solution 6mmol); after dropping, being heated to reflux 3 hours, reaction is completely; it is cooled to room temperature; solvent is evaporated off, and obtaining N '-(3-chlorine propiono) benzoyl hydrazine is white solid 0.49g, yield 44%.
2-chloroethyl-5-phenyl-1, the preparation of 3,4-thiadiazoles: by N '-(3-chlorine propiono) benzoyl hydrazine (0.45g; 2mmol) add to 40mL toluene, pump drainage air, backfilled with nitrogen; add lawesson reagent (1.21g; 3mmol), react 4 hours at 115 DEG C, solvent is evaporated off; separate through silica gel column chromatography; obtain light green solid, 0.36g, yield 54%.
The preparation of target compound: this target compound is with 2-chloroethyl-5-phenyl-1, and 3,4-thiadiazoles are the raw material B in universal method, prepared by the synthetic method with reference to [synthesis example], obtain white solid, yield 32%, fusing point 138-142 DEG C.
1H NMR(400MHz,CDCl3): δ 3.56-3.60 (t, J=6.8Hz, 2H), (3.77-3.81 t, J=6.8Hz, 2H), 4.97 (s, 2H), 7.27-7.30 (m, 1H), 7.48-7.49 (m, 3H), 7.70-7.73 (m, 2H), 7.94-7.95 (m, 2H), 8.56-8.60 (m, 2H).
HRMS(ESI+)m/z calcd for C17H16N4S3(M+H)+,373.0537,found373.0637.
Embodiment 2:3-pyridylmethyl dithiocarbonic acid (2-(benzothiazole-2-base)) ethyl ester
The preparation of 3-bromine tetrahydroform acid methyl ester hydrochloride salt: bromopropionitrile (2.66g, 20mmol) and methanol (1.28g, 40mmol) are added to 100mL ether, it is stirred at room temperature down, it is slowly introducing dry salt acid gas, after 6 hours, has a large amount of white crystal to produce, stopped reaction, filtering, solid absolute ether washes twice, and dries, obtain white crystal 2.08g, yield 63%.
The preparation of 2-(2-bromoethyl) benzothiazole: by 3-bromine tetrahydroform acid methyl ester hydrochloride salt (0.16g, 1mmol) with o-aminophenol (0.15g, 1.3mmol) add to 20mL ethanol, react 6 hours at 80 DEG C, stopped reaction, filters, and filtrate is concentrated to give 2-(2-bromoethyl) benzothiazole crude product, yellow oil, quantitative yield.
The preparation of target compound: this target compound with 2-(2-bromoethyl) benzothiazole as universal method in raw material B, prepare with reference to the synthetic method of [synthesis example], obtain white solid, yield 57%, fusing point 116-117 DEG C.
1H NMR(400MHz,CDCl3): δ 3.38-3.41 (t, J=6.8Hz, 2H), (3.80-3.84 t, J=6.8Hz, 2H), 4.95 (s, 2H), 7.25-7.33 (m, 3H), 7.48-7.70 (m, 3H), 8.17 (bs, 1H), 8.50-8.53 (m, 2H).
13C NMR(100MHz,CDCl3):δ28.96,31.81,48.16,110.46,119.63,123.68,124.29,124.84,136.05,149.19,149.37,150.86,164.88,197.75.
Anal.Cald for C16H15N3OS2:C,58.33；H,4.59；N,12.76；Found:C,58.08；H,4.69；N,12.50.
Embodiment 3:3-pyridylmethyl dithiocarbonic acid (2-(benzotriazole-2-base)) ethyl ester
2-(2-bromoethyl)-2H-benzo [1,2,3] preparation of triazole: by benzotriazole (1.19g, 10mmol), 1,2-Bromofume (1.86g, 10mmol), potassium hydroxide (1.12g, 20mmol) and tetrabutylammonium iodide (0.37g, 1mmol) add to 40mL DMF, react overnight at 90 DEG C.It is cooled to room temperature, adds 40mL water, extract by ethyl acetate (30mL × 3), merge organic facies, successively with water and saturated common salt washing, anhydrous sodium sulfate is dried, and filters, concentrate, silica gel column chromatography separates to obtain 2-(2-bromoethyl)-2H-benzo [1,2,3] triazole 0.72g, white solid, yield 23%.
The preparation of target compound: this target compound is with 2-(2-bromoethyl)-2H-benzo [1,2,3] triazole for raw material, and prepared by the synthetic method with reference to [synthesis example], obtain white solid, yield 63%, fusing point 147-148 DEG C.
1H NMR (400MHz, DMSO): δ 3.78-3.81 (t, J=6.8Hz, 2H), 3.82-3.84 (t, J=6.8Hz, 2H), 4.95 (m, 2H), 7.34-7.55 (m, 4H), 7.64-7.83 (m, 2H), 8.48-8.50 (m, 2H), (10.58 bs, 1H).
13C NMR(100MHz,DMSO):δ34.09,46.97,47.77,110.99,119.59,123.95,124.43,127.74,133.18,135.93,148.95,196.41.
HRMS(ESI+)m/z calcd for C15H15N5S2(M+H)+,330.0769,found330.0847.
Embodiment 4:3-pyridylmethyl dithiocarbonic acid (2-(3-phenyl-1,2,4-diazole-5-base)) ethyl ester
The preparation of N-hydroxy benzenes carboximidamide: by benzonitrile (1.03g, 10mmol), triethylamine (4.0g, 40mmol) with oxammonium hydrochloride. (1.39g, 20mmol) add to 60mL ethanol, react 12 hours at 90 DEG C, cooling, is evaporated off solvent, adds 20mL water, extract by ethyl acetate (20mL × 3), merging organic facies, anhydrous sodium sulfate is dried, and filters, concentrate, silica gel column chromatography separates to obtain nitrogen-hydroxy benzenes carboximidamide 1.31g, yellow oil, yield 96%.
The preparation of N-[(chlorine propiono) epoxide] benzimide amide: by N-hydroxy benzenes carboximidamide (0.63g; 5mmol) with triethylamine (0.5g; 5mmol) add to 30mL ethyl acetate; it is stirred at room temperature down; it is slowly dropped into chlorpromazine chloride (0.63g, 5mmol), finishes; reaction 2 hours is continued under room temperature; reaction completely, adds 20mL water, extraction; collect ester layer; anhydrous sodium sulfate is dried, and filters, is concentrated to give N-[(chlorine propiono) epoxide] benzimide crude amide; yellow oil, quantitative yield.
5-chloroethyl-3-phenyl-1; 2; the preparation of 4-diazole: N-[(chlorine propiono) epoxide] benzimide amide (0.23g, 1mmol) and potassium carbonate (0.28g, 2mmol) are added to 10mL 1; in 4-dioxane; reflux 6 hours, cooling, solvent is evaporated off; add 20mL water; extracting by ethyl acetate (20mL × 3), merge organic facies, anhydrous sodium sulfate is dried; filter; it is concentrated to give 5-chloroethyl-3-phenyl-1,2,4-diazole crude products; yellow oil, quantitative yield.
The preparation of target compound: this target compound is raw material with 5-chloroethyl-3-phenyl-1,2,4-diazole, prepared by the synthetic method with reference to [synthesis example], obtain white solid, yield 43%, fusing point 118-120 DEG C.
1H NMR(400MHz,CDCl3): δ 3.40-3.43 (t, J=6.8Hz, 2H), (3.80-3.84 t, J=6.8Hz, 2H), 4.95 (m, 2H), 7.25-7.28 (m, 1H), 7.45-7.51 (m, 3H), 7.68-7.70 (m, 1H), 8.06-8.08 (m, 2H), 8.53 (m, 2H).
13C NMR(100MHz,CDCl3):δ27.09,31.65,48.26,123.68,127.44,128.83,131.19,136.01,149.42,168.36,177.74,197.32.
Anal.Cald for C17H16N4OS2:C,57.28；H,4.52；N,15.72；Found:C,57.28；H,4.68；N,15.24.
Embodiment 5:3-pyridylmethyl dithiocarbonic acid-(2-(5-phenyl-1,3,4-diazole-2-base)) ethyl ester
2-bromoethyl-5-phenyl-1, the preparation of 3,4-diazole: by 3-bromine tetrahydroform acid methyl ester hydrochloride salt (0.16g, 1mmol) add to 20mL dichloromethane, under ice bath, be dividedly in some parts benzoyl hydrazine (0.16g, 1.3mmol), finish, reflux 6 hours, cooling, filters, is concentrated to give 2-bromoethyl-5-phenyl-1,3,4-diazole crude product, yellow oil, quantitative yield.
The preparation of target compound: this target compound is with 2-bromoethyl-5-phenyl-1, and 3,4-diazole are as the raw material B in universal method, and prepared by the synthetic method with reference to [synthesis example], obtain white solid, yield 62%, fusing point 134-136 DEG C.
1H NMR(400MHz,CDCl3): δ 3.35-3.38 (t, J=6.8Hz, 2H), 3.76-3.79 (t, J=6.8Hz, 2H), 4.95 (d, J=5.2Hz, 2H), 7.19-7.21 (m, 1H), 7.45-7.51 (m, 3H), 7.68-7.70 (m, 1H), 7.98-8.00 (m, 2H), 8.39-8.49 (m, 2H), 9.11 (bs, 1H).
13C NMR(100MHz,CDCl3):δ26.08,31.43,48.18,123.62,126.85,129.04,131.75,132.45,136.24,148.85,149.40,165.02,165.07,197.39.
Anal.Cald for C17H16N4OS2:C,57.28；H,4.52；N,15.72；Found:C,57.32；H,4.64；N,15.66.
Embodiment 6:3-pyridylmethyl dithiocarbonic acid (2-(benzimidazolyl-2 radicals-yl)) ethyl ester
The preparation of 2-(2-bromoethyl) benzimidazole: o-phenylenediamine (0.22g, 2mmol) and bromo-propionic acid (0.61g, 4mmol) are added to 15mL concentrated hydrochloric acid, reflux 6 hours, cooling, is slowly added to saturated sodium carbonate solution and is neutralized to pH=7, extracts by ethyl acetate (20mL × 3), merge organic facies, anhydrous sodium sulfate is dried, and filters, is concentrated to give 2-(2-bromoethyl) benzimidazole crude product, yellow oil, quantitative yield.
The preparation of target compound: this target compound is using 2-(2-bromoethyl) benzimidazole as the raw material B in universal method, and prepared by the synthetic method with reference to [synthesis example], obtain white solid, yield 33%, fusing point 149-151 DEG C.
1H NMR (400MHz, DMSO): δ 3.20-3.24 (t, J=6.8Hz, 2H), 3.67-3.71 (t, J=6.8Hz, 2H), 4.85 (d, J=5.2Hz, 2H), 7.13-7.15 (m, 2H), 7.35-7.38 (m, 1H), 7.48-7.50 (m, 2H), 7.68-7.70 (m, 1H), 8.47-8.52 (m, 2H), 10.54 (bs, 1H).
13C NMR(100MHz,DMSO):δ23.71,29.00,47.56,122.02,123.98,148.88,149.52,153.44,197.41.
Anal.Cald for C16H16N4S2:C,58.51；H,4.91；N,17.06；Found:C,58.64； H,4.58；N,16.69.
Embodiment 7:3-pyridylmethyl dithiocarbonic acid (2-(1H-TETRAZOLE-5-base)) ethyl ester
The preparation of 5-(2-bromoethyl)-1H-TETRAZOLE: β-bromopropionitrile (0.27g, 2mmol), Hydrazoic acid,sodium salt (0.16g, 2.5mmol) with ammonium chloride (0.13g, 2.5mmol) add to 20mL and be dried in DMF, react 6 hours at 100 DEG C, it is cooled to room temperature, reactant liquor is poured in 20mL mixture of ice and water, extract by ethyl acetate (20mL × 3), merge organic facies, anhydrous sodium sulfate is dried, and filters, and concentrates, silica gel column chromatography separates, obtain 5-(2-bromoethyl)-1H-TETRAZOLE 0.13g, pale yellow oil, yield 37%.
The preparation of target compound: this target compound is using 5-(2-bromoethyl)-1H-TETRAZOLE as the raw material B in universal method, and prepared by the synthetic method with reference to [synthesis example], obtain faint yellow solid, yield 49%, fusing point 121-124 DEG C.
1H NMR (400MHz, MeOD): δ 3.32-3.43 (t, J=6.8Hz, 2H), 3.69-3.72 (t, J=6.8Hz, 2H), 4.94 (s, 2H), 7.41-7.44 (m, 1H), 7.82-7.84 (m, 1H), (8.45-8.53 m, 2H).
13C NMR(100MHz,MeOD):δ23.77,31.81,47.01,123.88,134.01,136.77,147.40,148.19,155.64,197.56.
HRMS(ESI+)m/z calcd for C10H12N6S2(M+H)+,281.0565,found281.0640.
Embodiment 8:3-pyridylmethyl dithiocarbonic acid (2-(benzothiazole-2-base)) ethyl ester
The preparation of 2-(2-bromoethyl) benzothiazole: by near amino thiophenols (0.25g, 2mmol) add to 30mL ethyl acetate, under room temperature with triethylamine (0.20g, 2mmol), dropwise instill bromopropionitrile (0.26g, 2mmol), after dropping, room temperature reaction 6 hours, cooling, it is concentrated to give 2-(2-bromoethyl) benzothiazole crude product, the most purified, it is directly used in the next step.
The preparation of target compound: this target compound is using 2-(2-bromoethyl) benzothiazole as the raw material B in universal method, and prepared by the synthetic method with reference to [synthesis example], obtain white solid, yield 19%, fusing point 96-99 DEG C.
1H NMR(400MHz,DMSO):δ3.60-3.72(m,4H)4.85(s,2H),7.32-7.69(m,4H),8.48-8.53(m,2H),10.61(bs,1H).
13C NMR(100MHz,DMSO):δ32.04,34.12,47.78,110.70,118.78,123.99,124.80,125.10,133.24,141.72,148.95,149.56,151.77,164.16,196.49.
HRMS(ESI+)m/z calcd for C16H15N3S3(M+H)+,346.0428,found346.0522.
Embodiment 9:4-pyridylmethyl dithiocarbonic acid (2-(benzothiazole-2-base)) ethyl ester
This target compound is with 4-pyridyl-methanamine as raw material, prepared by the synthetic route with reference to embodiment 2, obtains white solid, yield 58%, fusing point 89-90 DEG C.
1H NMR (400MHz, DMSO): δ 3.33-3.37 (t, J=6.8Hz, 2H), 3.70-3.73 (t, J=6.8Hz, 2H), 4.85 (s, 2H), 7.22-7.383 (m, 4H), 7.66-7.71 (m, 2H), (8.49-8.50 m, 2H).
13C NMR(100MHz,DMSO):δ28.70,31.37,48.63,110.06,119.81,122.72,124.88,125.40,141.16,146.71,150.02,150.70,165.42,197.58.
Anal.Cald for C16H15N3OS2:C,58.33；H,4.59；N,12.76；Found:C,58.09；H,4.61；N,12.47.
Embodiment 10:4-pyridylmethyl dithiocarbonic acid (2-(5-phenyl-1,3,4-diazole-2-base)) ethyl ester
This target compound is with 4-pyridyl-methanamine as raw material, prepared by the synthetic route with reference to embodiment 5, obtains white solid, yield 65%, fusing point 131-132 DEG C.
1H NMR (400MHz, DMSO): δ 3.33-3.36 (t, J=6.8Hz, 2H), 3.69-3.73 (t, J=6.8Hz, 2H), 4.85 (s, 2H), 7.21-7.23 (m, 2H), 7.59-7.61 (m, 3H), 7.97-7.99 (m, 2H), (8.47-8.49 m, 2H).
13C NMR(100MHz,CDCl3):δ25.89,31.14,48.68,122.70,123.87,126.90,129.89,132.39,146.67,149.99,164.60,165.58,197.46.
Anal.Cald for C17H16N4OS2:C,57.28；H,4.52；N,15.72；Found:C,57.27；H,4.65；N,15.48.
Embodiment 11:3-pyridine ethylamino dithiocarbonic acid (2-(2-benzothiazole-2-base)) ethyl ester
This target compound is with 3-PEA as raw material, prepared by the synthetic route with reference to embodiment 2, obtains white solid, yield 59%, fusing point 123-124 DEG C.
1H NMR (400MHz, DMSO): δ 2.90-2.93 (t, J=7.2Hz, 2H), (3.29-3.32 t, J=6.8Hz, 2H), (3.65-3.69 t, J=6.8Hz, 2H), (3.79-3.82 t, J=7.2Hz, 2H), 7.31-7.37 (m, 3H), 7.66-7.71 (m, 3H), 8.43 (m, 2H).
13C NMR(100MHz,DMSO):δ28.78,30.81,31.09,47.73,111.06,119.79,124.03,124.86,125.38,134.89,141.17,147.90,150.06,150.69,165.46,195.99.
Anal.Cald for C17H17N3OS2:C,59.45；H,4.99；N,12.23；Found:C,59.17；H,4.94；N,12.47.
Embodiment 12:3-pyridine ethylamino dithiocarbonic acid-(2-(5-phenyl-1,3,4-diazole-2-base)) ethyl ester
This target compound is with 3-PEA as raw material, prepared by the synthetic route with reference to embodiment 5, obtains white solid, yield 59%, fusing point 124-126 DEG C.
1H NMR (400MHz, DMSO): δ 2.89-2.92 (t, J=6.8Hz, 2H), 3.30-3.32 (t, J=6.8Hz, 2H), 3.65-3.69 (t, J=6.8Hz, 2H), 3.77-3.81 (t, J=6.8Hz, 2H), 7.29-7.32 (m, 1H), 7.57-7.63 (m, 3H), 7.97-7.99 (m, 2H), 8.43 (m, 2H).
13C NMR(100MHz,CDCl3):δ25.97,30.79,30.85,47.78,123.86,123.97,126.90,129.87,132.36,134.81,136.70,147.99,150.17,164.58,165.60,195.85.
Anal.Cald for C18H18N4OS2:C,58.35；H,4.90；N,15.12；Found:C,58.17；H,5.01；N,14.87.
Embodiment 13:2-methoxyl group-3-pyridylmethyl dithiocarbonic acid (2-(5-phenyl-1,3,4-diazole-2-base)) ethyl ester
This target compound is with (2-methoxypyridine-3-base) methylamine and 2-chloroethyl-5-phenyl-1, and 3,4-diazole are raw material, and prepared by the synthetic method with reference to [synthesis example], obtain white solid, yield 31%, fusing point 109-113 DEG C.
1H NMR(400MHz,CDCl3): δ 3.71-3.80 (m, 4H), 4.01 (s, 3H), 4.92 (d, J=5.6Hz, 2H), 7.19-7.21 (m, 1H), 6.87-6.90 (m, 1H), 7.50-7.57 (m, 4H), (8.04-8.09 m, 3H).
13C NMR(100MHz,CDCl3):δ26.12,31.51,46.24,53.65,116.91,123.87,126.87,129.03,131.67,138.81,146.57,165.05,196.72.
HRMS(ESI+)m/z calcd for C18H18N4O2S2(M+H)+,387.0871,found387.0955.
Embodiment 14:3-pyridylmethyl dithiocarbonic acid (2-(5-(2-fluorophenyl)-1,3,4-diazole-2-base)) ethyl ester
2-bromoethyl-5-(2-fluorophenyl)-1, the preparation of 3,4-diazole: by 3-bromine tetrahydroform acid methyl ester hydrochloride salt (0.16g, 1mmol) add to 20mL dichloromethane, under ice bath, be dividedly in some parts 2-fluorobenzoyl hydrazine (0.18g, 1.3mmol), finish, reflux 6 hours, cooling, filters, is concentrated to give 2-bromoethyl-5-(2-fluorophenyl)-1,3,4-diazole crude product, yellow oil, quantitative yield.
The preparation of target compound: this target compound is with 3-pyridyl-methanamine and 2-chloroethyl-5-phenyl-1, and 3,4-diazole are as the raw material A in universal method and B, prepared by the synthetic method with reference to [synthesis example], obtain white solid, yield 67%, fusing point 108-110 DEG C.
1H NMR (400MHz, DMSO): δ 3.35-3.38 (t, J=6.8Hz, 2H), 3.67-3.71 (t, J=6.8Hz, 2H), 4.85 (d, J=5.2Hz, 2H), 7.36-8.00 (m, 6H), 8.47-8.52 (m, 2H), 10.62 (bs, 1H).
13C NMR(100MHz,DMSO):δ25.88,31.06,47.70,110.00,117.76,124.03,125.81,130.03,133.31,134.55,134.63,136.10,148.80,149.41,161.14,165.80,196.84.
Anal.Cald for C17H15FN4OS2:C,54.53；H,4.04；N,14.96；Found:C,54.26；H,4.11；N,14.69.
Embodiment 15:3-pyridylmethyl dithiocarbonic acid { 2-[5-(4-methoxyphenyl)-1,3,4-diazole-2-base] } ethyl ester
This target compound is with 4-methoxybenzoyl hydrazine and 2-chloroethyl-5-phenyl-1, and 3,4-diazole are raw material, prepared by the synthetic route with reference to embodiment 14, obtain white solid, yield 70%, fusing point 149-151 DEG C.
1H NMR (400MHz, DMSO): δ 3.30-3.33 (t, J=6.8Hz, 2H), 3.67-3.71 (t, J=6.8Hz, 2H), 3.85 (s, 3H), 4.85 (d, J=5.2Hz, 2H), 7.13-7.37 (m, 3H), 7.67-7.69 (m, 1H), 7.90-7.93 (m, 2H), 8.47-8.52 (m, 2H), 10.59 (bs, 1H).
13C NMR(100MHz,DMSO):δ25.88,31.10,47.70,55.98,115.32,116.27,123.98,128.73,133.26,135.96,148.92,149.53,162.40,164.46,164.99,196.85.
Anal.Cald for C18H18N4O2S2:C,55.94；H,4.69；N,14.50；Found:C, 56.20；H,4.71；N,14.94.
Embodiment 16:3-pyridylmethyl dithiocarbonic acid { 2-[5-(4-trifluoromethyl)-1,3,4-diazole-2-base] } ethyl ester
This target compound is with 4-trifluoromethylbenzoyl hydrazine and 2-chloroethyl-5-phenyl-1, and 3,4-diazole are prepared as raw material, the synthetic route with reference to embodiment 14, obtain white solid, yield 65%, fusing point 145-146 DEG C.
1H NMR (400MHz, DMSO): δ 3.36-3.39 (t, J=6.8Hz, 2H), 3.69-3.73 (t, J=6.8Hz, 2H), 4.85 (d, J=5.2Hz, 2H), 7.33-7.37 (m, 1H), 7.67-7.69 (m, 1H), 7.90-7.93 (m, 2H), 8.18-8.20 (m, 2H), 8.47-8.51 (m, 2H), 10.60 (bs, 1H).
13C NMR(100MHz,DMSO):δ26.00,31.01,47.72,123.95,126.91,127.78,133.23,135.94,148.92,149.54,163.57,166.26,196.83.
Anal.Cald for C18H15F3N4OS2:C,50.93；H,3.56；N,13.20；Found:C,50.81；H,4.01；N,12.91.
Embodiment 17:3-pyridylmethyl dithiocarbonic acid { 2-[5-(4-chlorphenyl)-1,3,4-diazole-2-base] } ethyl ester
The preparation of 4-chlorobenzoyl hydrazine: by 4-chlorobenzoic acid (3.2g, 20mmol) it is dissolved in 30mL methanol, thionyl chloride 2mL it is slowly added dropwise under ice bath, drip and finish, heat 50 DEG C of reaction 4h, cooling, excessive methanol is evaporated off, add appropriate saturated sodium bicarbonate solution, be extracted with ethyl acetate (15mL × 3), be spin-dried for standby；Previous step crude product is dissolved in 30mL ethanol, adds 80% hydrazine hydrate 4mL, heating reflux reaction 4h, cooling, separate out white solid, sucking filtration is dried, and obtains white solid 2.5g, yield 74%.
2-bromoethyl-5-(4-chlorphenyl)-1,3, the preparation of 4-diazole: by 3-bromo-propionic acid (0.46g, 3mmol) it is dissolved in 5mL phosphorus oxychloride, add 4-chlorobenzoyl hydrazine (0.47g, 3mmol) oil bath 80 DEG C heating 6h, cooling, reactant liquor is poured slowly in frozen water, hydro-oxidation sodium solution regulation to pH 7-8, dichloromethane extraction (20mL × 3), merge organic layer, anhydrous sodium sulfate is dried, and is spin-dried for solvent and obtains yellow solid 0.31g, crude yield 36%.
The preparation of target compound: by 3-aminomethyl-pyridine (0.1mL, 1mmol) it is dissolved in 20mL acetone, add anhydrous phosphoric acid potassium (0.43g, 2mmol), 5mL water, Carbon bisulfide (0.15mL, 2mmol), 2-bromoethyl-5 (4-chlorphenyl)-1,3 is added after stirring at normal temperature 30min, 4-diazole (0.29g, 1mmol), 50 DEG C of reaction 6h, cooling are heated, reactant liquor is layered, isolate organic layer, silica gel column chromatography (petroleum ether: ethyl acetate=1:1), obtain white solid 0.25g, yield 64%, fusing point 126-127 DEG C.
1H NMR (400MHz, DMSO) δ: 10.59 (t, J=5.3Hz, 1H), 8.52 (d, J=1.6Hz, 1H), 8.48 (dd, J=4.7,1.4Hz, 1H), 8.07 8.01 (m, 2H), 7.69 (d, J=7.8Hz, 1H), 7.45 (t, J=8.9Hz, 2H), 7.36 (dd, J=7.7,4.8Hz, 1H), (4.85 d, J=5.5Hz, 2H), (3.70 t, J=6.9Hz, 2H), 3.34 (t, J=6.9Hz, 2H).
13C NMR(101MHz,DMSO)δ:196.84,165.60,163.82,149.55,148.93,135.93,133.24,129.63,129.54,123.95,120.57,117.24,117.01,47.72,31.06,25.92.
HRMS:Calcd for C17H16ClN4OS2(M++ H): 391.91020, Found:391.91023.
Embodiment 18:3-pyridylmethyl dithiocarbonic acid { 2-[5-(4-nitrobenzophenone)-1,3,4-diazole-2-base] } ethyl ester
The preparation of 4-nitrobenzoyl hydrazides: in addition to using 4-nitrobenzoic acid and replacing 4-chlorobenzoic acid, with reference to embodiment 17, obtains white solid, yield 64%.
2-bromoethyl-5-(4-nitrobenzophenone)-1, the preparation of 3,4-diazole: with reference to embodiment 17, obtain white solid, yield 58%.
The preparation of target compound: with reference to embodiment 17, obtain white solid, yield 37%, fusing point 157-158 DEG C.
1H NMR (400MHz, DMSO) δ: 10.62 (s, 1H), 8.48 (dd, J=15.4,11.6Hz, 2H), 8.40 (t, J=7.7Hz, 2H), 8.24 8.19 (m, 2H), 7.69 (d, J=7.3Hz, 1H), 7.43 7.32 (m, 1H), 4.84 (d, J=5.1Hz, 2H), 3.72 (t, J=6.6Hz, 2H), 3.39 (t, J=6.6Hz, 2H).
13C NMR(101MHz,DMSO)δ:196.80,166.57,163.26,149.44,148.82,136.06,133.27,129.36,128.24,128.18,125.06,123.98,47.71,31.00,26.04.
HRMS:Calcd for C17H16N5O3S2(M++ H): 402.06891, Found:402.06957.
Embodiment 19:3-pyridylmethyl dithiocarbonic acid { 2-[5-(pyrroles's-3-base)-1,3,4-diazole-2-base] } ethyl ester
The preparation of pyrroles's-3-formylhydrazine: in addition to using pyrroles's-3-formic acid and replacing 4-chlorobenzoic acid, with reference to embodiment 17, obtains white solid, yield 60%.
2-bromoethyl-5-(3-pyrrole radicals)-1, the preparation of 3,4-diazole: with reference to embodiment 17, obtain white solid, yield 25%.
The preparation of target compound: with reference to embodiment 17, obtain white solid, yield 73%, fusing point 167-168 DEG C.
1nullH NMR(400MHz,DMSO)δ:12.16(s,1H),10.60(t,J=5.5Hz,1H),8.53(d,J=1.6Hz,1H),8.48(dd,J=4.7,1.3Hz,1H),7.69(d,J=7.9Hz,1H),7.37(dd,J=7.8,4.8Hz,1H),7.07(dd,J=3.9,2.6Hz,1H),6.78(d,J=3.5Hz,1H),6.25(dd,J=5.8,2.4Hz,1H),4.86(d,J=5.5Hz,2H),3.66(t,J=6.9Hz,2H),3.28(t,J=6.9Hz,2H).
13C NMR(101MHz,DMSO)δ:196.83,163.61,159.77,149.55,148.93,135.98,133.26,123.99,123.90,115.79,112.25,110.32,47.71,31.14,25.73.
HRMS:Calcd for C15H16N5OS2(M++ H): 346.07908, Found:346.07884.
Embodiment 20:3-pyridylmethyl dithiocarbonic acid { 2-[5-(furan-2-base)-1,3,4-diazole-2-base] } ethyl ester
The preparation of furan-2-formylhydrazine: in addition to using furan-2-formic acid and replacing 4-chlorobenzoic acid, with reference to embodiment 17, obtains white solid, yield 65%.
2-bromoethyl-5-(2-furyl)-1, the preparation of 3,4-diazole: with reference to embodiment 17, obtain pale yellow oil, yield 49%.
The preparation of target compound: with reference to embodiment 17, obtain white solid, yield 85%, fusing point 155-156 DEG C.
1H NMR (400MHz, DMSO) δ: 10.58 (t, J=5.3Hz, 1H), 8.52 (d, J=1.5Hz, 1H), 8.48 (dd, J=4.7,1.2Hz, 1H), 8.04 (d, J=1.0Hz, 1H), 7.68 (d, J=7.8Hz, 1H), 7.37 (dd, J=7.7,4.8Hz, 1H), 7.31 (d, J=3.5Hz, 1H), (6.79 dd, J=3.5,1.7Hz, 1H), (4.85 d, J=5.5Hz, 2H), (3.67 t, J=6.9Hz, 2H), 3.32 (t, J=6.9Hz, 2H).
13C NMR(101MHz,DMSO)δ:196.79,164.85,157.52,149.55,148.93,147.28,139.10,135.93,133.23,123.96,114.73,113.01,47.72,31.05,25.76.
HRMS:Calcd for C15H15N4O2S2(M++ H): 347.06309, Found:347.06367.
Embodiment 21:3-pyridylmethyl dithiocarbonic acid { 2-[5-(thiene-3-yl)-1,3,4-diazole-2-base] } ethyl ester
The preparation of thiophene-3-formylhydrazine: in addition to using thiophene-3-formic acid and replacing 4-chlorobenzoic acid, with reference to embodiment 17, obtains white solid, yield 61%.
2-bromoethyl-5-(3-thienyl)-1, the preparation of 3,4-diazole: with reference to embodiment 17, obtain yellow oil, yield 30%.
The preparation of LP-05 target compound: with reference to embodiment 17, obtain white solid, yield 89%, fusing point 141-142 DEG C.
1H NMR (400MHz, DMSO) δ: 10.60 (s, 1H), 8.52 (s, 1H), 8.48 (d, J=4.5Hz, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.68 (d, J=7.6Hz, 1H), 7.60 (d, J=4.9Hz, 1H), 7.40 7.33 (m, 1H), 4.85 (d, J=5.2Hz, 2H), 3.68 (t, J=6.7Hz, 2H), 3.32 (t, J=6.8Hz, 2H).
13C NMR(101MHz,DMSO)δ:196.81,164.85,161.48,149.54,148.93,135.95,133.25,129.48,128.93,125.99,124.97,123.98,47.71,31.08,25.84.
HRMS:Calcd for C15H15N4OS3(M++ H): 363.04025, Found:363.03961.
Embodiment 22:3-pyridylmethyl dithiocarbonic acid { 2-[5-(thiophene-2-base)-1,3,4-diazole-2-base] } ethyl ester
The preparation of thiophene-2-formylhydrazine: in addition to using thiophene-2-carboxylic acid and replacing 4-chlorobenzoic acid, with reference to embodiment 17, obtains white solid, yield 60%.
2-bromoethyl-5-(2-thienyl)-1, the preparation of 3,4-diazole: with reference to embodiment 17, obtain yellow oil, yield 23%.
The preparation of target compound: with reference to embodiment 17, obtain white solid, yield 92%, fusing point 145-146 DEG C.
1H NMR (400MHz, DMSO) δ: 10.59 (t, J=5.4Hz, 1H), 8.52 (d, J=1.7Hz, 1H), 8.48 (dd, J=4.7,1.5Hz, 1H), 7.92 (dd, J=5.0,1.2Hz, 1H), 7.78 (dt, J=6.4,3.2Hz, 1H), 7.71 7.66 (m, 1H), 7.38 7.34 (m, 1H), 7.28 (dd, J=5.0,3.7Hz, 1H), (4.85 d, J=5.6Hz, 2H), (3.68 t, J=6.9Hz, 2H), 3.32 (t, J=6.9Hz, 2H).
13C NMR(101MHz,DMSO)δ:196.82,165.00,160.87,149.55,148.93,135.94,133.24,131.81,130.51,129.15,124.83,123.96,47.73,31.07,25.84.
HRMS:Calcd for C15H15N4OS3(M++ H): 363.04025, Found:363.04064.
Embodiment 23:3-pyridylmethyl dithiocarbonic acid { 2-[5-(5-methyl isoxazole-3-base)-1,3,4-diazole-2-base] } ethyl ester
The preparation of 5-methyl-isoxazole-3-formylhydrazine: 5-methyl-isoxazole-3-Ethyl formate (3.1g, 20mmol) is dissolved in 30mL ethanol, adds 80% hydrazine hydrate 4mL, heating reflux reaction 24h, cooling, separate out white solid, sucking filtration is dried, and obtains white solid 2.1g, yield 75%.
2-bromoethyl-5-[3-(5-methyl isoxazolyl)]-1, the preparation of 3,4-diazole: with reference to embodiment 17, obtain white solid, yield 36%.
The preparation of target compound: with reference to embodiment 17, obtain white solid, yield 75%, fusing point 149-150 DEG C.
1H NMR (400MHz, DMSO) δ: 10.56 (s, 1H), 8.47 (s, 1H), 8.43 (d, J=3.4Hz, 1H), 7.64 (d, J=7.2Hz, 1H), 7.37 7.28 (m, 1H), 6.84 (s, 1H), 4.80 (d, J=4.7Hz, 2H), 3.63 (t, J=6.4Hz, 2H), 3.33 (t, J=6.3Hz, 2H), 2.49 (s, 3H).
13C NMR(101MHz,DMSO)δ:196.74,172.78,166.61,157.39,150.44,149.55,148.92,135.95,133.22,123.96,101.59,47.74,30.96,25.90,12.27.
HRMS:Calcd for C15H16N5O2S2(M++ H): 362.07399, Found:362.07377.
Embodiment 24:3-pyridylmethyl dithiocarbonic acid { 2-[5-(pyridin-3-yl)-1,3,4-diazole-2-base] } ethyl ester
The preparation of pyridine-3-formylhydrazine: in addition to using Nicotinicum Acidum and replacing 4-chlorobenzoic acid, with reference to embodiment 17, obtains white solid, yield 74%.
2-bromoethyl-5-(3-pyridine radicals)-1, the preparation of 3,4-diazole: with reference to embodiment 17, obtain white solid, yield 20%.
The preparation of target compound: with reference to embodiment 17, obtain white solid, yield 75%, fusing point 151-152 DEG C.
1H NMR (400MHz, DMSO): δ 10.64 (s, 1H), 9.17 (s, 1H), 8.81 (d, J=3.7Hz, 1H), 8.54 (s, 1H), 8.50 (d, J=3.7Hz, 1H), 8.35 (d, J=7.8Hz, 1H), 7.71 (d, J=7.5Hz, 1H), 7.64 (dd, J=7.7,4.8Hz, 1H), 7.37 (dd, J=7.4,4.8Hz, 1H), (4.87 d, J=5.2Hz, 2H), (3.74 t, J=6.7Hz, 2H), 3.39 (t, J=6.6Hz, 2H).
13C NMR(101MHz,DMSO):δ196.82,166.02,162.81,152.87,149.53,148.90,147.57,135.97,134.48,133.23,124.78,123.95,120.44,47.74,31.04,25.98.
HRMS:Calcd for C16H16N5OS2(M++ H): 358.07908, Found:358.07826.
Embodiment 25:3-pyridylmethyl dithiocarbonic acid { 2-[5-(6-chloropyridine-3-base)-1,3,4-diazole-2-base] } ethyl ester
The preparation of 6-chloropyridine-3-formylhydrazine: in addition to using 6-chloropyridine-3-formic acid and replacing 4-chlorobenzoic acid, with reference to embodiment 17, obtains white solid, yield 73%.
2-bromoethyl-5-[3-(6-chloropyridine base)-1, the preparation of 3,4-diazole: with reference to embodiment 17, obtain white solid, yield 15%.
The preparation of target compound: with reference to embodiment 17, obtain white solid, yield 75%.
HRMS:Calcd for C16H15ClN5OS2(M++ H): 392.04011, Found:392.04021.
Embodiment 26:3-pyridylmethyl dithiocarbonic acid { 2-[5-(pyrazine-2-base)-1,3,4-diazole-2-base] } ethyl ester
The preparation of pyrazine-2-formylhydrazine: in addition to using pyrazine-2-formic acid and replacing 4-chlorobenzoic acid, with reference to embodiment 17, obtains white solid, yield 64%.
2-bromoethyl-5-(2-pyrazinyl)-1, the preparation of 3,4-diazole: with reference to embodiment 17, obtain yellow oil.
The preparation of target compound: with reference to embodiment 17, obtain white solid, yield 88%, fusing point 143-144 DEG C.
1H NMR (400MHz, DMSO) δ: 10.60 (s, 1H), 9.35 (s, 1H), 8.88 (d, J=5.8Hz, 2H), 8.52 (s, 1H), 8.48 (d, J=3.6Hz, 1H), 7.69 (d, J=7.6Hz, 1H), 7.37 (dd, J=7.3,4.9Hz, 1H), 4.85 (d, J=5.3Hz, 2H), 3.71 (t, J=6.8Hz, 2H), 3.41 (t, J=6.8Hz, 2H).
13C NMR(101MHz,DMSO)δ:196.77,166.87,162.55,149.54,148.92,147.43,145.49,143.96,139.51,135.96,133.23,123.97,47.73,31.03,26.00.
HRMS:Calcd for C15H16N6OS2(M++ H): 359.07433, Found:359.07482.
Embodiment 27:3-pyridylmethyl dithiocarbonic acid { 2-[5-(quinoline-6-base)-1,3,4-diazole-2-base] } ethyl ester
The preparation of quinoline-6-formylhydrazine: in addition to using quinoline-6-formic acid and replacing 4-chlorobenzoic acid, with reference to embodiment 17, obtains white solid, yield 67%.
2-bromoethyl-5-(6-quinolyl)-1, the preparation of 3,4-diazole: with reference to embodiment 17, obtain white solid, yield 43%.
The preparation of target compound: with reference to embodiment 17, obtain white solid, yield 54%, fusing point 165-166 DEG C.
1H NMR (400MHz, DMSO): δ 10.63 (s, 1H), 9.01 (d, J=3.6Hz, 1H), 8.65 (s, 1H), 8.58 (d, J=8.2Hz, 1H), 8.52 (s, 1H), 8.47 (d, J=4.4Hz, 1H), 8.29 (d, J=8.8Hz, 1H), 8.18 (d, J=8.8Hz, 1H), 7.73 7.61 (m, 2H), 7.35 (dd, J=7.6,4.8Hz, 1H), 4.85 (s, 2H), 3.74 (t, J=6.7Hz, 2H), 3.40 (t, J=6.8Hz, 2H).
13C NMR(101MHz,DMSO):δ196.81,165.93,164.29,152.92,149.55,149.07,148.92,137.48,135.95,133.24,130.82,128.17,127.61,126.87,123.95,123.11,121.70,47.73,31.09,26.02.
HRMS:Calcd for C20H18N5OS2(M++ H): 408.09473, Found:408.09520.
Embodiment 28:3-pyridylmethyl dithiocarbonic acid-{ 2-[5-(quinoline-2-base)-1,3,4-diazole-2-base] } ethyl ester
The preparation of quinoline-2-formylhydrazine: in addition to using quinoline-2-formic acid and replacing 4-chlorobenzoic acid, with reference to embodiment 17, obtains white solid, yield 75%.
2-bromoethyl-5-(2-quinolyl)-1, the preparation of 3,4-diazole: with reference to embodiment 17, obtain white solid, yield 21%.
The preparation of target compound: with reference to embodiment 17, obtain white solid, yield 81%, fusing point 139-140 DEG C.
1nullH NMR(400MHz,DMSO)δ:10.63(s,1H),8.63(d,J=8.5Hz,1H),8.53(s,1H),8.48(d,J=4.4Hz,1H),8.27(d,J=8.5Hz,1H),8.18(d,J=8.4Hz,1H),8.12(d,J=7.8Hz,1H),7.90(t,J=7.5Hz,1H),7.75(t,J=7.5Hz,1H),7.71(d,J=7.6Hz,1H),7.41–7.34(m,1H),4.86(d,J=5.3Hz,2H),3.73(t,J=6.8Hz,2H),3.44(t,J=6.8Hz,2H).
13C NMR(101MHz,DMSO)δ:196.81,166.84,164.39,149.52,148.88,147.62,143.36,138.52,136.02,133.27,131.37,129.77,128.85,128.78,128.68,123.98,119.93,47.74,31.12,26.07.
HRMS:Calcd for C20H18N5OS2(M++ H): 408.09473, Found:408.09504.
Embodiment 29:3-pyridylmethyl dithiocarbonic acid { 2-[5-(benzothiophene-2-base)-1,3,4-diazole-2-base] } ethyl ester
The preparation of benzothiophene-2-formylhydrazine: in addition to using benzothiophene-2-formic acid and replacing 4-chlorobenzoic acid, with reference to embodiment 17, obtains white solid, yield 52%.
2-bromoethyl-5-(2-quinolyl)-1, the preparation of 3,4-diazole: with reference to embodiment 17, obtain white solid, yield 48%.
The preparation of target compound: with reference to embodiment 17, obtain white solid, yield 53%, fusing point 249-250 DEG C.
1H NMR (400MHz, DMSO) δ: 10.66 (s, 1H), 8.52 (d, J=1.7Hz, 1H), 8.47 (dd, J=4.7,1.5Hz, 1H), 8.12 (d, J=7.8Hz, 1H), 8.04 (dd, J=6.9,1.8Hz, 1H), 7.71 7.67 (m, 1H), 7.52 (dd, J=7.2,5.6Hz, 2H), 7.36 (dd, J=7.8,4.8Hz, 1H), 4.85 (s, 2H), 3.70 (t, J=6.9Hz, 2H), 3.40 3.31 (m, 2H).
13C NMR(101MHz,DMSO)δ:196.67,165.71,160.98,149.57,148.88,140.39,139.28,135.96,133.29,127.35,125.89,125.74,124.67,123.93,123.35,47.71,31.03,25.96.
HRMS:Calcd for C19H17N4OS3(M++ H): 413.05590, Found:413.05648
Test example 1
Use attached cell mtt assay to measure the activity of the compound in the embodiment of the present invention, comprise the following steps that described.
In vitro culture breast carcinoma cell strain SKBr-3, breast carcinoma cell strain MDA-MB-468, colon cancer cell line HCT116 and hepatoma cell strain Bel7402.Cell grows to logarithmic growth after date, collects cell, and 1000rpm is centrifuged 5 minutes, and abandoning supernatant suspends by appropriate culture medium, adjusts cell concentration to 3 × 104/ml.By in cell suspension inoculation to 96 porocyte culture plates, every hole 100 μ l, put into cell culture incubator (37 DEG C, 5%CO2After cultivating 24h in), add medicine to be measured (from 10-4～102Selected eight concentration in μM, for not being: 1 × 10-4μM、1×10-3μM、1×10-2μM、1×10-1μM、1μM、10μM、1×101 . 5μM、1×102μM).Negative control group adds DMSO (final concentration of 0.5%), and each group is all provided with 3 multiple holes.After cultivating 72h in incubator, every hole adds the MTT 20 μ l of 5mg/ml, places 3h in 37 DEG C.Every hole adds 150 μ l DMSO, and 37 DEG C of shaking tables vibration 5min, 492nm/620nm survey absorbance (OD).Use Prism Graphpad statistical software calculate IC50 value (by μM in terms of).Acquired results is summarized in table 1 below.
Table 1
| Compound | SKBr-3 | MDA-MB-468 | HCT116 | Bel7402 |
| Embodiment 1 | 1.005 | 5.861 | 9.969 | 13.48 |
| Embodiment 2 | 0.828 | 4.307 | 4.167 | 2.887 |
| Embodiment 3 | 0.989 | 11.61 | 11.33 | 2.664 |
| Embodiment 4 | 1.294 | 10.06 | 12.44 | 2.808 |
| Embodiment 5 | 0.584 | 4.299 | 8.207 | 1.233 |
| Embodiment 6 | 1.691 | 11.53 | 11.71 | 9.300 |
| Embodiment 7 | >100 | >100 | >100 | 57.67 |
| Embodiment 8 | 1.397 | 9.711 | 10.19 | 2.567 |
| Embodiment 9 | 5.227 | 3.849 | 17.89 | 3.863 |
| Embodiment 10 | 8.248 | 5.013 | 26.39 | 5.209 |
| Embodiment 11 | 1.878 | 3.997 | 4.621 | 6.842 |
| Embodiment 12 | 3.408 | 4.684 | 5.355 | 2.613 |
| Embodiment 13 | 0.3825 | 9.447 | 13.65 | 3.293 |
Test example 2: in addition to extra employing Prostatic cancer cell lines KB, use the method identical with test example 1 that the activity of the compound in remaining embodiment is tested (with Lapatinib as positive control).Acquired results is summarized in table 2 below.
Table 2
| Compound | SKBr-3 | MDA-MB-468 | HCT116 | Bel7402 | KB |
| Embodiment 14 | 5.541 | 1.667 | 5.382 | 3.427 | 4.699 |
| Embodiment 15 | 1.545 | 5.228 | 15.10 | 6.341 | 2.968 |
| Embodiment 16 | 1.222 | 5.492 | 12.96 | 4.089 | 2.408 |
| Embodiment 17 | 1.265 | 3.783 | 10.22 | 1.978 | 0.8699 |
| Embodiment 18 | 1.844 | 3.134 | 9.050 | 4.601 | 1.546 |
| Embodiment 19 | 1.173 | 5.074 | 9.478 | 2.047 | 0.8257 |
| Embodiment 20 | 1.596 | 3.586 | 7.293 | 3.329 | 0.8100 |
| Embodiment 21 | 1.237 | 5.868 | 10.24 | 3.263 | 1.037 |
| Embodiment 22 | 1.346 | 5.443 | 11.15 | 3.414 | 1.071 |
| Embodiment 23 | 1.687 | 3.356 | 9.114 | 6.149 | 1.738 |
| Embodiment 24 | 1.377 | 2.597 | 9.012 | 3.168 | 0.8012 |
| Embodiment 25 | 1.250 | 4.732 | 10.35 | 1.550 | 0.9424 |
| Embodiment 26 | 1.439 | 3.881 | 7.588 | 1.716 | 1.290 |
| Embodiment 27 | 1.791 | 4.205 | 8.299 | 1.696 | 0.8563 |
| Embodiment 28 | 1.953 | 13.21 | 13.35 | 3.500 | 0.7932 |
| Embodiment 29 | 6.892 | 3.345 | 44.50 | 6.772 | 5.329 |
| Lapatinib | 126.4 | 17.97 | 4.714 | 7.884 | 3.502 |
Claims (10)
1. lead to the compound shown in formula (I) or its pharmaceutically acceptable salt or solvate:
Wherein, n is the integer of 1-4；
Y1、Y2、Y3、Y4And Y5In at least two be the hetero atom selected from O, N and S, remaining is C atom, and Y1It is not O or S；
R1Representing the substituent group being optionally present on pyridine ring, p represents substituent R1Quantity, for the integer of 0-4, the above-mentioned substituent R being optionally present1For alkoxyl；
R represents the substituent group being optionally present on five yuan of hetero-aromatic rings; m represents the quantity of substituent R; integer for 0-3; the above-mentioned substituent R being optionally present is independently selected from the group being made up of aryl, heteroaryl, benzo, alkoxyl, cycloalkyloxy, aryloxy, alkyl sulfenyl, cycloalkylsulfanyl, artyl sulfo, acyl group, Thioacyl, acyloxy, haloalkyl, nitro, nitroso-group, sulfanyl and silicyl, and the one or more group R being optionally independently selected from lower group2It is further substituted with: alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical, cycloheteroalkylalkyl, alkoxyl, cycloalkyloxy, aryloxy, alkyl sulfenyl, cycloalkylsulfanyl, artyl sulfo, alkoxy carbonyl, aryloxycarbonyl, acyl group, Thioacyl, acyloxy, amide groups, urea groups, sulfinyl, alkyl sulphonyl, aryl sulfonyl, haloalkyl, carbamyl, halogen, cyano group, isocyano group, nitro, nitroso-group, thiocyanogen, isothiocyano, hydrazide group, sulfanyl, the group that sulfo group and silicyl are formed.
2. compound as claimed in claim 1 or its pharmaceutically acceptable salt or solvate, wherein, it is one or more that the definition of logical formula (I) meets in condition defined below (1) to (6):
(1) n be the integer of 1-3, preferably n be 1 or 2；
(2) substituent R being optionally present1For C1-C4Alkoxyl, preferably methoxyl group；
(3) p be the integer of 0-3, preferably p be the integer of 0-2, more preferably p be 0 or 1；
(4) m be the integer of 0-2, more preferably m be 0 or 1；
(5)It is connected to 2 of pyridine ring, 3 or 4；And/or
(6)Y1、Y2、Y3、Y4And Y5The five yuan of hetero-aromatic rings constituted contain 2-4 the hetero atom selected from O, N and S, the most described five yuan of hetero-aromatic rings contain 1-4 atom N and 0-1 O or S atom, and the most described five yuan of hetero-aromatic rings are selected from the group being made up of azoles, isoxazole, imidazoles, thiazole, triazole, diazole, thiadiazoles and tetrazolium.
3. compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt or solvate, wherein, the substituent R being optionally present is selected from the group being made up of phenyl, benzo and the heteroaryl that comprises 5-12 annular atoms, and the one or more group R being optionally independently selected from lower group2It is further substituted with: C1-C4Alkyl, C1-C4Alkoxyl, C1-C4Haloalkyl, C1-C4Halogenated alkoxy, halogen, nitro.
null4. compound as claimed in claim 3 or its pharmaceutically acceptable salt or solvate，Wherein，The described heteroaryl of 5-12 annular atoms that comprises is selected from by oxazolyl、Isoxazolyl、Imidazole radicals、Furyl、Indyl、Isoindolyl、Pyrrole radicals、Triazolyl、Triazine radical、Tetrazole radical、Thienyl、Thiazolyl、Isothiazolyl、Pyridine radicals、Pyrimidine radicals、Pyrazinyl、Pyridazinyl、Benzofuranyl、Benzothiazolyl、Benzoxazolyl group、Benzimidazolyl、Benzothienyl、Benzopyranyl、Carbazyl、Quinolyl、Isoquinolyl、Quinazolyl、Cinnolines base、Naphthyridinyl、Pteridyl、Purine radicals、Quinolyl、Thiadiazolyl group、Indolizinyl、Acridinyl、Phenazinyl、Phthalazinyl、Coumarin base、Pyrazolopyridine base、Pyrido pyridazinyl、Pyrrolopyridinyl、Imidazopyridyl、Pyrazolo pyridazine base.
5. compound as described in claim 3 or 4 or its pharmaceutically acceptable salt or solvate, wherein, the one or more group R2It is independently selected from fluorine, chlorine, bromine, iodine, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy, nitro.
6. compound as claimed in claim 1 or its pharmaceutically acceptable salt or solvate, wherein, described compound is selected from the group being made up of to (29) following compound (1):
(1) 3-pyridylmethyl dithiocarbonic acid (2-(5-phenyl-1,3,4-thiadiazoles-2-base)) ethyl ester；
(2) 3-pyridylmethyl dithiocarbonic acid (2-(benzothiazole-2-base)) ethyl ester；
(3) 3-pyridylmethyl dithiocarbonic acid (2-(benzotriazole-2-base)) ethyl ester；
(4) 3-pyridylmethyl dithiocarbonic acid (2-(3-phenyl-1,2,4-diazole-5-base)) ethyl ester；
(5) 3-pyridylmethyl dithiocarbonic acid-(2-(5-phenyl-1,3,4-diazole-2-base)) ethyl ester；
(6) 3-pyridylmethyl dithiocarbonic acid (2-(benzimidazolyl-2 radicals-yl)) ethyl ester；
(7) 3-pyridylmethyl dithiocarbonic acid (2-(1H-TETRAZOLE-5-base)) ethyl ester；
(8) 3-pyridylmethyl dithiocarbonic acid (2-(benzothiazole-2-base)) ethyl ester；
(9) 4-pyridylmethyl dithiocarbonic acid (2-(benzothiazole-2-base)) ethyl ester；
(10) 4-pyridylmethyl dithiocarbonic acid (2-(5-phenyl-1,3,4-diazole-2-base)) ethyl ester；
(11) 3-pyridine ethylamino dithiocarbonic acid (2-(2-benzothiazole-2-base)) ethyl ester；
(12) 3-pyridine ethylamino dithiocarbonic acid-(2-(5-phenyl-1,3,4-diazole-2-base)) ethyl ester；
(13) 2-methoxyl group-3-pyridylmethyl dithiocarbonic acid (2-(5-phenyl-1,3,4-diazole-2-base)) ethyl ester；
(14) 3-pyridylmethyl dithiocarbonic acid (2-(5-(2-fluorophenyl)-1,3,4-diazole-2-base)) ethyl ester；
(15) 3-pyridylmethyl dithiocarbonic acid { 2-[5-(4-methoxyphenyl)-1,3,4-diazole-2-base] } ethyl ester；
(16) 3-pyridylmethyl dithiocarbonic acid { 2-[5-(4-trifluoromethyl)-1,3,4-diazole-2-base] } ethyl ester；
(17) 3-pyridylmethyl dithiocarbonic acid { 2-[5-(4-chlorphenyl)-1,3,4-diazole-2-base] } ethyl ester；
(18) 3-pyridylmethyl dithiocarbonic acid { 2-[5-(4-nitrobenzophenone)-1,3,4-diazole-2-base] } ethyl ester；
(19) 3-pyridylmethyl dithiocarbonic acid { 2-[5-(pyrroles's-3-base)-1,3,4-diazole-2-base] } ethyl ester；
(20) 3-pyridylmethyl dithiocarbonic acid { 2-[5-(furan-2-base)-1,3,4-diazole-2-base] } ethyl ester；
(21) 3-pyridylmethyl dithiocarbonic acid { 2-[5-(thiene-3-yl)-1,3,4-diazole-2-base] } ethyl ester；
(22) 3-pyridylmethyl dithiocarbonic acid { 2-[5-(thiophene-2-base)-1,3,4-diazole-2-base] } ethyl ester；
(23) 3-pyridylmethyl dithiocarbonic acid { 2-[5-(5-methyl isoxazole-3-base)-1,3,4-diazole-2-base] } ethyl ester；
(24) 3-pyridylmethyl dithiocarbonic acid { 2-[5-(pyridin-3-yl)-1,3,4-diazole-2-base] } ethyl ester；
(25) 3-pyridylmethyl dithiocarbonic acid { 2-[5-(6-chloropyridine-3-base)-1,3,4-diazole-2-base] } ethyl ester；
(26) 3-pyridylmethyl dithiocarbonic acid { 2-[5-(pyrazine-2-base)-1,3,4-diazole-2-base] } ethyl ester；
(27) 3-pyridylmethyl dithiocarbonic acid { 2-[5-(quinoline-6-base)-1,3,4-diazole-2-base] } ethyl ester；
(28) 3-pyridylmethyl dithiocarbonic acid-{ 2-[5-(quinoline-2-base)-1,3,4-diazole-2-base] } ethyl ester；
(29) 3-pyridylmethyl dithiocarbonic acid { 2-[5-(benzothiophene-2-base)-1,3,4-diazole-2-base] } ethyl ester.
7. a pharmaceutical composition, described pharmaceutical composition comprises: compound according to any one of claim 1-6 or its pharmaceutically acceptable salt or solvate；And pharmaceutically acceptable carrier.
8. the method for compound according to any one of preparation claim 1-6, described method includes the following coupling reaction that raw material A, Carbon bisulfide and raw material B occurred in the presence of organic base, preferred triethylamine:
The most each substituent group is as defined in logical formula (I), and X represents halogen atom.
9. compound according to any one of claim 1-6 and pharmaceutically acceptable salt thereof or solvate are in preparation purposes in terms of anti-tumor drug.
10. purposes as claimed in claim 9, described tumor is selected from the group being made up of pulmonary carcinoma, breast carcinoma, hepatocarcinoma, gastric cancer, cervical cancer, colon cancer and epithelial cancer.
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| CN106966978A (en) * | 2017-03-05 | 2017-07-21 | 北京化工大学 | A kind of amides compound and its production and use |
| WO2018161476A1 (en) * | 2017-03-05 | 2018-09-13 | 北京化工大学 | Amide compound and preparation method and use thereof |
| CN106966978B (en) * | 2017-03-05 | 2020-06-26 | 北京化工大学 | Amide compound and preparation method and application thereof |
| CN113024514A (en) * | 2021-03-26 | 2021-06-25 | 北京大学 | Aminodithioformate compound, preparation method thereof, pharmaceutical composition and application thereof |
| WO2022199367A1 (en) * | 2021-03-26 | 2022-09-29 | 北京大学 | Dithiocarbamate compound and preparation method therefor, pharmaceutical composition, and applications |
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