CN106146487B - Pyridylmethyl dithiocarbonic acid hetero-aromatic ring alkyl esters compound and its preparation method and application - Google Patents
Pyridylmethyl dithiocarbonic acid hetero-aromatic ring alkyl esters compound and its preparation method and application Download PDFInfo
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- 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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- 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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- 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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- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The present invention relates to logical formula (I) compound represented or its pharmaceutically acceptable salt or solvate, the preparation method and its purposes in terms of preparing for anti-tumor drug that further relate to above compound.
Description
Technical field
The present invention relates to a kind of compounds with anti-tumor activity.Specifically, the present invention relates to logical formula (I) compounds
And preparation method thereof, logical formula (I) compound is further related in the purposes of anti-tumor aspect.
Background technique
Dithiocarbamates compound has extensive bioactivity, especially anti-tumor activity.Such as Li Run
Great waves et al. disclose the general formula of such compound in Chinese invention patent application CN200410054686.9:
Wherein, R2Selected from-(CH2)n-R3、-CH2-R4、-(CH2)m-COR5Or-(CH2)m-COCO2R6。
The present inventor passes through a large amount of experimental study, carried out on the basis of above-mentioned general formula continuous optimization and
Transformation, it was found that a kind of novel amino dithiocarbonic acid ethyl ester compound with anti-tumor activity.
Summary of the invention
In the first aspect of the present invention, logical formula (I) compound represented or its pharmaceutically acceptable salt or molten are provided
Agent compound:
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；
R1Indicate that optionally existing substituent group, p indicate substituent R on pyridine ring1Quantity, be 0-4 integer, above-mentioned
Select existing substituent R1For alkoxy；
R indicates that optionally existing substituent group, m indicate the quantity of substituent R on five yuan of hetero-aromatic rings, is the integer of 0-3, above-mentioned
The substituent R being optionally present be independently selected from by aryl, heteroaryl, benzo, alkoxy, cycloalkyloxy, aryloxy,
Alkyl sulfenyl, cycloalkylsulfanyl, artyl sulfo, acyl group, Thioacyl, acyloxy, halogenated alkyl, nitro, nitroso, sulfane
Group composed by base and silicyl, and the one or more group R being optionally independently selected from the following group2Further take
Generation: alkyl, naphthenic base, alkenyl, cycloalkenyl, alkynyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, heterocycle, heterocycle
Alkyl, alkoxy, cycloalkyloxy, aryloxy, alkyl sulfenyl, cycloalkylsulfanyl, artyl sulfo, alkoxy carbonyl, aryl oxide
It is base carbonyl, acyl group, Thioacyl, acyloxy, amide groups, urea groups, sulfinyl, alkyl sulphonyl, aryl sulfonyl, halogenated
Alkyl, carbamyl, halogen, cyano, isocyano group, nitro, nitroso, thiocyanogen, isothiocyano, hydrazide group, sulfanyl, sulfo group
With group composed by silicyl.
In a preferred embodiment, the definition for leading to formula (I) meets one or more of condition defined below (1) into (6)
:
(1) n is the integer of 1-3, and preferably n is 1 or 2；
(2) substituent R being optionally present1For C1-C4Alkoxy, preferably methoxyl group；
(3) p is the integer of 0-3, and preferably p is the integer of 0-2, and more preferable p is 0 or 1；
(4) m is the integer of 0-2, and more preferable m is 0 or 1；
(5)It is connected to 2,3 or 4 of pyridine ring；And/or
(6)Y1、Y2、Y3、Y4And Y5The five yuan of hetero-aromatic rings constituted contain the 2-4 hetero atoms for being selected from O, N and S, preferably institute
State five yuan of hetero-aromatic rings and contain 1-4 N atom and 0-1 O or S atom, more preferable five yuan of hetero-aromatic rings be selected from by oxazole,
Group composed by isoxazole, imidazoles, thiazole, triazole, oxadiazoles, thiadiazoles and tetrazolium.
In a preferred embodiment, the substituent R being optionally present is selected from by phenyl, benzo and comprising 5-12 ring original
Group composed by the heteroaryl of son, and the one or more group R being optionally independently selected from the following group2It is further substituted with:
C1-C4Alkyl, C1-C4Alkoxy, C1-C4Halogenated alkyl, C1-C4Halogenated alkoxy, halogen, nitro.
In a preferred embodiment, the heteroaryl comprising 5-12 annular atom is selected from by oxazolyl, isoxazole
It is base, imidazole radicals, furyl, indyl, isoindolyl, pyrrole radicals, triazolyl, triazine radical, tetrazole radical, thienyl, thiazolyl, different
Thiazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazole
Base, benzothienyl, benzopyranyl, carbazyl, quinolyl, isoquinolyl, quinazolyl, cinnoline base, naphthyridines base, pteridine
Base, purine radicals, quinoxaline base, thiadiazolyl group, indolizine base, acridinyl, phenazinyl, phthalazinyl, cumarin base, Pyrazolopyridine
Base, pyrido pyridazinyl, pyrrolopyridinyl, imidazopyridyl, pyrazolo pyridazine base.
In a preferred embodiment, one or more of group R2It is independently selected from fluorine, chlorine, bromine, iodine, first
Base, methoxyl group, trifluoromethyl, trifluoromethoxy, nitro.
In the second aspect of the present invention, a kind of pharmaceutical composition is provided, described pharmaceutical composition includes: the present invention first
The aspect compound or its pharmaceutically acceptable salt or solvate；And pharmaceutically acceptable carrier.
In the third aspect of the present invention, the method for compound described in preparation first aspect present invention, the method are provided
Including in the presence of organic base, preferably triethylamine coupling reaction is occurred for raw material A, carbon disulfide and raw material B as follows:
Wherein each substituent group such as first aspect present invention is defined, and X indicates halogen atom.
In the fourth aspect of the present invention, compound described in first aspect present invention and its pharmaceutically acceptable is provided
The purposes of salt or solvate in terms of preparing for anti-tumor drug.
In a preferred embodiment, the tumour is selected from by lung cancer, breast cancer, liver cancer, gastric cancer, cervical carcinoma, colon
Group composed by cancer and epithelioma.
Specific embodiment
Term used in the present invention " alkyl ", which refers to, to be only made of carbon atom and hydrogen atom and not to have degree of unsaturation
The group of (such as double bond, three keys or ring) covers various possible geometrical isomerism groups and alloisomerism group.The group
It is connected by singly-bound with the rest part of molecule.As the non-limiting example of alkyl, following linear chain or branched chain can be enumerated
Group: methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl and its it is other seven kinds it is different
Structure body, n-hexyl and its other 16 kinds of isomers, n-heptyl and its various isomers, n-octyl and its various isomers, just
Nonyl and its various isomers, positive decyl and its various isomers.
Term used in the present invention " naphthenic base " refers to the non-aromatic ring system of saturation being made of at least three carbon atom, should
Ring system can be monocycle, bicyclic, polycyclic, be also possible to condensed ring, bridged ring, loop coil.It, can be with as the non-limiting example of naphthenic base
Enumerate following group: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl；And by two
Condensed ring, bridged ring or the spiro-cyclic groups that a or multiple above-mentioned monocycles are formed by common edge and public carbon atom.
Term used in the present invention " alkenyl " refers to that in abovementioned alkyl group, there are one or more (in addition to methyl)
Group is formed by the case where double bond.
Term used in the present invention " cycloalkenyl " refers to has one or more double bonds in above-mentioned group of naphthene base
In the case of be formed by group.
Term used in the present invention " alkynyl " refers to that in abovementioned alkyl group, there are one or more (in addition to methyl)
Group is formed by the case where three key.
Term used in the present invention " alkoxy " refer to oxygen atom be connected with abovementioned alkyl and by the oxygen atom with
Singly-bound is connected to the group of molecule rest part, covers various possible geometrical isomerism groups and alloisomerism group.Make
For the non-limiting example of alkoxy, the group of following linear chain or branched chain can be enumerated: methoxyl group, ethyoxyl, positive propoxy, different
Propoxyl group, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy and its other seven kinds of isomers, just own oxygen
Base and its other 16 kinds of isomers, positive oxygroup in heptan and its various isomers, n-octyloxy and its various isomers, positive nonyl epoxide
And its various isomers, n-decyloxy and its various isomers.
Term used in the present invention " aryl " refers to the aromatic ring being made of at least six carbon atom, which can be with
It is monocycle, bicyclic, polycyclic, wherein bicyclic and polycyclic can be formed by monocycle by singly-bound connection type or condensed mode.As
The non-limiting example of aryl, can enumerate following group: phenyl, naphthalene, anthryl, phenanthryl, indenyl, pyrenyl, base, azulenyl,
Pentalene base, heptalene base, acenaphthenyl, fluorenyl, that non-alkenyl, firefly anthryl, vinegar phenanthrene alkenyl, benzo acenaphthenyl, triphenylene,Base,
Aphthacene base, Pi base, pentaphene base, pentacene, four adjacent phenylenes, hexaphene base, hexacene base, cool base, three naphthylenes, heptaphene
Base, heptacene base, pyrrole anthryl, ovalene base, xenyl, binaphthyl.
Term used in the present invention " heteroaryl ", which refers to, has one or more hetero atoms independently selected from N, O or S
5-14 member heteroaromatic ring system, which can be monocycle, bicyclic, polycyclic, wherein bicyclic and polycyclic can be led to by monocycle
It crosses singly-bound connection type or condensed mode is formed.As the non-limiting example of heteroaryl, following group: oxazole can be enumerated
Base, isoxazolyl, imidazole radicals, furyl, indyl, isoindolyl, pyrrole radicals, triazolyl, triazine radical, tetrazole radical, thienyl,
Thiazolyl, isothiazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl,
Benzimidazolyl, benzothienyl, benzopyranyl, carbazyl, quinolyl, isoquinolyl, quinazolyl, cinnoline base, naphthyridines
Base, pteridyl, purine radicals, quinoxaline base, thiadiazolyl group, indolizine base, acridinyl, phenazinyl, phthalazinyl, cumarin base, pyrrole
Azoles and pyridyl group, pyrido pyridazinyl, pyrrolopyridinyl, imidazopyridyl, pyrazolo pyridazine base；And by above-mentioned heteroaryl
The group that base is formed by singly-bound connection type or condensed mode.
Term used in the present invention " heterocycle " refers to by carbon atom and is independently selected from what the hetero atom of N, O or S formed
Non-aromatic 3-15 member ring system, the ring system can be monocycle, bicyclic or polycyclic, be also possible to condensed ring, bridged ring, loop coil, and can
Optionally comprising one or more double bonds.As the non-limiting example of heterocycle, following group: azepine can be enumerated
Base, acridinyl, benzodioxole group, benzo dioxacyclohexyl, chromanyl, dioxolanyl, two
Oxygen phospha cyclopenta, Decahydroisoquinolinpreparation base, indanyl, indoline base, isoindoline base, isochroman base, isothiazole
Alkyl, isoxazolidinyl, morpholinyl, oxazoline group, oxazolidinyl, oxadiazoles base, 2- oxopiperazinyl, 2- oxo-piperidine base,
2- oxo-pyrrolidine base, 2- oxo azepineBase, octahydro indyl, octahydro isoindolyl, perhydroazepineBase, piperazinyl,
4- piperidone base, piperidyl, phenothiazinyl, phenoxazine base, quininuclidinyl, tetrahydro isoquinolyl, tetrahydrofuran base, oxinane
Base, nafoxidine base, thiazolinyl, thiazolidinyl, thio-morpholinyl, thiomorpholino sulfoxide and thio-morpholinyl sulfone.
Term used in the present invention " aryl alkyl " refers to the alkyl that one or more hydrogen atoms are independently replaced by aryl,
Wherein the aryl and alkyl are as hereinbefore defined.
Term used in the present invention " heteroaryl alkyl " refers to what one or more hydrogen atoms were independently replaced by heteroaryl
Alkyl, wherein the heteroaryl and alkyl is as hereinbefore defined.
Term " halogen " or " halo " used in the present invention refers to fluorine, chlorine, bromine or iodine.
Term used in the present invention " benzo " refers to that phenyl ring is fused to substituted cyclic group with two adjacent carbon atoms
The case where two adjacent carbon atoms of group.
When being described in the present invention to substituent group, used " optional " word indicates that substituent group may exist,
It can be not present.For example, " on five yuan of hetero-aromatic rings optionally existing substituent group " indicate five yuan of hetero-aromatic rings either replacing,
It is also possible to unsubstituted.
Pharmaceutical composition in the present invention contains compound described in first aspect present invention as active constituent.In addition,
The pharmaceutical composition also may include pharmaceutically acceptable carrier, including but not limited to: water, salting liquid, alcohol, polyethylene glycol, more
Castor oil, peanut oil, olive oil, gelatin, lactose, land plaster, sucrose, dextrin, magnesium carbonate, sugar, the ring paste of hydroxyl-oxethyl
Essence, amylose, magnesium stearate, talcum, gelatin, agar, pectin, Arabic gum, stearic acid or the low alkyl ether of cellulose, silicon
Acid, fatty acid, fatty acid amine, glycerine monofatty ester and two glyceride, pentaerythrite fat sour ether, polyoxyethylene, methylol
Cellulose and polyvinylpyrrolidone.The pharmaceutical composition also may include one or more pharmaceutically acceptable adjuvants, profit
Humectant, emulsifier, suspending agent, preservative, osmotic pressure regulator, buffer, sweetener, corrigent, colorant or above-mentioned times
Meaning combination.
Any type of preparation, such as capsule, tablet, aerosol, solution can be made in pharmaceutical composition of the invention
Agent, suspending agent, sugar-coat agent, pastille, syrup, emulsion, ointment, paste, injection, powder, granule, paste, sustained release agent,
Foaming agent.According to administration route, oral administration preparation, nasal administration preparation, pulmonary administration system can be made in drug of the invention
Agent, buccal preparation, transdermal formulations, intradermal administration preparation, percutaneous drug administration preparation, parenteral administration preparation, rectum are given
Medicine preparation, reservoir type drug-delivery preparation, preparation for intravenous administration, drug-delivery preparation, intramuscular administration preparation, intranasal administration system in urethra
Agent, ophthalmic administration preparation, epidural administration preparation or local administration preparation.
" cancer " in the present invention includes various cancers as known in the art, including but not limited to: lung cancer, liver cancer, stomach
Cancer, cervical carcinoma, colon cancer, breast cancer, leukaemia, non-small cell carcinoma, prostate cancer or tired melanoma, the cancer of the brain, cutaneum carcinoma, bone
Cancer, lymph cancer, nasopharyngeal carcinoma, laryngocarcinoma, cancer of the esophagus, duodenal cancer, carcinoma of small intestine, colorectal cancer, cancer of pancreas, kidney, genital cancer,
Thyroid cancer.
Embodiment
Next, being illustrated in further detail by embodiment to the present invention, but the present invention is not limited only to these realities
Apply example.
In an illustrative embodiment, the compound of the present invention is synthesized by following universal method, wherein
For each substituent group as defined in logical formula (I), X indicates that halogen atom, organic base are triethylamine (TEA).
Those skilled in the art are after reading this paper, condition needed for capable of being readily ascertained by such coupling reaction.One
In a illustrative compound 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
3- pyridyl-methanamine (108mg, 1mmol), triethylamine (100mg, 1mmol) are added in 10ml water, stir 5 at room temperature
After minute, carbon disulfide (91mg, 1.2mmol) is added dropwise, stirs at room temperature after five minutes, addition 3- bromopropyl alcohol (138mg,
1mmol), it reacting 2 hours, is extracted with ethyl acetate (15mL × 3), merge organic phase, anhydrous sodium sulfate dries, filters, it is concentrated,
Silica gel column chromatography separation, obtains white solid 191mg, yield 79%, fusing point: 70-71 DEG C.
In above-mentioned synthesis example and following embodiment, all source chemicals are that commercially available chemistry is pure or the pure examination of analysis
Agent is directly used without processing.Other related experiment instrument conditions are 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: 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: benzoyl hydrazine (0.68g, 5mmol) is dissolved in 50mL TEA,
It is stirred at room temperature down, the ethyl acetate solution of chlorpromazine chloride (0.76g, 6mmol) is added dropwise, after being added dropwise, it is small to be heated to reflux 3
When, fully reacting is cooled to room temperature, and solvent is evaporated off, and obtaining N '-(3- chlorine propiono) benzoyl hydrazine is white solid 0.49g, is received
Rate 44%.
The preparation of 2- chloroethyl -5- phenyl -1,3,4- thiadiazoles: by N '-(3- chlorine propiono) benzoyl hydrazine (0.45g,
It 2mmol) is added into 40mL toluene, pump drainage air, backfilled with nitrogen, is added lawesson reagent (1.21g, 3mmol), it is anti-at 115 DEG C
It answers 4 hours, solvent is evaporated off, is separated through silica gel column chromatography, obtain light green solid, 0.36g, yield 54%.
The preparation of target compound: the target compound is using 2- chloroethyl -5- phenyl -1,3,4- thiadiazoles as universal method
In raw material B obtain white solid referring to the synthetic method preparation of [synthesis example], yield 32%, 138-142 DEG C of fusing point.
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- (benzoxazoles -2- base)) ethyl ester
The preparation of 3- bromine tetrahydroform acid methyl ester hydrochloride salt: by bromopropionitrile (2.66g, 20mmol) and methanol (1.28g,
It 40mmol) is added into 100mL ether, is stirred at room temperature down, is slowly introducing dry hydrogen chloride gas, after 6 hours, there is a large amount of white crystals
It generates, stops reaction, filtering, solid is washed twice with anhydrous ether, is dried, is obtained white crystal 2.08g, yield 63%.
The preparation of 2- (2- bromoethyl) benzoxazoles: by 3- bromine tetrahydroform acid methyl ester hydrochloride salt (0.16g, 1mmol) and neighbour
Amino-phenol (0.15g, 1.3mmol) is added into 20mL ethyl alcohol, reacts 6 hours at 80 DEG C, stops reaction, filtering, filtrate
It is concentrated to give 2- (2- bromoethyl) benzoxazoles crude product, yellow oil, quantitative yield.
The preparation of target compound: the target compound is using 2- (2- bromoethyl) benzoxazoles as the raw material in universal method
B obtains white solid referring to the synthetic method preparation of [synthesis example], yield 57%, and 116-117 DEG C of fusing point.
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
The preparation of 2- (2- bromoethyl) -2H- benzo [1,2,3] triazole: by benzotriazole (1.19g, 10mmol), 1,2-
Bromofume (1.86g, 10mmol), potassium hydroxide (1.12g, 20mmol) and tetrabutylammonium iodide (0.37g, 1mmol) are added
Into 40mL DMF, reacted overnight at 90 DEG C.It is cooled to room temperature, 40mL water is added, extracted with ethyl acetate (30mL × 3), closed
And organic phase, it is successively washed with water and saturated common salt, anhydrous sodium sulfate dries, filters, and is concentrated, and 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: the target compound with 2- (2- bromoethyl) -2H- benzo [1,2,3] triazole be raw material,
Referring to the synthetic method preparation of [synthesis example], white solid is obtained, yield 63%, 147-148 DEG C of fusing point.
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- oxadiazoles -5- base)) ethyl ester
The preparation of N- hydroxy benzenes carboximidamide: by benzonitrile (1.03g, 10mmol), triethylamine (4.0g, 40mmol) and
Hydroxylamine hydrochloride (1.39g, 20mmol) is added into 60mL ethyl alcohol, reacts 12 hours at 90 DEG C, cooling, and solvent is evaporated off, and is added
20mL water is extracted with ethyl acetate (20mL × 3), merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated, silica gel column chromatography
Separate to obtain nitrogen-hydroxy benzenes carboximidamide 1.31g, yellow oil, yield 96%.
The preparation of N- [(chlorine propiono) oxygroup] benzimide amide: by N- hydroxy benzenes carboximidamide (0.63g,
It 5mmol) is added with triethylamine (0.5g, 5mmol) into 30mL ethyl acetate, is stirred at room temperature down, is slowly dropped into chlorpromazine chloride
(0.63g, 5mmol), finishes, and the reaction was continued at room temperature 2 hours, fully reacting, and 20mL water is added, and ester layer is collected in extraction, anhydrous
Sodium sulphate dries, filters, and is concentrated to give N- [(chlorine propiono) oxygroup] benzimide crude amide, yellow oil, quantitative yield.
The preparation of 5- chloroethyl -3- phenyl -1,2,4- oxadiazoles: by N- [(chlorine propiono) oxygroup] benzimide amide
(0.23g, 1mmol) and potassium carbonate (0.28g, 2mmol) are added into 10mL Isosorbide-5-Nitrae-dioxane, flow back 6 hours, cooling, steam
Except solvent, 20mL water is added, is extracted with ethyl acetate (20mL × 3), merges organic phase, anhydrous sodium sulfate dries, filters, and is concentrated
Obtain 5- chloroethyl -3- phenyl -1,2,4- oxadiazoles crude product, yellow oil, quantitative yield.
The preparation of target compound: for the target compound with 5- chloroethyl -3- phenyl -1,2,4- oxadiazoles is raw material, ginseng
According to the synthetic method preparation of [synthesis example], white solid is obtained, yield 43%, 118-120 DEG C of fusing point.
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- oxadiazoles -2- base)) ethyl ester
The preparation of 2- bromoethyl -5- phenyl -1,3,4- oxadiazoles: by 3- bromine tetrahydroform acid methyl ester hydrochloride salt (0.16g,
It 1mmol) is added into 20mL methylene chloride, under ice bath, benzoyl hydrazine (0.16g, 1.3mmol) is added portionwise, finishes, reflux 6
Hour, cooling, filtering is concentrated to give 2- bromoethyl -5- phenyl -1,3,4- oxadiazoles crude product, yellow oil, quantitative yield.
The preparation of target compound: the target compound is using 2- bromoethyl -5- phenyl -1,3,4- oxadiazoles as general side
Raw material B in method obtains white solid referring to the synthetic method preparation of [synthesis example], yield 62%, and 134-136 DEG C of fusing point.
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: by o-phenylenediamine (0.22g, 2mmol) and bromo-propionic acid (0.61g,
It 4mmol) is added into 15mL concentrated hydrochloric acid, flows back 6 hours, it is cooling, it is slowly added to saturated sodium carbonate solution and is neutralized to pH=7, use
Ethyl acetate (20mL × 3) extraction, merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated to give 2- (2- bromoethyl) benzo miaow
Azoles crude product, yellow oil, quantitative yield.
The preparation of target compound: the target compound is using 2- (2- bromoethyl) benzimidazole as the original in universal method
Expect B, referring to the synthetic method preparation of [synthesis example], obtains white solid, yield 33%, 149-151 DEG C of fusing point.
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), sodium azide (0.16g,
It 2.5mmol) is added with ammonium chloride (0.13g, 2.5mmol) into the dry DMF of 20mL, is reacted 6 hours at 100 DEG C, be cooled to room
Reaction solution is poured into 20mL mixture of ice and water by temperature, is extracted with ethyl acetate (20mL × 3), and organic phase, anhydrous slufuric acid are merged
Sodium dries, filters, concentration, and silica gel column chromatography separation obtains 5- (2- bromoethyl) -1H-TETRAZOLE 0.13g, light yellow oil, yield
37%.
The preparation of target compound: the target compound is using 5- (2- bromoethyl) -1H-TETRAZOLE as the original in universal method
Expect B, referring to the synthetic method preparation of [synthesis example], obtains faint yellow solid, yield 49%, 121-124 DEG C of fusing point.
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) and triethylamine (0.20g,
It 2mmol) is added into 30mL ethyl acetate, at room temperature, instills bromopropionitrile (0.26g, 2mmol) dropwise, after being added dropwise, room temperature
Reaction 6 hours, it is cooling, it is concentrated to give 2- (2- bromoethyl) benzothiazole crude product, it is not purified, it is directly used in the next step.
The preparation of target compound: the target compound is using 2- (2- bromoethyl) benzothiazole as the original in universal method
Expect B, referring to the synthetic method preparation of [synthesis example], obtains white solid, yield 19%, 96-99 DEG C of fusing point.
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- (benzoxazoles -2- base)) ethyl ester
The target compound prepares referring to the synthetic route of embodiment 2 using 4- pyridyl-methanamine as raw material, it is solid to obtain white
Body, yield 58%, 89-90 DEG C of fusing point.
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- oxadiazoles -2- base)) ethyl ester
The target compound prepares referring to the synthetic route of embodiment 5 using 4- pyridyl-methanamine as raw material, it is solid to obtain white
Body, yield 65%, 131-132 DEG C of fusing point.
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- benzoxazoles -2- base)) ethyl ester
The target compound prepares referring to the synthetic route of embodiment 2 using 3- pyridine ethylamine as raw material, it is solid to obtain white
Body, yield 59%, 123-124 DEG C of fusing point.
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- oxadiazoles -2- base)) ethyl ester
The target compound prepares referring to the synthetic route of embodiment 5 using 3- pyridine ethylamine as raw material, it is solid to obtain white
Body, yield 59%, 124-126 DEG C of fusing point.
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- oxadiazoles -2-
Base)) ethyl ester
The target compound is with (2- methoxypyridine -3- base) methylamine and 2- chloroethyl -5- phenyl -1,3,4- oxadiazoles
Raw material obtains white solid referring to the synthetic method preparation of [synthesis example], yield 31%, and 109-113 DEG C of fusing point.
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- oxadiazoles -2- base)) second
Ester
The preparation of 2- bromoethyl -5- (2- fluorophenyl) -1,3,4- oxadiazoles: by 3- bromine tetrahydroform acid methyl ester hydrochloride salt
(0.16g, 1mmol) is added into 20mL methylene chloride, and under ice bath, 2- fluorobenzoyl hydrazine (0.18g, 1.3mmol) is added portionwise,
It finishes, flows back 6 hours, cooling, filtering is concentrated to give -1,3,4- oxadiazoles crude product of 2- bromoethyl -5- (2- fluorophenyl), yellow oil
Shape object, quantitative yield.
The preparation of target compound: the target compound dislikes two with 3- pyridyl-methanamine and 2- chloroethyl -5- phenyl -1,3,4-
Azoles obtains white solid, yield referring to the synthetic method preparation of [synthesis example] as the raw material A and B in universal method
67%, 108-110 DEG C of fusing point.
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- oxadiazoles -2-
Base] } ethyl ester
For the target compound with 4- methoxybenzoyl hydrazine and 2- chloroethyl -5- phenyl -1,3,4- oxadiazoles is raw material, ginseng
According to the synthetic route preparation of embodiment 14, white solid is obtained, yield 70%, 149-151 DEG C of fusing point.
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- oxadiazoles -2-
Base] } ethyl ester
The target compound is using 4- trifluoromethylbenzoyl hydrazine and 2- chloroethyl -5- phenyl -1,3,4- oxadiazoles as original
Material prepares referring to the synthetic route of embodiment 14, obtains white solid, yield 65%, and 145-146 DEG C of fusing point.
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- oxadiazoles -2- base] } second
Ester
The preparation of 4- chlorobenzoyl hydrazine: 4- chlorobenzoic acid (3.2g, 20mmol) is dissolved in 30mL methanol, under ice bath slowly
Thionyl chloride 2mL is added dropwise, drop finishes, and heats 50 DEG C of reaction 4h, and it is cooling, excessive methanol is evaporated off, it is molten that appropriate saturated sodium bicarbonate is added
(15mL × 3) are extracted with ethyl acetate in liquid, are spin-dried for spare；Previous step crude product is dissolved in 30mL ethyl alcohol, 80% hydration is added
Hydrazine 4mL, heating reflux reaction 4h, it is cooling, white solid is precipitated, filters drying, obtains white solid 2.5g, yield 74%.
The preparation of 3,4- oxadiazoles: 2- bromoethyl -5- (4- chlorphenyl) -1 3- bromo-propionic acid (0.46g, 3mmol) is dissolved in
In 5mL phosphorus oxychloride, 80 DEG C of heating 6h of 4- chlorobenzoyl hydrazine (0.47g, 3mmol) oil bath are added, it is cooling, reaction solution is slow
It pours into ice water, adding sodium hydroxide solution is adjusted to pH 7-8, and methylene chloride extracts (20mL × 3), merges organic layer, anhydrous sulphur
Sour sodium is dry, is spin-dried for solvent and obtains yellow solid 0.31g, crude yield 36%.
The preparation of target compound: 3- aminomethyl-pyridine (0.1mL, 1mmol) is dissolved in 20mL acetone, anhydrous phosphorus is added
2- bromoethyl -5 is added after stirring at normal temperature 30min for sour potassium (0.43g, 2mmol), 5mL water, carbon disulfide (0.15mL, 2mmol)
(4- chlorphenyl) -1,3,4- oxadiazoles (0.29g, 1mmol) heat 50 DEG C of reaction 6h, cooling, and reaction liquid layer has been isolated
Machine layer, silica gel column chromatography (petroleum ether: ethyl acetate=1:1) obtain white solid 0.25g, yield 64%, and 126-127 DEG C of fusing point.
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- oxadiazoles -2- base] }
Ethyl ester
The preparation of 4- nitrobenzoyl hydrazides: in addition to replacing 4- chlorobenzoic acid using 4- nitrobenzoic acid, reference embodiment 17,
Obtain white solid, yield 64%.
2- bromoethyl -5- (4- nitrobenzophenone) -1, the preparation of 3,4- oxadiazoles: referring to embodiment 17, obtaining white solid, receives
Rate 58%.
The preparation of target compound: referring to embodiment 17, obtaining white solid, yield 37%, and 157-158 DEG C of fusing point.
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 -3- base) -1,3,4- oxadiazoles -2- base] }
Ethyl ester
The preparation of pyrroles's -3- formylhydrazine: it in addition to replacing 4- chlorobenzoic acid using pyrroles -3- formic acid, referring to embodiment 17, obtains
White solid, yield 60%.
The preparation of 3,4- oxadiazoles: 2- bromoethyl -5- (3- pyrrole radicals) -1 referring to embodiment 17, obtains white solid, yield
25%.
The preparation of target compound: referring to embodiment 17, obtaining white solid, yield 73%, and 167-168 DEG C of fusing point.
1H 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- (furans -2- base) -1,3,4- oxadiazoles -2- base] }
Ethyl ester
The preparation of furans -2- formylhydrazine: it in addition to replacing 4- chlorobenzoic acid using furans -2- formic acid, referring to embodiment 17, obtains
White solid, yield 65%.
2- bromoethyl -5- (2- furyl) -1, the preparation of 3,4- oxadiazoles: referring to embodiment 17, obtaining light yellow oil,
Yield 49%.
The preparation of target compound: referring to embodiment 17, obtaining white solid, yield 85%, and 155-156 DEG C of fusing point.
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- oxadiazoles -2- base] }
Ethyl ester
The preparation of thiophene -3- formylhydrazine: it in addition to replacing 4- chlorobenzoic acid using thiophene -3- formic acid, referring to embodiment 17, obtains
White solid, yield 61%.
2- bromoethyl -5- (3- thienyl) -1, the preparation of 3,4- oxadiazoles: referring to embodiment 17, obtaining yellow oil, receives
Rate 30%.
The preparation of LP-05 target compound: referring to embodiment 17, obtaining white solid, yield 89%, and 141-142 DEG C of fusing point.
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- oxadiazoles -2- base] }
Ethyl ester
The preparation of thiophene -2- formylhydrazine: it in addition to replacing 4- chlorobenzoic acid using thiophene -2-carboxylic acid, referring to embodiment 17, obtains
White solid, yield 60%.
2- bromoethyl -5- (2- thienyl) -1, the preparation of 3,4- oxadiazoles: referring to embodiment 17, obtaining yellow oil, receives
Rate 23%.
The preparation of target compound: referring to embodiment 17, obtaining white solid, yield 92%, and 145-146 DEG C of fusing point.
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.
{ [5- (5- methylisoxazole -3- base) -1,3,4- dislikes two to 2- to embodiment 23:3- pyridylmethyl dithiocarbonic acid
Azoles -2- base] } ethyl ester
5- methyl-isoxazole -3- formylhydrazine preparation: by 5- methyl-isoxazole -3- Ethyl formate (3.1g, 20mmol)
It being dissolved in 30mL ethyl alcohol, 80% hydrazine hydrate 4mL is added, heating reflux reaction is for 24 hours, cooling, and white solid is precipitated, drying is filtered,
Obtain white solid 2.1g, yield 75%.
The preparation of 3,4- oxadiazoles: 2- bromoethyl -5- [3- (5- methylisoxazole base)] -1 referring to embodiment 17, is obtained white
Color solid, yield 36%.
The preparation of target compound: referring to embodiment 17, obtaining white solid, yield 75%, and 149-150 DEG C of fusing point.
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- oxadiazoles -2- base] }
Ethyl ester
The preparation of pyridine -3- formylhydrazine: it in addition to replacing 4- chlorobenzoic acid using Nicotinicum Acidum, referring to embodiment 17, obtains
White solid, yield 74%.
The preparation of 3,4- oxadiazoles: 2- bromoethyl -5- (3- pyridyl group) -1 referring to embodiment 17, obtains white solid, yield
20%.
The preparation of target compound: referring to embodiment 17, obtaining white solid, yield 75%, and 151-152 DEG C of fusing point.
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- oxadiazoles -2-
Base] } ethyl ester
The preparation of 6- chloropyridine -3- formylhydrazine: in addition to replacing 4- chlorobenzoic acid using 6- chloropyridine -3- formic acid, referring to real
Example 17 is applied, white solid, yield 73% are obtained.
[preparation of 3,4- oxadiazoles: 3- (6- chloropyridine base) -1 referring to embodiment 17, is obtained white solid 2- bromoethyl -5-
Body, yield 15%.
The preparation of target compound: referring to embodiment 17, white solid, yield 75% are obtained.
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- oxadiazoles -2- base] }
Ethyl ester
The preparation of pyrazine -2- formylhydrazine: it in addition to replacing 4- chlorobenzoic acid using pyrazine -2- formic acid, referring to embodiment 17, obtains
White solid, yield 64%.
The preparation of 3,4- oxadiazoles: 2- bromoethyl -5- (2- pyrazinyl) -1 referring to embodiment 17, obtains yellow oil.
The preparation of target compound: referring to embodiment 17, obtaining white solid, yield 88%, and 143-144 DEG C of fusing point.
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- oxadiazoles -2- base] }
Ethyl ester
The preparation of quinoline -6- formylhydrazine: it in addition to replacing 4- chlorobenzoic acid using quinoline -6- formic acid, referring to embodiment 17, obtains
White solid, yield 67%.
The preparation of 3,4- oxadiazoles: 2- bromoethyl -5- (6- quinolyl) -1 referring to embodiment 17, obtains white solid, yield
43%.
The preparation of target compound: referring to embodiment 17, obtaining white solid, yield 54%, and 165-166 DEG C of fusing point.
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- oxadiazoles -2- base] }
Ethyl ester
The preparation of quinoline -2- formylhydrazine: it in addition to replacing 4- chlorobenzoic acid using quinoline -2- formic acid, referring to embodiment 17, obtains
White solid, yield 75%.
The preparation of 3,4- oxadiazoles: 2- bromoethyl -5- (2- quinolyl) -1 referring to embodiment 17, obtains white solid, yield
21%.
The preparation of target compound: referring to embodiment 17, obtaining white solid, yield 81%, and 139-140 DEG C of fusing point.
1H 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- oxadiazoles -2-
Base] } ethyl ester
The preparation of benzothiophene -2- formylhydrazine: in addition to replacing 4- chlorobenzoic acid using benzothiophene -2- formic acid, referring to real
Example 17 is applied, white solid, yield 52% are obtained.
The preparation of 3,4- oxadiazoles: 2- bromoethyl -5- (2- quinolyl) -1 referring to embodiment 17, obtains white solid, yield
48%.
The preparation of target compound: referring to embodiment 17, obtaining white solid, yield 53%, and 249-250 DEG C of fusing point.
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
Using the activity of the compound in the attached cell mtt assay measurement embodiment of the present invention, it is described that specific step is as follows.
In vitro culture breast carcinoma cell strain SKBr-3, breast carcinoma cell strain MDA-MB-468, colon cancer cell line HCT116
With hepatoma cell strain Bel7402.After cell grows to logarithmic growth phase, cell is collected, 1000rpm is centrifuged 5 minutes, discards supernatant
Liquid is suspended with appropriate culture medium, adjustment cell concentration to 3 × 104/ml.By cell suspension inoculation to 96 hole cell culture
In plate, every 100 μ l of hole, be put into cell incubator (37 DEG C, 5%CO2) in culture for 24 hours after, drug to be measured is added (from 10-4~102
Eight concentration are selected in μM, are other are as follows: 1 × 10-4μM、1×10-3μM、1×10-2μM、1×10-1μM、1μM、10μM、1×101 . 5
μM、1×102μM).DMSO is added in negative control group, and (final concentration of 0.5%), each group are all provided with 3 multiple holes.It is cultivated in incubator
After 72h, the 20 μ l of MTT of 5mg/ml is added in every hole, in 37 DEG C of placement 3h.150 μ l DMSO, 37 DEG C of shaking table oscillations are added in every hole
5min, 492nm/620nm survey absorbance (OD).With Prism Graphpad statistical software calculate IC50 value (by μM in terms of).Institute
Result is obtained to be summarized in following table 1.
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 additionally using Prostatic cancer cell lines KB, using method identical with test example 1 to remaining
The activity of compound in embodiment is tested (using Lapatinib as positive control).Acquired results are summarized in following table 2
In.
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 (17)
1. logical formula (I) compound represented or its pharmaceutically acceptable salt:
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；
R1Indicate that optionally existing substituent group, p indicate substituent R on pyridine ring1Quantity, be 0-4 integer, it is above-mentioned optionally to deposit
Substituent R1For alkoxy；
Optionally existing substituent group, m indicate the quantity of substituent R on R five yuan of hetero-aromatic rings of expression, are the integer of 0-3, above-mentioned optional
Existing substituent R is independently selected from the group as composed by phenyl, benzo and heteroaryl comprising 5-12 annular atom,
And the one or more group R being optionally independently selected from the following group2It is further substituted with: C1-C4Alkyl, C1-C4Alkoxy,
C1-C4Halogenated alkyl, C1-C4Halogenated alkoxy, halogen, group composed by nitro.
2. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein the definition of logical formula (I) meets following
Qualifications (1) are one or more into (6):
(1) n is the integer of 1-3；
(2) substituent R being optionally present1For C1-C4Alkoxy；
(3) p is the integer of 0-3；
(4) m is the integer of 0-2；
(5)It is connected to 2,3 or 4 of pyridine ring；And/or
(6)Y1、Y2、Y3、Y4And Y5The five yuan of hetero-aromatic rings constituted contain the 2-4 hetero atoms for being selected from O, N and S.
3. compound as claimed in claim 2 or its pharmaceutically acceptable salt, wherein the n is 1 or 2.
4. compound as claimed in claim 2 or its pharmaceutically acceptable salt, wherein the substituent R1For methoxyl group.
5. compound as claimed in claim 2 or its pharmaceutically acceptable salt, wherein the p is the integer of 0-2.
6. compound as claimed in claim 5 or its pharmaceutically acceptable salt, wherein the p is 0 or 1.
7. compound as claimed in claim 2 or its pharmaceutically acceptable salt, wherein the m is 0 or 1.
8. compound as claimed in claim 2 or its pharmaceutically acceptable salt, wherein five yuan of hetero-aromatic rings contain 1-4
A N atom and 0-1 O or S atom.
9. compound as claimed in claim 8 or its pharmaceutically acceptable salt, wherein five yuan of hetero-aromatic rings be selected from by
Group composed by oxazole, isoxazole, imidazoles, thiazole, triazole, oxadiazoles, thiadiazoles and tetrazolium.
10. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein described includes 5-12 annular atom
Heteroaryl be selected from by oxazolyl, isoxazolyl, imidazole radicals, furyl, indyl, isoindolyl, pyrrole radicals, triazolyl,
Triazine radical, tetrazole radical, thienyl, thiazolyl, isothiazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, benzofuranyl,
Benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazyl, quinolyl, isoquinolin
Base, quinazolyl, cinnoline base, naphthyridines base, pteridyl, purine radicals, quinoxaline base, thiadiazolyl group, indolizine base, acridinyl, pheno
Piperazine base, phthalazinyl, cumarin base, Pyrazolopyridine base, pyrido pyridazinyl, pyrrolopyridinyl, imidazopyridyl, pyrazoles
And pyridazinyl.
11. compound or its pharmaceutically acceptable salt as described in claim 1 or 10, wherein one or more of bases
Group R2It is independently selected from fluorine, chlorine, bromine, iodine, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy, nitro.
12. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein the compound is selected under
State group composed by compound (1) to (29):
(1) 3- pyridylmethyl dithiocarbonic acid (2- (5- phenyl -1,3,4- thiadiazoles -2- base)) ethyl ester；
(2) 3- pyridylmethyl dithiocarbonic acid (2- (benzoxazoles -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- oxadiazoles -5- base)) ethyl ester；
(5) 3- pyridylmethyl dithiocarbonic acid-(2- (5- phenyl -1,3,4- oxadiazoles -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- (benzoxazoles -2- base)) ethyl ester；
(10) 4- pyridylmethyl dithiocarbonic acid (2- (5- phenyl -1,3,4- oxadiazoles -2- base)) ethyl ester；
(11) 3- pyridine ethylamino dithiocarbonic acid (2- (2- benzoxazoles -2- base)) ethyl ester；
(12) 3- pyridine ethylamino dithiocarbonic acid-(2- (5- phenyl -1,3,4- oxadiazoles -2- base)) ethyl ester；
(13) 2- methoxyl group -3- pyridylmethyl dithiocarbonic acid (2- (5- phenyl -1,3,4- oxadiazoles -2- base)) ethyl ester；
(14) 3- pyridylmethyl dithiocarbonic acid (2- (5- (2- fluorophenyl) -1,3,4- oxadiazoles -2- base)) ethyl ester；
(15) 3- pyridylmethyl dithiocarbonic acid { 2- [5- (4- methoxyphenyl) -1,3,4- oxadiazoles -2- base] } ethyl ester；
(16) 3- pyridylmethyl dithiocarbonic acid { 2- [5- (4- trifluoromethyl) -1,3,4- oxadiazoles -2- base] } ethyl ester；
(17) 3- pyridylmethyl dithiocarbonic acid { 2- [5- (4- chlorphenyl) -1,3,4- oxadiazoles -2- base] } ethyl ester；
(18) 3- pyridylmethyl dithiocarbonic acid { 2- [5- (4- nitrobenzophenone) -1,3,4- oxadiazoles -2- base] } ethyl ester；
(19) 3- pyridylmethyl dithiocarbonic acid { 2- [5- (pyrroles -3- base) -1,3,4- oxadiazoles -2- base] } ethyl ester；
(20) 3- pyridylmethyl dithiocarbonic acid { 2- [5- (furans -2- base) -1,3,4- oxadiazoles -2- base] } ethyl ester；
(21) 3- pyridylmethyl dithiocarbonic acid { 2- [5- (thiene-3-yl) -1,3,4- oxadiazoles -2- base] } ethyl ester；
(22) 3- pyridylmethyl dithiocarbonic acid { 2- [5- (thiophene -2- base) -1,3,4- oxadiazoles -2- base] } ethyl ester；
(23) 3- pyridylmethyl dithiocarbonic acid { 2- [5- (5- methylisoxazole -3- base) -1,3,4- oxadiazoles -2- base] } second
Ester；
(24) 3- pyridylmethyl dithiocarbonic acid { 2- [5- (pyridin-3-yl) -1,3,4- oxadiazoles -2- base] } ethyl ester；
(25) 3- pyridylmethyl dithiocarbonic acid { 2- [5- (6- chloropyridine -3- base) -1,3,4- oxadiazoles -2- base] } ethyl ester；
(26) 3- pyridylmethyl dithiocarbonic acid { 2- [5- (pyrazine -2- base) -1,3,4- oxadiazoles -2- base] } ethyl ester；
(27) 3- pyridylmethyl dithiocarbonic acid { 2- [5- (quinoline -6- base) -1,3,4- oxadiazoles -2- base] } ethyl ester；
(28) 3- pyridylmethyl dithiocarbonic acid-{ 2- [5- (quinoline -2- base) -1,3,4- oxadiazoles -2- base] } ethyl ester；
(29) 3- pyridylmethyl dithiocarbonic acid { 2- [5- (benzothiophene -2- base) -1,3,4- oxadiazoles -2- base] } ethyl ester.
13. a kind of pharmaceutical composition, described pharmaceutical composition include: compound described in any one of claim 1-12 or its medicine
Acceptable salt on；And pharmaceutically acceptable carrier.
14. the method for preparing compound described in any one of claim 1-12, the method includes as follows by raw material A, two sulphur
Change carbon and in the presence of organic base coupling reaction occur for raw material B:
Wherein for each substituent group as defined in logical formula (I), X indicates halogen atom.
15. method as claimed in claim 14, wherein the organic base is triethylamine.
16. compound of any of claims 1-12 and its pharmaceutically acceptable salt are in preparation for antitumor
Purposes in terms of drug.
17. purposes as claimed in claim 16, the tumour is selected from by lung cancer, breast cancer, liver cancer, gastric cancer, cervical carcinoma, knot
Group composed by intestinal cancer and epithelioma.
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| CN1683344A (en) * | 2005-03-09 | 2005-10-19 | 首都师范大学 | 4-quinazolone derivative and its use in anti-tumor medicine |
| 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 |
| CN101899011A (en) * | 2009-05-26 | 2010-12-01 | 北京大学 | Dithiocarbamates compound, 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN1683344A (en) * | 2005-03-09 | 2005-10-19 | 首都师范大学 | 4-quinazolone derivative and its use in anti-tumor medicine |
| CN101899011A (en) * | 2009-05-26 | 2010-12-01 | 北京大学 | Dithiocarbamates compound, 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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