CN108715589A - A kind of coumarin derivatives and its application as caspase-3 activator - Google Patents
A kind of coumarin derivatives and its application as caspase-3 activator Download PDFInfo
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Abstract
The present invention discloses a kind of coumarin derivatives as caspase-3 activator, in similar product and has not seen that similar structure design and use, such compound have significant caspase-3 activations, can be used for treating caspase has related disorders.The present invention also aims to provide application of the above-mentioned coumarin derivatives in preparing treatment and/or the drug of pre- anti-cancer and other proliferative diseases.
Description
Technical field
The present invention relates to technical field of medicine preparation, and in particular to be a kind of tonka-bean as caspase-3 activator
Plain analog derivative and it prepare treatment and/or the drug of pre- anti-cancer and other proliferative diseases in application.
Background technology
Tumour is a kind of disease seriously threatening human life and health, in recent years, the incidence and the death rate of tumour be in by
The trend that year rises.Cytotoxic drug can kill tumour cell, but lack selectivity to cancer cell and normal cell, therefore
With stronger toxic side effect, searching can selectively kill cancer cell and resist on targeting of the normal proliferating cells without influence
Tumour medicine has become the important directions of new type antineoplastic medicine research and development.
Apoptosis refers to a kind of intracellular independence regulated and controled by gene, orderly death process, it is considered that, it dislikes
Property conversion tumour cell be because uncontrolled growth, hyper-proliferative caused by, tumour is then considered from the point of view of Apoptosis
Apoptosis mechanism be suppressed and cannot be normally carried out cell death removing result.There is a series of oncogene in tumour cell
It is activated with proto-oncogene, and overexpression state is presented.Have extremely between the activation of these genes and the occurrence and development of tumour
Close relationship.After the oncogene expression of numerous species, the apoptotic process of tumour cell is blocked, tumor cell number is made to increase
Add.Therefore, by Apoptosis angle and mechanism come design the therapy to tumour be exactly rebuild tumour cell apoptosis believe
Number transmission system, that is, inhibit tumour cell lifetime because expression, activate the expression of death gene.
Caspase families belong to the special cysteine proteinase of aspartic acid, for thin in multicellular organism body
Born of the same parents' apoptotic process plays key effect.Have been found that there are 14 kinds of caspase in human body, only some participates in cell
Apoptotic process, wherein Caspase-3 are as most important a member in caspase families, on the co-route in Apoptosis,
It is one of the key executor of Apoptosis.Under normal circumstances caspase-3 in cytoplasm with inactive zymogen forms
(procaspase-3) exist, only when it is active caspase-3 that extraneous apoptotic signal, which is allowed to activation, can just cause thin
The key protein enzyme of cytoplasm, nucleus and cell framework inactivates, and leads to Apoptosis.In tumour cell, caspase-3 be by
Arrive inhibition, if it is possible to caspase-3 is reactivated, then Apoptosis will be restarted, to inhibit tumor cell proliferation.
Currently, research has proven to be suppressed due to caspase-3, cause procaspase-3 in many tumour cells
The state of height expression is presented, such as：Lymthoma；Leukaemia；Melanoma；Neuroblastoma；Liver cancer；Lung cancer；Breast cancer and
Colon cancer.It will be further appreciated that procaspase-3 belongs to the downstream albumen in apoptosis pathway, if cancer
Be since downstream protein mutation causes, then the apoptotic signal of upstream cannot correctly send downstream albumen to, to
Cause in acting on/antitumor drug of upstream apoptotic signal will cannot play the effect for inhibiting tumour cell to increase.Therefore, if
Meter synthesis directly activates the micromolecular compound of caspase-3, and then catalyzing hydrolysis multiple protein substrate for induction tumour cell withers
Die the new method that will be a safely and effectively seeking antitumor medicine.
PAC-1, which is first of report, can directly act on Caspase -3- proenzyme procaspase-3, activate
It becomes the micromolecular compound of active caspase-3.Experiment show PAC-1 by direct activation procaspase-3 at
For caspase-3, and then inducing apoptosis of tumour cell, then catalyzing hydrolysis multiple protein substrate, final play inhibit tumour thin
The effect of born of the same parents' proliferation；PAC-1 is in a clinical phase conceptual phase at present, Orphan drug is awarded within 2016.
1541 series have obtained a series of cumarin of structure novels by carrying out high flux screening to 6200 compounds
Derivative, wherein compound 1541,1541B, 1541C and 1541D show Activation Activity outstanding to procaspase-3, change
It is most strong to close object 1541B activity, EC50It is 1.3 μM.Studies have shown that 1541B is activated by being self-assembly of fiber molecule
Procaspase-3 becomes caspase-3, and then inducing apoptosis of tumour cell.
The present inventor has carried out extensive research to coumarin kind compound, by the way that multiple structural points are modified and changed
It makes, has synthesized a series of coumarin derivatives containing aryl of structure novels.Vigor is activated by testing its caspase-3,
It was found that such compound has significant caspase-3 activations.
Invention content
The purpose of the present invention is to provide a kind of coumarin derivatives as caspase-3 activator, such chemical combination
Object has significant caspase-3 activations.
The present invention also aims to provide above-mentioned coumarin derivatives to prepare treatment and/or pre- anti-cancer and its
Application in the drug of its proliferative disease.
In order to achieve the above objectives, solution of the invention is：
A kind of coumarin derivatives as caspase-3 activator, general structure as shown in I,
Wherein, X CH2, O, S, NH or NHNHCONH；Integers of the n between 1-6；R1For H or be 1~3 be selected from hydroxyl
Base, halogen, nitro, amino, cyano, the alkyl of C1-C6, the alkenyl of C1-C6, the alkynyl of C1-C6, the alkoxy of C1-C6, C1-
The alkyl sulfide of the alkyl sulfenyl of C6, the alkyl of the C1-C6 replaced by hydroxyl, amino or halogen or the alkoxy of C1-C6 or C1-C6
Base, by single or two C1-C6 alkyl-substituted amino, the alkyl amido of C1-C6, free, at salt, esterification sum
Amidated carboxyl, the alkyl sulphinyl of C1-C6, the sulfonyl of C1-C6, the alkyl acyl of C1-C6, carbamoyl, quilt
Single or two C1-C6 alkyl-substituted carbamoyl, the substituent group of the alkylenedioxy group of C1-C3；
R2And R3It is identical or different, R2And R3Separately it is selected from hydrogen, the alkyl of C1-C10, the naphthenic base of C3-C7, C2-
The alkenyl of C10 or the alkynyl of C2-C10；
Or R2、R3With with R2、R3The nitrogen-atoms connected forms 5~10 circle heterocyclic ring bases or 5~10 unit's heteroaryls together, and
The R2、R3Heterocycle or heteroaryl on contain 1~3 identical or different substituent R4, R4For benzyl, the alkane of C1-C4
Base, the alkoxy of C1-C4, halogen, hydroxyl, carboxyl or ester group；
Ar is the aryl or 5~10 unit's heteroaryls of C6-C10, wherein is selected from containing 1~3 in the heteroaryl of the Ar
N, the hetero atom of O and/or S.
Preferably, the R2、R3Heterocycle or heteroaryl in addition to R2And R3Outside the nitrogen-atoms of connection, contain 1~4
Hetero atom selected from N, O and S, the R2、R3Heterocycle in the carbon-carbon triple bond containing 1~2 carbon-carbon double bond or 1~2,
Contain 1~3 identical or different substituent R on the heteroaryl of the Ar5；R5For hydrogen, hydroxyl, halogen, nitro, amino, cyanogen
Base, the alkyl of C1-C6, the alkenyl of C1-C6, the alkynyl of C1-C6, the alkoxy of C1-C6, the alkylthio group of C1-C6, by hydroxyl, ammonia
The alkoxy of the alkyl or C1-C6 of base or the C1-C6 of halogen substitution, by single or two alkyl-substituted amino of C1-C6, C1-
C6 alkyl amidos, free, at salt, esterification and amidated carboxyl, the alkyl sulphinyl of C1-C6, the sulphur of C1-C6
Acyl group, the alkyl acyl of C1-C6, carbamoyl, by single or two C1-C6 alkyl-substituted carbamoyl, C1-C3
Alkylenedioxy group.
Preferably, X O, S, NH or NHNHCONH；Integers of the n between 1-4；R1For H or be 1~3 be selected from hydroxyl
Base, halogen, nitro, amino, cyano, the alkyl of C1-C6, the alkenyl of C1-C6, the alkynyl of C1-C6, the alkoxy of C1-C6, C1-
The alkyl sulfide of the alkyl sulfenyl of C6, the alkyl of the C1-C6 replaced by hydroxyl, amino or halogen or the alkoxy of C1-C6 or C1-C6
Base, by single or two C1-C6 alkyl-substituted amino, the alkyl amido of C1-C6, free, at salt, esterification sum
Amidated carboxyl, the alkyl sulphinyl of C1-C6, the sulfonyl of C1-C6, the alkyl acyl of C1-C6, carbamoyl, quilt
Single or two C1-C6 alkyl-substituted carbamoyl, the substituent group of the alkylenedioxy group of C1-C3；
R2And R3It is identical or different, R2And R3Separately it is selected from hydrogen, the alkyl of C1-C10, the naphthenic base of C3-C7, C2-
The alkenyl of C10 or the alkynyl of C2-C10；
Or R2、R3With with R2、R3The nitrogen-atoms connected forms 5~10 circle heterocyclic ring bases or 5~10 unit's heteroaryls together, and
The R2、R3Heterocycle or heteroaryl on contain 1~3 identical or different substituent R4, R4For benzyl, the alkane of C1-C4
Base, the alkoxy of C1-C4, halogen, hydroxyl, carboxyl or ester group；
Ar is the aryl or 5~10 unit's heteroaryls of C6-C10, wherein is selected from containing 1~3 in the heteroaryl of the Ar
N, the hetero atom of O and/or S.
Preferably, X O, NH or NHNHCONH；Integers of the n between 1-4；R1For H or be 1~3 selected from hydroxyl,
The substituent group of halogen, the alkyl of C1-C4, the alkoxy of C1-C4, trifluoromethyl and trifluoromethoxy；
R2And R3It is identical or different, R2And R3Separately it is selected from the alkyl of C1-C6 or the naphthenic base of C3-C6；
Or R2、R3With with R2、R3The nitrogen-atoms connected forms 5~6 circle heterocyclic ring bases, and the R together2、R3Heterocycle
On contain 1~3 identical or different substituent R4, R4For benzyl, the alkyl of C1-C4, the alkoxy of C1-C4, halogen, hydroxyl,
Carboxyl or ester group；
Ar is phenyl, naphthalene, pyrrole radicals, furyl, thienyl, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl, oxazole
Base, isoxazolyl, 1,2,3- triazol radical, 1,2,4- triazol radical, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, benzo thiophene
Pheno base, benzofuranyl, indyl, benzimidazolyl, benzopyrazoles base, benzothiazolyl, benzoxazolyl, quinolyl are different
Quinolyl, benzo pyrimidine radicals, benzo pyridazinyl, benzopyrazines base, Thienopyrimidine base, pyrrolo-pyrimidine radicals, thienopyridine
Base or thienopyridine base；R5For hydrogen, halogen, trifluoromethyl, trifluoromethoxy, amino, nitro, the alkyl of C1-C4, C1-
The alkynyl of C4, the alkoxy of C1-C4 or the alkylthio group of C1-C4.
Preferably, X is NH or NHNHCONH；N is 1；R1For hydroxyl or methoxyl group；
R2And R3Take identical substituent group, R2And R3It is respectively selected from the alkyl of C1-C6；
Or R2、R3With with R2、R3The nitrogen-atoms connected forms 5~6 circle heterocyclic ring bases, and the R together2、R3Heterocycle
Contain 1~3 identical or different substituent R on base4, R4For the alkyl of C1-C4；
Ar is phenyl, pyrrole radicals, thienyl, imidazole radicals, pyrazolyl, thiazolyl, 1,2,3- triazol radical, 1,2,4- tri- nitrogen
Oxazolyl, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, benzothienyl, benzofuranyl, indyl, benzimidazolyl, benzo
Pyrazolyl, benzothiazolyl, benzoxazolyl, benzo pyrimidine radicals or Thienopyrimidine base；R5For hydrogen, halogen, trifluoromethyl,
The alkyl of trifluoromethoxy, amino or C1-C4.
Preferably, X is NH or NHNHCONH；N is 1；R1For hydroxyl or methoxyl group；
In Formulas IForOr
Ar is phenyl or benzothiazolyl；R5For hydrogen, halogen, trifluoromethyl, trifluoromethoxy, amino or C1-C4
Alkyl.
Preferably, it should be selected from as the coumarin derivatives of caspase-3 activator：
N- [2- (6- (diethylamino methyl) benzo [d] thiazolyl)] -8- hydroxyl -2- oxo -2H- chromenes -3-
Formamide,
N- [2- (6- (diethylamino methyl) benzo [d] thiazolyl)] -8- methoxyl group -2- oxo -2H- chromenes -
3- formamides,
N- [2- (6- (4- methyl piperidines ylmethyl) benzo [d] thiazolyl)] -8- hydroxyl -2- oxo -2H- chromenes -
3- formamides,
N- [2- (6- (4- methyl piperidines ylmethyl) benzo [d] thiazolyl)] -8- methoxyl group -2- oxo -2H- benzo pyrroles
It mutters -3- formamides,
N- [2- (6- (dimethylaminomethyl) benzo [d] thiazolyl)] -8- hydroxyl -2- oxo -2H- chromenes -3-
Formamide,
N- [2- (6- (dimethylaminomethyl) benzo [d] thiazolyl)] -8- methoxyl group -2- oxo -2H- chromenes -
3- formamides,
N- [4- (4- methyl piperidines ylmethyl) phenyl] -8- hydroxyl -2- oxo -2H- chromene -3- formamides,
N- [4- (4- methyl piperidines ylmethyl) phenyl] -8- methoxyl group -2- oxo -2H- chromene -3- formamides,
N- [4- (diethylin methyl) phenyl] -8- hydroxyl -2- oxo -2H- chromene -3- formamides,
N- [4- (diethylin methyl) phenyl] -8- methoxyl group -2- oxo -2H- chromene -3- formamides,
N- [4- (dimethylamino methyl) phenyl] -8- hydroxyl -2- oxo -2H- chromene -3- formamides,
N- [4- (dimethylamino methyl) phenyl] -8- methoxyl group -2- oxo -2H- chromene -3- formamides,
N- [4- (diethylin methyl) phenyl] -2- (8- hydroxyl -2- oxo -2H- chromene -3- carbonyls) hydrazine -1- first
Amide,
N- [4- (diethylin methyl) phenyl] -2- (8- methoxyl group -2- oxo -2H- chromene -3- carbonyls) hydrazine -1-
Formamide,
N- [4- (4- methyl piperidines ylmethyl) phenyl] -2- (8- hydroxyl -2- oxo -2H- chromene -3- carbonyls) hydrazine -
1- formamides,
N- [4- (4- methyl piperidines ylmethyl) phenyl] -2- (8- methoxyl group -2- oxo -2H- chromene -3- carbonyls)
Hydrazine -1- formamides,
N- [4- (dimethylamino methyl) phenyl] -2- (8- hydroxyl -2- oxo -2H- chromene -3- carbonyls) hydrazine -1- first
Amide,
N- [4- (dimethylamino methyl) phenyl] -2- (8- methoxyl group -2- oxo -2H- chromene -3- carbonyls) hydrazine -1-
Formamide,
N- [6- (diethylin methyl) benzothiazole -2- bases] -2- (8- hydroxyl -2- oxo -2H- chromene -3- carbonyls
Base) hydrazine -1- formamides,
N- [6- (diethylin methyl) benzothiazole -2- bases] -2- (8- methoxyl group -2- oxo -2H- chromene -3- carbonyls
Base) hydrazine -1- formamides,
N- [6- (4- methyl piperidines ylmethyl) benzothiazole -2- bases] -2- (8- hydroxyl -2- oxo -2H- chromenes -3-
Carbonyl) hydrazine -1- formamides,
N- [6- (4- methyl piperidines ylmethyl) benzothiazole -2- bases] -2- (8- methoxyl group -2- oxo -2H- chromenes -
3- carbonyls) hydrazine -1- formamides,
N- [6- (dimethylamino methyl) benzothiazole -2- bases] -2- (8- hydroxyl -2- oxo -2H- chromene -3- carbonyls
Base) hydrazine -1- formamides,
Or N- [6- (dimethylamino methyl) benzothiazole -2- bases] -2- (8- methoxyl group -2- oxo -2H- chromenes -3-
Carbonyl) hydrazine -1- formamides.
In addition, the invention also includes the prodrugs of derivative of the present invention.The prodrug of derivative of the present invention is the derivative of general formula I
Object, their own may have weaker activity even without activity, but upon administration, in physiological conditions (such as pass through
Metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
" halogen " refers to fluorine, chlorine, bromine or iodine generation in the present invention；" alkyl " refers to the alkyl of linear chain or branched chain；" alkylidene "
It refer to the alkylidene of linear chain or branched chain；" aryl " refers to unsubstituted or is connected with the phenyl of substituent group；" heteroaryl " refer to containing
One or more is armaticity selected from the heteroatomic monocycles of N, O, S or polycyclic cyclic annular system, cyclic annular system, such as thiazolyl,
Imidazole radicals, pyridyl group, pyrazolyl, (1,2,3)-and (1,2,4)-triazolyl, furyl, thienyl, pyrrole radicals, benzothiazole
Ji , oxazolyl , isoxazolyls, naphthalene, quinolyl, isoquinolyl, benzimidazolyl and benzoxazolyl etc..
A kind of preparation method of the coumarin derivatives as caspase-3 activator, according to the method for route 1 by phase
The compound with general structure shown in formula I is prepared in the intermediate A answered and the reaction of corresponding intermediate B：
Wherein, the preparation method of intermediate A is as shown in Scheme 2, substituent R1As defined above：
When X is NH, Ar is phenyl, when n is 1, the preparation method such as route 3 of intermediate B -1, and substituent R2And R3It is such as above-mentioned
It is defined：
When X is NH, Ar is benzothiazolyl, when n is 1, the preparation method such as route 4 of intermediate B -2, and substituent R2And R3
As defined above：
When X is NHNHCONH, Ar is phenyl, when n is 1, the preparation method such as route 5 of intermediate B -3, and substituent R2And R3
As defined above：
When X is NHNHCONH, Ar is benzothiazolyl, when n is 1, the preparation method such as route 6 of intermediate B -4, and substituent group
R2And R3As defined above：
The coumarin derivatives for being used as caspase-3 activator are preparing treatment and/or pre- anti-cancer and other increasings
Application in the drug of natural disposition disease.
After adopting the above technical scheme, a kind of coumarin derivatives as caspase-3 activator of the present invention, same
It in class product and has not seen similar structure design and use, there is significant caspase-3 activations, treated preparing
And/or the drug field of pre- anti-cancer and other proliferative diseases has application prospect.
Specific implementation mode
In order to further explain the technical solution of the present invention, being explained in detail the present invention below by specific embodiment
It states.
One, synthesis example：
Each embodiment agents useful for same is to analyze pure or chemical pure, the nuclear magnetic resonance spectroscopy Bruker of the compound of synthesis
ARX-400 is measured, and mass spectrum is measured with Agilent 1100LC/MSD.
Embodiment 1
Step A, the preparation of 8- hydroxyls -2- oxos -2H- chromene -3- carboxylic acids：
The Maxwell acid of 2, the 3- 4-dihydroxy benzaldehydes of 0.1mol and 0.11mol is added in 80ml water, 80 DEG C of reactions are stirred
2h is mixed, is cooled down after completion of the reaction, filters, obtains product Intermediate A, yield 92.5%, MS (ESI) m/z (%):205.1[M-
H]-；1H NMR(400MHz,DMSO)δ10.35(s,1H),8.68(s,1H),7.35–7.29(m,1H),7.24–7.18(m,
2H)。
Step B, the preparation of N- ethyls-N- (4- nitrobenzyls) ethamine (1)
The diethylamine (0.19mol) to nitro bromobenzyl (0.092mol) and 14.14g of 20g is added in 80ml acetonitriles,
5h is stirred at room temperature, after completion of the reaction, 200ml water and 200ml dichloromethane are added into reaction solution, extraction obtains organic layer, nothing
Aqueous sodium persulfate is dried, solvent evaporated, yield 73.1%, MS (ESI) m/z (%):208.4[M+H]+；1H NMR(400MHz,
CDCl3) δ 8.21-8.13 (d, J=8.6Hz, 2H), 7.56 (d, J=8.6Hz, 2H), 3.69 (s, 2H), 2.57 (q, J=
7.2Hz, 4H), 1.07 (t, J=7.2Hz, 6H).
Step C, the preparation of 4-(diethylamino methyl) aniline (B-1)：
N- ethyls-N- (4- nitrobenzyls) ethamine (0.096mol) of 20g is dissolved in 80mL90% ethyl alcohol, stirring heating
To 60 DEG C, the Iron(III) chloride hexahydrate (0.022mol) and trace active charcoal of 6.07g is added, 53.5g hydrazine hydrates are added dropwise
(1.05mol), after be warming up to 80 DEG C, back flow reaction filters while hot after reaction, into filtrate be added 250ml water, then
100ml dichloromethane is added, extracts twice, dichloromethane layer is added to saturated sodium-chloride and is extracted again one time, then with anhydrous
Sodium sulphate is dried, solvent evaporated, yield 66.2%, MS (ESI) m/z (%):178.6[M+H]+；1H NMR(400MHz,CDCl3)
δ 7.13 (d, J=8.4Hz, 2H), 6.66 (d, J=8.4Hz, 2H), 3.63 (s, 2H), 3.50 (s, 2H), 2.53 (q, J=
7.2Hz, 4H), 1.06 (t, J=7.2Hz, 6H).
Step D, the preparation of 6-(diethylamino methyl) benzo [d] thiazole-2- amine (B-2)：
4-(diethylamino methyl) aniline (0.036mol), the rhodan ammonium (0.182mol) of 13.9g of 6.5g is molten
In 50ml acetic acid, 0.5h is stirred, 10 DEG C is cooled to hereinafter, the acetic acid solution of 2.25ml bromines is slowly added dropwise, reacts at room temperature 5h, instead
After answering, reaction solution is poured into 200ml water, pH is adjusted to alkalinity with NaOH solution, filters and remove insoluble matter, by filtrate after
It is continuous to adjust pH to 10 with NaOH solution, there is solid precipitation, filters, obtain yellow solid, yield 58.9%, MS (ESI) m/z (%):
236.0[M+H]+；1H NMR (400MHz, DMSO) δ 7.55 (s, 1H), 7.37 (s, 2H), 7.26 (d, J=8.4Hz, 1H), 7.14
(dd, J=8.4,1.2Hz, 1H), 3.52 (s, 2H), 2.45 (q, J=7.2Hz, 4H), 0.97 (t, J=7.2Hz, 6H).
Step E, N- [2- (6- (diethylamino methyl) benzo [d] thiazolyl)] -8- hydroxyl -2- oxo -2H- benzo pyrroles
It mutters the preparations of -3- formamides：
By the 8- hydroxyl base -2- oxo -2H- chromene -3- carboxylic acids (0.009mol) of 2.9g, 0.16ml DIPEA and
6.9g HATU (0.018mol) are dissolved in 20ml DMF, and after stirring 2h, 6- (diethylamino methyl)-benzo of 1.6g is added
[d] thiazole -2- amine (0.009mol), room temperature reaction 1h after completion of the reaction pour into reaction solution in 30ml water, there is solid precipitation,
2h is stirred at room temperature, filters, washs filter cake with methanol, is filtered after stirring 4h, obtain yellow solid, structure is shown in Table 1, yield：45.1%；
MS (ESI) m/z (%):424.1[M+H]+；1H NMR(400MHz,DMSO)δ9.00(s,1H),7.97(s,1H),7.75(d,J
=8.4Hz, 1H), 7.49-7.45 (m, 1H), 7.45-7.41 (m, 1H), 7.31 (s, 1H), 7.30 (s, 1H), 3.68 (s, 2H),
2.58-2.51 (m, 4H), 1.02 (t, J=7.2Hz, 6H)；13C NMR(101MHz,DMSO)δ161.01,160.85,156.99,
149.90,148.01,145.15,143.24,132.27,127.77,125.98,122.00,121.62,120.99,120.94,
119.79,117.92,57.18,46.59,11.94。
Embodiment 2
8- methoxyl groups -2- is prepared using 2- hydroxyls m-methoxybenzaldehyde as raw material with reference to the step A in embodiment 1
Oxo -2H- chromene -3- carboxylic acids, yield 88.7%, MS (ESI) m/z (%):219.1[M-H]-；1H NMR(400MHz,
DMSO)δ8.71(s,1H),7.46–7.43(m,1H),7.43–7.39(m,1H),7.37–7.30(m,1H),3.93(s,3H)。
With reference to step B, step C, the step D in embodiment 1,6-(diethylamino methyl) benzo [d] thiophenes are prepared
Azoles -2- amine (B-2), referring finally to the step E in embodiment 1, with 8- methoxyl group -2- oxo -2H- chromene -3- carboxylic acids and
6-(diethylamino methyl) benzo [d] thiazole-2- amine (B-2) are raw material, and N- [2- (6- (diethylacbamazines are prepared
Base) benzo [d] thiazolyl)] -8- methoxyl group -2- oxo -2H- chromene -3- formamides, structure is shown in Table 1, yield：
46.2%；MS (ESI) m/z (%):437.0[M+H]+；1H NMR(400MHz,DMSO)δ9.02(s,1H),8.20(s,1H),
7.98–7.85(m,1H),7.65–7.53(m,2H),7.53–7.47(m,1H),7.46–7.37(m,1H),4.41(s,2H),
3.97 (s, 3H), 3.22-3.02 (d, J=7.0Hz, 4H), 1.26 (t, J=7.0Hz, 6H).
Embodiment 3
With reference to the step A in embodiment 1,8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to the step B in embodiment 1, as raw material, 4- methyl-1s-are prepared to nitro bromobenzyl and 4- methyl piperidines
(4- nitrobenzophenones) piperidines (1), using 4- methyl-1s-(4- nitrobenzophenones) piperidines as raw material, is prepared with reference to the step C of embodiment 1
4-(4- methyl piperidines ylmethyl) aniline (B-1) are obtained, with reference to the method for the step D in embodiment one, with 4-(4- methyl piperidines
Ylmethyl) aniline be raw material, 6- (4- methyl piperidines ylmethyl) benzo [d] thiazole -2- amine (B-2), yield is prepared：
85.3%；MS (ESI) m/z (%):262.1[M+H]+；1H NMR(400MHz,DMSO)δ7.75(s,1H),7.65(s,2H),
7.38 (d, J=8.0Hz, 1H), 7.30 (d, J=8.0Hz, 1H), 4.22 (s, 2H), 3.33 (m, 2H), 2.77 (m, 2H), 1.77
(m, 2H), 1.56 (m, 1H), 1.29 (m, 2H), 0.90 (d, J=5.4Hz, 3H).
Referring finally to the step E in embodiment 1, with 8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids and 6- (4- first
Phenylpiperidines ylmethyl) benzo [d] thiazole -2- amine (B-2) be raw material, N- [2- (6- (4- methyl piperidines ylmethyl) benzene is prepared
And [d] thiazolyl)] -8- hydroxyl -2- oxo -2H- chromene -3- formamides, structure is shown in Table 1, yield：55.7%；MS
(ESI) m/z (%):450.2[M+H]+；1H NMR (400MHz, DMSO) δ 9.00 (s, 1H), 7.94 (s, 1H), 7.75 (d, J=
8.4Hz, 1H), 7.47 (t, J=4.8Hz, 1H), 7.41 (dd, J=8.4,1.6Hz, 1H), 7.31 (s, 1H), 7.30 (s, 1H),
3.57(s,2H),2.87–2.73(m,2H),2.04–1.90(m,2H),1.64–1.51(m,2H),1.39–1.29(m,1H),
1.19-1.10 (m, 2H), 0.89 (d, J=6.4Hz, 3H)；13C NMR(101MHz,DMSO)δ161.04,160.84,157.32,
157.06,149.90,148.07,145.14,144.49,143.25,140.05,132.26,129.11,127.98,127.17,
125.99,123.99,122.26,121.62,121.24,121.00,120.93,119.79,118.69,117.95,62.72,
53.70,34.32,30.70,22.27。
Embodiment 4
8- methoxyl groups -2- is prepared using 2- hydroxyls m-methoxybenzaldehyde as raw material with reference to the step A in embodiment 1
Oxo -2H- chromene -3- carboxylic acids.
With reference to step B, step C, the step D in embodiment 3,6- (4- methyl piperidines ylmethyl) benzo [d] is prepared
Thiazole -2- amine (B-2), referring finally to the step E in embodiment 1, with 8- methoxyl group -2- oxo -2H- chromene -3- carboxylic acids
It is raw material with 6- (4- methyl piperidines ylmethyl) benzo [d] thiazole -2- amine (B-2), N- [2- (6- (4- methyl piperidines is prepared
Ylmethyl) benzo [d] thiazolyl)] -8- methoxyl group -2- oxo -2H- chromene -3- formamides, structure is shown in Table 1, yield：
61.3%；MS (ESI) m/z (%):464.3[M+H]+；1H NMR(400MHz,DMSO)δ8.87(s,1H),7.61–7.51(m,
3H),7.49–7.43(m,2H),7.43–7.37(m,1H),4.16(s,2H),3.96(s,3H),3.30–3.17(m,2H),
2.93-2.75 (m, 2H), 1.83-1.67 (m, 2H), 1.63-1.51 (m, 1H), 1.51-1.32 (m, 2H), 0.90 (d, J=
5.4Hz,3H)。
Embodiment 5
With reference to the step A in embodiment 1,8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to the step B in embodiment 1, nitro bromobenzyl and dimethylamine as raw material, to be prepared N- methyl-N- (4-
Nitrobenzyl) methylamine (1), with reference to embodiment 1 step C, as raw material, be prepared into using N- methyl-N- (4- nitrobenzyls) methylamine
To 4-(dimethylaminomethyl) aniline (B-1), with reference to the method for the step D in embodiment 1, with 4-(dimethylaminomethyls)
Aniline is raw material, 6-(dimethylaminomethyl) benzo [d] thiazole-2- amine (B-2) is prepared, referring finally in embodiment 1
Step E, with 8- hydroxyl-2- oxo-2H- chromene-3- carboxylic acids and 6-((dimethylamino) methyl) benzo [d] thiazoles-
2- amine (B-2) is raw material, and N- [2- (6- (dimethylaminomethyl) benzo [d] thiazolyl)] -8- hydroxyl -2- oxygen is prepared
Generation -2H- chromene -3- formamides, structure are shown in Table 1, yield：51.1%；MS (ESI) m/z (%):396.1[M+H]+；1H
NMR (400MHz, DMSO) δ 9.01 (s, 1H), 8.17 (d, J=1.2Hz, 1H), 7.92 (d, J=8.4Hz, 1H), 7.60 (dd, J
=8.4,1.6Hz, 1H), 7.50-7.45 (m, 1H), 7.32 (d, J=4.4Hz, 2H), 4.38 (s, 2H), 2.76 (s, 6H)；13CNMR(101MHz,DMSO)δ161.38,160.79,158.59,150.04,149.70,145.14,143.25,132.60,
129.69,126.70,126.05,125.19,121.70,121.60,121.05,119.76,117.89,60.29,42.37。
Embodiment 6
8- methoxyl groups -2- is prepared using 2- hydroxyls m-methoxybenzaldehyde as raw material with reference to the step A in embodiment 1
Oxo -2H- chromene -3- carboxylic acids.
With reference to step B, step C, the step D in embodiment 5,6-(dimethylaminomethyl) benzo [d] thiophenes are prepared
Azoles -2- amine (B-2), referring finally to the step E in embodiment 1, with 8- methoxyl group -2- oxo -2H- chromene -3- carboxylic acids and
6-(dimethylaminomethyl) benzo [d] thiazole-2- amine (B-2) are raw material, and N- [2- (6- (dimethylamino first is prepared
Base) benzo [d] thiazolyl)] -8- methoxyl group -2- oxo -2H- chromene -3- formamides, structure is shown in Table 1, yield：
53.2%；MS (ESI) m/z (%):409.8[M+H]+；1H NMR(400MHz,DMSO)δ9.04(s,1H),8.22(s,1H),
7.88 (d, J=8.4Hz, 1H), 7.67 (dd, J=8.4,1.4Hz, 1H), 7.61-7.56 (m, 1H), 7.52 (d, J=7.2Hz,
1H), 7.44 (t, J=8.0Hz, 1H), 4.36 (s, 2H), 3.97 (s, 3H), 2.72 (s, 6H)；13C NMR(101MHz,DMSO)δ
161.24,160.52,158.42,149.77,149.56,146.89,143.92,132.50,129.76,126.93,125.99,
125.15,122.06,121.50,119.34,118.27,117.60,60.03,56.84,42.16。
Embodiment 7
With reference to the step A in embodiment 2,8- methoxyl group -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to step B, the step C in embodiment 3,4-(4- methyl piperidines ylmethyl) aniline (B-1) are prepared, finally
With reference to the step E in embodiment 1, with 8- methoxyl group-2- oxo-2H- chromene-3- carboxylic acids and 4-(4- methyl piperidines Ji Jia
Base) aniline (B-1) be raw material, N- [4- (4- methyl piperidines ylmethyl) phenyl] -8- methoxyl group -2- oxo -2H- benzene is prepared
And pyrans -3- formamides, structure are shown in Table 1, yield：61.4%；MS (ESI) m/z (%):464.0[M+H]+；1H NMR
(400MHz,DMSO)δ8.87(s,1H),7.61–7.51(m,3H),7.49–7.43(m,2H),7.43–7.37(m,1H),4.16
(s,2H),3.96(s,3H),3.30–3.17(m,2H),2.93–2.75(m,2H),1.83–1.67(m,2H),1.63–1.51
(m, 1H), 1.51-1.32 (m, 2H), 0.90 (d, J=5.4Hz, 3H).
Embodiment 8
With reference to the step A in embodiment 1,8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to step B, the step C in embodiment 3,4-(4- methyl piperidines ylmethyl) aniline (B-1) are prepared, finally
With reference to the step E in embodiment 1, with 8- hydroxyl-2- oxo-2H- chromene-3- carboxylic acids and 4-(4- methyl piperidines ylmethyls)
Aniline (B-1) is raw material, and N- [4- (4- methyl piperidines ylmethyl) phenyl] -8- hydroxyl -2- oxo -2H- benzo pyrroles are prepared
It mutters -3- formamides, structure is shown in Table 1, yield：55.7%；MS (ESI) m/z (%):450.1[M+H]+；1H NMR(400MHz,
DMSO) δ 9.00 (s, 1H), 7.94 (s, 1H), 7.75 (d, J=8.4Hz, 1H), 7.47 (t, J=4.8Hz, 1H), 7.41 (dd, J
=8.4,1.6Hz, 1H), 7.31 (s, 1H), 7.30 (s, 1H), 3.57 (s, 2H), 2.87-2.73 (m, 2H), 2.04-1.90 (m,
2H), 1.64-1.51 (m, 2H), 1.39-1.29 (m, 1H), 1.19-1.10 (m, 2H), 0.89 (d, J=6.4Hz, 3H)；13C
NMR(101MHz,DMSO)δ161.04,160.84,157.32,157.06,149.90,148.07,145.14,144.49,
143.25,140.05,132.26,129.11,127.98,127.17,125.99,123.99,122.26,121.62,121.24,
121.00,120.93,119.79,118.69,117.95,62.72,53.70,34.32,30.70,22.27。
Embodiment 9
With reference to the step A in embodiment 2,8- methoxyl group -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to step B, the step C in embodiment 1,4-(diethylamino methyl) aniline (B-1) are prepared, finally join
According to the step E in embodiment 1, with 8- methoxyl group-2- oxo-2H- chromene-3- carboxylic acids and 4-(diethylamino methyl) benzene
Amine (B-1) is raw material, and N- [4- (diethylin methyl) phenyl] -8- methoxyl group -2- oxo -2H- chromenes -3- is prepared
Formamide, structure are shown in Table 1, yield:51%；MS (ESI) m/z (%):381.0[M+H]+；1HNMR(400MHz,DMSO)δ8.90
(s, 1H), 7.85 (d, J=8.4Hz, 2H), 7.58-7.53 (m, 3H), 7.49 (dd, J=8.4,1.2Hz, 1H), 7.45-7.39
(m, 1H), 4.30 (d, J=5.2Hz, 2H), 3.97 (s, 3H), 3.19-2.96 (m, 4H), 1.24 (t, J=7.2Hz, 6H)；13C
NMR(101MHz,DMSO)δ160.60,160.58,148.28,146.83,143.71,139.40,132.34,128.28,
125.76,121.70,120.55,120.40,119.48,116.85,112.63,56.74,55.01,46.37,8.92。
Embodiment 10
With reference to the step A in embodiment 1,8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids are prepared.
According to step B, the step C in embodiment 1,4-(diethylamino methyl) aniline (B-1) are prepared, referring finally to
Step E in embodiment 1, with 8- hydroxyl-2- oxo-2H- chromene-3- carboxylic acids and 4-(diethylamino methyl) aniline
(B-1) it is raw material, N- [4- (diethylin methyl) phenyl] -8- hydroxyl -2- oxo -2H- chromene -3- formyls is prepared
Amine, structure are shown in Table 1, yield:57%；MS (ESI) m/z (%):367.8[M+H]+；1H NMR(400MHz,DMSO)δ8.85(s,
1H), 7.78 (d, J=8.4Hz, 2H), 7.72-7.56 (m, 2H), 7.43-7.34 (m, 2H), 7.26 (t, J=8.0Hz, 1H),
4.17(s,2H),2.95(s,4H),1.23(s,6H)。
Embodiment 11
With reference to the step A in embodiment 1,8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to the step B in embodiment 5,4-(dimethylaminomethyl) aniline (B-1) step C, are prepared, finally join
According to the step E in embodiment 1, with 8- hydroxyl-2- oxo-2H- chromene-3- carboxylic acids and 4-(dimethylaminomethyl) aniline
(B-1) it is raw material, N- [4- (dimethylamino methyl) phenyl] -8- hydroxyl -2- oxo -2H- chromene -3- formyls is prepared
Amine, structure are shown in Table 1, yield:49%；MS(ESI)m/z:393.6[M+H]+；1H NMR(400MHz,DMSO)δ8.98(s,1H),
7.87-7.82 (m, 1H), 7.80 (d, J=7.0Hz, 2H), 7.58 (t, J=8.0Hz, 1H), 7.48 (d, J=7.0Hz, 2H),
7.29–7.26(m,1H),4.13(s,2H),3.26–3.17(m,2H),2.86–2.66(m,2H),1.81–1.71(m,2H),
1.57 (s, 1H), 1.38-1.23 (m, 2H), 0.92 (d, J=6.4Hz, 3H).
Embodiment 12
With reference to the step A in embodiment 2,8- methoxyl group -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to step B, the step C in embodiment 5,4-(dimethylaminomethyl) aniline (B-1) are prepared, finally join
According to the step E in embodiment 1, with 8- methoxyl group-2- oxo-2H- chromene-3- carboxylic acids and 4-(dimethylaminomethyl) benzene
Amine (B-1) is raw material, and N- [4- (dimethylamino methyl) phenyl] -8- methoxyl group -2- oxo -2H- chromenes -3- is prepared
Formamide, structure are shown in Table 1, yield:57%；MS(ESI)m/z:407.60[M+H]+；1H NMR(400MHz,DMSO)δ8.90(s,
1H), 7.84 (d, J=8.4Hz, 2H), 7.58-7.54 (m, 1H), 7.51 (d, J=8.4Hz, 2H), 7.48 (s, 1H), 7.45-
7.38(m,1H),4.26(s,2H),3.97(s,3H),3.39–3.34(m,2H),3.01–2.81(m,2H),1.89–1.70(m,
3H), 1.69-1.52 (m, 2H), 1.37-1.21 (m, 2H), 0.92 (d, J=6.4Hz, 3H)；13C NMR(101MHz,DMSO)δ
160.62,160.58,148.27,146.84,143.72,139.49,132.67,125.78,121.71,120.48,119.49,
116.89,59.33,56.77,52.12,31.28,28.58,21.53。
Embodiment 13
With reference to the step A in embodiment 1,8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids are prepared.
Step F, the preparation of N- [4- (Diethylaminomethyl) phenyl] phenyl carbamate (2)：
4- (Diethylaminomethyl) aniline (0.02mol) of 5g is dissolved in 20ml dichloromethane, stirring adds
4.27ml pyridines (0.053mol) cool to 0 DEG C hereinafter, 1.94g phenyl chloroformates (0.028mol) are added dropwise, and drop finishes gradually heating
To room temperature, after completion of the reaction, solvent evaporated, then plus water stirring, suction filtration obtain solid product, yield 70.1%, MS (ESI)
M/z (%):298.9[M+H]+。
Step G, the preparation of N- [4- (diethylin methyl) phenyl] carbamyl hydrazine (B-3)：
N- [4- (Diethylaminomethyl) phenyl] phenyl carbamate (0.015mol) of 5g is dissolved in 30ml dioxane
In, agitation and dropping 1.45ml hydrazine hydrates (0.03mol) are warming up to 80 DEG C of reaction 5h, after completion of the reaction, stop heating, cooling, steam
Dry solvent is added ether and stirs 2h, filters to obtain white solid, yield 55.2%, MS (ESI) m/z (%):236.8[M+H]+。
According to the method for step E, the N- being prepared with 8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids and step G
[4- (diethylin methyl) phenyl] carbamyl hydrazine is raw material, and N- [4- (diethylin methyl) phenyl] -2- (8- are prepared
Hydroxyl -2- oxo -2H- chromene -3- carbonyls) hydrazine -1- formamides, structure is shown in Table 1, yield：49.9%；MS(ESI)m/z
(%):425.2[M+H]+。
Embodiment 14
With reference to the step A in embodiment 2,8- methoxyl group -2- oxo -2H- chromene -3- carboxylic acids are prepared.
According to step F, the step G in embodiment 13, N- [4- (diethylin methyl) phenyl] carbamyl hydrazine is prepared
(B-3), referring finally to the step E in embodiment 1, with 8- methoxyl group -2- oxo -2H- chromene -3- carboxylic acids and N- [4- (two
Ethamine ylmethyl) phenyl] carbamyl hydrazine (B-3) be raw material, N- [4- (diethylin methyl) phenyl] -2- (8- are prepared
Methoxyl group -2- oxo -2H- chromene -3- carbonyls) hydrazine -1- formamides, yield：58.9%；MS (ESI) m/z (%):439.0
[M+H]+, structure is shown in Table 1.
Embodiment 15
With reference to the step A in embodiment 1,8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to step B, the step C in embodiment 3,4-(4- methyl piperidines ylmethyl) aniline (B-1), reference is prepared
Step F in embodiment 13 is that N- [4- (4- methyl piperazines are prepared in raw material with 4-(4- methyl piperidines ylmethyl) aniline (B-1)
Piperidinyl methyl) phenyl] phenyl carbamate (2), with reference to the step G in embodiment 13, with N- [4- (4- methyl piperidines ylmethyl)
Phenyl] phenyl carbamate (2) be raw material N- [4- (4- methyl piperidines ylmethyl) phenyl] carbamyl hydrazine (B- is prepared
3), referring finally to the step E in embodiment 1, with 8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids and N- [4- (4- methyl
Piperidino methyl) phenyl] carbamyl hydrazine (B-3) be raw material, N- [4- (4- methyl piperidines ylmethyl) phenyl] -2- is prepared
(8- hydroxyl -2- oxo -2H- chromene -3- carbonyls) hydrazine -1- formamides, structure are shown in Table 1, yield：62.1%；MS(ESI)m/
Z (%):451.1[M+H]+。
Embodiment 16
With reference to the step A in embodiment 2,8- methoxyl group -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to step B, step C, step F, the step G in embodiment 15, N- [4- (4- methyl piperidines Ji Jia are prepared
Base) phenyl] carbamyl hydrazine (B-3), referring finally to the step E in embodiment 1, with 8- methoxyl group -2- oxo -2H- benzo pyrroles
Mutter -3- carboxylic acids and N- [4- (4- methyl piperidines ylmethyl) phenyl] carbamyl hydrazine (B-3) is raw material, and N- [4- (4- are prepared
Methyl piperidine ylmethyl) phenyl] -2- (8- methoxyl group -2- oxo -2H- chromene -3- carbonyls) hydrazine -1- formamides, structure is shown in
Table 1, yield：68.2%；MS (ESI) m/z (%):465.1[M+H]+。
Embodiment 17
With reference to the step A in embodiment 1,8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to step B, the step C in embodiment 5,4-(dimethylaminomethyl) aniline (B-1) are prepared, with reference to real
The step F in example 13 is applied, with 4-(dimethylaminomethyl) aniline (B-1) for raw material, N- [4- (dimethylamino first is prepared
Base) phenyl] phenyl carbamate (2), with reference to the step G in embodiment 13, with N- [4- (dimethylamino methyl) phenyl] amino
Phenyl formate (2) is raw material, N- [4- (dimethylamino methyl) phenyl] carbamyl hydrazine (B-3) is prepared, referring finally to reality
The step E in example 1 is applied, with 8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids and N- [4- (dimethylamino methyl) phenyl] ammonia
Base formylhydrazine (B-3) is raw material, and N- [4- (dimethylamino methyl) phenyl] -2- (8- hydroxyl -2- oxo -2H- benzos are prepared
Pyrans -3- carbonyls) hydrazine -1- formamides, structure is shown in Table 1, yield：50.2%；MS (ESI) m/z (%):397.0[M+H]+。
Embodiment 18
With reference to the step A in embodiment 2,8- methoxyl group -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to step B, the step C in embodiment 5,4-(dimethylaminomethyl) aniline (B-1) are prepared, with reference to real
The step F in example 13 is applied, with 4-(dimethylaminomethyl) aniline (B-1) for raw material, N- [4- (dimethylamino first is prepared
Base) phenyl] phenyl carbamate (2), with reference to the step G in embodiment 13, with N- [4- (dimethylamino methyl) phenyl] amino
Phenyl formate (2) is raw material, and N- [4- (dimethylaminomethyl) phenyl] carbamyl hydrazine (B-3) is prepared, referring finally to
Step E in embodiment 1, with 8- methoxyl group -2- oxo -2H- chromene -3- carboxylic acids and N- [4- (dimethylamino methyl) benzene
Base] carbamyl hydrazine (B-3) be raw material, N- [4- (dimethylamino methyl) phenyl] -2- (8- methoxyl group -2- oxos-are prepared
2H- chromene -3- carbonyls) hydrazine -1- formamides, structure is shown in Table 1, yield：62.1%；MS (ESI) m/z (%):411.0[M+
H]+。
Embodiment 19
With reference to the step A in embodiment 1,8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to step B, step C, the step D in embodiment 1,6-(diethylamino methyl) benzo [d] thiophenes are prepared
Azoles -2- amine (B-2).
Step H, the preparation of N- (6-(diethylamino methyl) benzo [d] thiazole-2- amino) phenyl formate (3)：
6-(diethylamino methyl) benzo [d] thiazole-2- amine (0.02mol) of 5g are dissolved in 20ml dichloromethane,
Stirring adds 4.27ml pyridines (0.053mol), cools to 0 DEG C hereinafter, dropwise addition 1.94g phenyl chloroformates (0.028mol), drop
Finish and be gradually warming up to room temperature, after completion of the reaction, solvent evaporated, then plus water stirring, suction filtration obtain solid product, yield
82.4%, MS (ESI) m/z (%):335.8[M+H]+。
Step I, the preparation of N- [6-(diethylamino methyl) benzo [d] thiazole-2- amino] formylhydrazine (B-4)：
N- (6-(diethylamino methyl) benzo [d] thiazole-2- amino) phenyl formate (0.015mol) of 5g is dissolved in
In 30ml dioxane, agitation and dropping 1.45ml hydrazine hydrates (0.03mol) are warming up to 80 DEG C of reaction 5h and stop after completion of the reaction
Heating, cooling, solvent evaporated are added ether and stir 2h, filter to obtain white solid, yield 64.5%, MS (ESI) m/z (%):
294.8[M+H]+。
With reference to the step E in embodiment 1, it is prepared into 8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids and step I
N- [6-(diethylamino methyl) benzo [d] thiazole-2- amino] formylhydrazine arrived is raw material, and N- [6- (diethylamine is prepared
Ylmethyl) benzothiazole -2- bases] -2- (8- hydroxyl -2- oxo -2H- chromene -3- carbonyls) hydrazine -1- formamides, structure is shown in
Table 1, yield：49.9%；MS (ESI) m/z (%):482.1[M+H]+。
Embodiment 20
With reference to the step A in embodiment 2,8- methoxyl group -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to step B, step C, step D, step H, the step I in embodiment 19, N- [6-(diethyl aminos are prepared
Ylmethyl) benzo [d] thiazole -2- amino] formylhydrazine (B-4), referring finally to the step E in embodiment 1, with 8- methoxyl groups -2-
Oxo-2H- chromene-3- carboxylic acids and N- [6-(diethylamino methyl) benzo [d] thiazole-2- amino] formylhydrazine (B-4)
For raw material, N- [6- (diethylin methyl) benzothiazole -2- bases] -2- (8- methoxyl group -2- oxo -2H- benzo pyrroles are prepared
Mutter -3- carbonyls) hydrazine -1- formamides, yield：55.7%；MS (ESI) m/z (%):496.9[M+H]+, structure is shown in Table 1.
Embodiment 21
With reference to the step A in embodiment 1,8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to step B, step C, the step D in embodiment 3,6- (4- methyl piperidines ylmethyl) benzo [d] is prepared
Thiazole -2- amine (B-2), with reference to the step H in embodiment 19, with 6- (4- methyl piperidines ylmethyl) benzo [d] thiazole -2- amine
(B-2) it is raw material, N- (6- (4- methyl piperidines ylmethyl) benzo [d] thiazole -2- amino) phenyl formate (3) is prepared, joins
It is original with N- (6- (4- methyl piperidines ylmethyl) benzo [d] thiazole -2- amino) phenyl formate according to the step I in embodiment 19
Material, is prepared N- [6- (4- methyl piperidines ylmethyl) benzo [d] thiazole -2- amino] formylhydrazine (B-4), referring finally to implementation
Step E in example 1, with 8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids and N- [6- (4- methyl piperidines ylmethyl) benzos
[d] thiazole -2- amino] formylhydrazine (B-4) be raw material, N- [6- (4- methyl piperidines ylmethyl) benzothiazole -2- are prepared
Base] -2- (8- hydroxyl -2- oxo -2H- chromene -3- carbonyls) hydrazine -1- formamides, yield：45.9%；MS(ESI)m/z
(%):508.9[M+H]+, structure is shown in Table 1.
Embodiment 22
With reference to the step A in embodiment 2,8- methoxyl group -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to step B, step C, step D, step H, the step I in embodiment 21, N- [6- (4- methyl piperazines are prepared
Piperidinyl methyl) benzo [d] thiazole -2- amino] formylhydrazine (B-4), referring finally to the step E in embodiment 1, with 8- methoxyl groups -
2- oxo -2H- chromene -3- carboxylic acids and N- [6- (4- methyl piperidines ylmethyl) benzo [d] thiazole -2- carbamyl hydrazines (B-
4) it is raw material, N- [6- (4- methyl piperidines ylmethyl) benzothiazole -2- bases] -2- (8- methoxyl group -2- oxos -2H- is prepared
Chromene -3- carbonyls) hydrazine -1- formamides, yield：51.6%；MS (ESI) m/z (%):522.8[M+H]+, structure is shown in Table 1.
Embodiment 23
With reference to the step A in embodiment 1,8- hydroxyl -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to step B, step C, the step D in embodiment 5,6-(dimethylaminomethyl) benzo [d] thiophenes are prepared
Azoles-2- amine (B-2), with reference to the step H in embodiment 19, with 6-(dimethylaminomethyl) benzo [d] thiazole-2- amine (B-2)
For raw material, N- (6-(dimethylaminomethyl) benzo [d] thiazole-2- amino) phenyl formate (3) is prepared, with reference to embodiment
Step I in 19 is prepared with N- (6-(dimethylaminomethyl) benzo [d] thiazole-2- amino) phenyl formate (3) for raw material
N- [6-(dimethylaminomethyl) benzo [d] thiazole-2- amino] formylhydrazine (B-4) is obtained, referring finally to the step in embodiment 1
Rapid E, with 8- hydroxyl-2- oxo-2H- chromene-3- carboxylic acids and N- [6-(dimethylaminomethyl) benzo [d] thiazole-2- ammonia
Base] formylhydrazine (B-4) be raw material, N- [6- (dimethylamino methyl) benzothiazole -2- bases] -2- (8- hydroxyl -2- oxygen is prepared
Generation -2H- chromene -3- carbonyls) hydrazine -1- formamides, yield：43.1%；MS (ESI) m/z (%):454.8[M+H]+, structure
It is shown in Table 1.
Embodiment 24
With reference to the step A in embodiment 2,8- methoxyl group -2- oxo -2H- chromene -3- carboxylic acids are prepared.
With reference to step B, step C, step D, step H, the step I in embodiment 23, N- [6-(dimethylaminos are prepared
Ylmethyl) benzo [d] thiazole -2- amino] formylhydrazine (B-4), referring finally to the step E in embodiment 1, with 8- methoxyl groups -2-
Oxo-2H- chromene-3- carboxylic acids and N- [6-(dimethylaminomethyl) benzo [d] thiazole-2- amino] formylhydrazine (B-4)
For raw material, N- [6- (dimethylamino methyl) benzothiazole -2- bases] -2- (8- methoxyl group -2- oxo -2H- benzo pyrroles are prepared
Mutter -3- carbonyls) hydrazine -1- formamides, yield：50.9%；MS (ESI) m/z (%):468.8[M+H]+, structure is shown in Table 1.
The chemical name and structural formula of 1 each embodiment of table
Two, external caspase-3 has been carried out to the compound with Formulas I structure that Examples 1 to 24 is prepared to activate
Vigor filler test, detailed process are as follows.
U-937 suspension cell cultures are in without phenol red RPMI-1640 complete mediums (50000 cells/well), by 100 μ
L U937 cell suspending liquids are inoculated into respectively in two piece of 96 orifice plate, then at 37 DEG C, 5%CO2It is cultivated 15 hours in incubator.
Each compound (including compound in Examples 1 to 24, PAC-1) is configured to 3x final concentrations (with 3% using complete medium respectively
DMSO is blank control), while 50 μ L compounds are added in corresponding hole into two piece of 96 orifice plate, each compound is arranged six times
It repeats.Into first piece of 96 orifice plate, 50 μ L difunctional cell crackings/Caspase Activity buffer solution is added, using microplate reader,
Fluorescence intensity (ex.400nm, em.505nm) is read at intervals of two minutes, is persistently read 1 hour, slope indicates caspase-3 vigor,
The value is the caspase vigor of the U937 cells before compound is handled.Second piece of 96 orifice plate is at 37 DEG C, 5%CO2Environment
Under, continue to be incubated 15 hours, the difunctional cell crackings of 50 μ L/Caspase Activity buffer solution is added later, equally every 2 points
Clock reads fluorescence intensity (ex.400nm, em.505nm), persistently reads 1 hour, subtracts the U937 cells before compound processing
Caspase vigor, finally calculate compound processing 16h when after cell caspase vigor, with positive control PAC-1's
Caspase vigor is 100%, finally finds out activity ratio percentage of each compound relative to PAC-1, the results are shown in Table 2,
In ,+indicate that caspase-3 activates degree between 10%~50%, ++ indicate that caspase-3 activates degree 50%~70%
Between, ++ indicate that caspase-3 activates degree between 70%~100%.
There is table 2 the external caspase-3 of the compound of Formulas I structure to activate vigor test result
From above-mentioned test result it can be clearly seen that the compound of claimed formula I of the invention has significantly
Caspase-3 Activation Activities, quite or better than comparison medicine PAC-1.
The product form and style of above-described embodiment and the non-limiting present invention, the ordinary skill people of any technical field
The appropriate changes or modifications that member does it all should be regarded as the patent category for not departing from the present invention.
Claims (8)
1. a kind of coumarin derivatives as caspase-3 activator, it is characterised in that：Its general structure as shown in I,
Wherein, X CH2, O, S, NH or NHNHCONH；Integers of the n between 1-6；R1For H or be 1~3 be selected from hydroxyl, halogen
Element, nitro, amino, cyano, the alkyl of C1-C6, the alkenyl of C1-C6, the alkynyl of C1-C6, the alkoxy of C1-C6, the alkane of C1-C6
The alkyl sulfenyl of base sulfenyl, the alkyl of the C1-C6 replaced by hydroxyl, amino or halogen or the alkoxy of C1-C6 or C1-C6, quilt
Single or two C1-C6 alkyl-substituted amino, the alkyl amido of C1-C6, free, at salt, esterification and amide
The carboxyl of change, the alkyl sulphinyl of C1-C6, the sulfonyl of C1-C6, the alkyl acyl of C1-C6, carbamoyl are single
Or the alkyl-substituted carbamoyl of two C1-C6, the substituent group of the alkylenedioxy group of C1-C3；
R2And R3It is identical or different, R2And R3Separately it is selected from hydrogen, the alkyl of C1-C10, the naphthenic base of C3-C7, C2-C10
The alkynyl of alkenyl or C2-C10；
Or R2、R3With with R2、R3The nitrogen-atoms connected forms 5~10 circle heterocyclic ring bases or 5~10 unit's heteroaryls together, and described
R2、R3Heterocycle or heteroaryl on contain 1~3 identical or different substituent R4, R4For benzyl, the alkyl of C1-C4, C1-
Alkoxy, halogen, hydroxyl, carboxyl or the ester group of C4；
Ar is the aryl or 5~10 unit's heteroaryls of C6-C10, wherein is selected from N, O containing 1~3 in the heteroaryl of the Ar
And/or the hetero atom of S.
2. a kind of coumarin derivatives as caspase-3 activator according to claim 1, it is characterised in that：
The R2、R3Heterocycle or heteroaryl in addition to R2And R3Outside the nitrogen-atoms of connection, the miscellaneous original selected from N, O and S containing 1~4
Son, the R2、R3Heterocycle in the carbon-carbon triple bond containing 1~2 carbon-carbon double bond or 1~2, on the heteroaryl of the Ar
Contain 1~3 identical or different substituent R5；R5For hydrogen, hydroxyl, halogen, nitro, amino, cyano, the alkyl of C1-C6, C1-
The alkenyl of C6, the alkynyl of C1-C6, the alkoxy of C1-C6, the alkylthio group of C1-C6, the C1-C6 replaced by hydroxyl, amino or halogen
Alkyl or C1-C6 alkoxy, by single or two alkyl-substituted amino of C1-C6, C1-C6 alkyl amidos, it is free,
At salt, esterification and amidated carboxyl, the alkyl sulphinyl of C1-C6, the sulfonyl of C1-C6, the alkyl acyl of C1-C6
Base, carbamoyl, by single or two C1-C6 alkyl-substituted carbamoyl, the alkylenedioxy group of C1-C3.
3. a kind of coumarin derivatives as caspase-3 activator according to claim 2, it is characterised in that：X
For O, S, NH or NHNHCONH；Integers of the n between 1-4；R1For H or be 1~3 be selected from hydroxyl, halogen, nitro, amino,
Cyano, the alkyl of C1-C6, the alkenyl of C1-C6, the alkynyl of C1-C6, the alkoxy of C1-C6, the alkyl sulfenyl of C1-C6, by hydroxyl
The alkyl sulfenyl of base, the alkyl of C1-C6 of amino or halogen substitution or the alkoxy of C1-C6 or C1-C6, by single or two
The alkyl-substituted amino of C1-C6, the alkyl amido of C1-C6, free, at salt, esterification and amidated carboxyl,
The alkyl sulphinyl of C1-C6, the sulfonyl of C1-C6, the alkyl acyl of C1-C6, carbamoyl, by single or two C1-
The alkyl-substituted carbamoyl of C6, the substituent group of the alkylenedioxy group of C1-C3；
R2And R3It is identical or different, R2And R3Separately it is selected from hydrogen, the alkyl of C1-C10, the naphthenic base of C3-C7, C2-C10
The alkynyl of alkenyl or C2-C10；
Or R2、R3With with R2、R3The nitrogen-atoms connected forms 5~10 circle heterocyclic ring bases or 5~10 unit's heteroaryls together, and described
R2、R3Heterocycle or heteroaryl on contain 1~3 identical or different substituent R4, R4For benzyl, the alkyl of C1-C4, C1-
Alkoxy, halogen, hydroxyl, carboxyl or the ester group of C4；
Ar is the aryl or 5~10 unit's heteroaryls of C6-C10, wherein is selected from N, O containing 1~3 in the heteroaryl of the Ar
And/or the hetero atom of S.
4. a kind of coumarin derivatives as caspase-3 activator according to claim 3, it is characterised in that：X
For O, NH or NHNHCONH；Integers of the n between 1-4；R1For H or be 1~3 selected from hydroxyl, halogen, C1-C4 alkyl,
The alkoxy of C1-C4, the substituent group of trifluoromethyl and trifluoromethoxy；
R2And R3It is identical or different, R2And R3Separately it is selected from the alkyl of C1-C6 or the naphthenic base of C3-C6；
Or R2、R3With with R2、R3The nitrogen-atoms connected forms 5~6 circle heterocyclic ring bases, and the R together2、R3Heterocycle on contain
There is 1~3 identical or different substituent R4, R4For benzyl, the alkyl of C1-C4, the alkoxy of C1-C4, halogen, hydroxyl, carboxyl
Or ester group；
Ar is phenyl, naphthalene, pyrrole radicals, furyl, thienyl, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,
Isoxazolyl, 1,2,3- triazol radical, 1,2,4- triazol radical, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, benzothiophene
Base, benzofuranyl, indyl, benzimidazolyl, benzopyrazoles base, benzothiazolyl, benzoxazolyl, quinolyl, isoquinoline
Quinoline base, benzo pyrimidine radicals, benzo pyridazinyl, benzopyrazines base, Thienopyrimidine base, pyrrolo-pyrimidine radicals, thienopyridine base
Or thienopyridine base；R5For hydrogen, halogen, trifluoromethyl, trifluoromethoxy, amino, nitro, the alkyl of C1-C4, C1-C4
Alkynyl, the alkoxy of C1-C4 or the alkylthio group of C1-C4.
5. a kind of coumarin derivatives as caspase-3 activator according to claim 4, it is characterised in that：X
For NH or NHNHCONH；N is 1；R1For hydroxyl or methoxyl group；
R2And R3Take identical substituent group, R2And R3It is respectively selected from the alkyl of C1-C6；
Or R2、R3With with R2、R3The nitrogen-atoms connected forms 5~6 circle heterocyclic ring bases, and the R together2、R3Heterocycle on
Contain 1~3 identical or different substituent R4, R4For the alkyl of C1-C4；
Ar is phenyl, pyrrole radicals, thienyl, imidazole radicals, pyrazolyl, thiazolyl, 1,2,3- triazol radical, 1,2,4- triazole
Base, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, benzothienyl, benzofuranyl, indyl, benzimidazolyl, benzo pyrrole
Oxazolyl, benzothiazolyl, benzoxazolyl, benzo pyrimidine radicals or Thienopyrimidine base；R5For hydrogen, halogen, trifluoromethyl, three
The alkyl of fluorine methoxyl group, amino or C1-C4.
6. a kind of coumarin derivatives as caspase-3 activator according to claim 5, it is characterised in that：X
For NH or NHNHCONH；N is 1；R1For hydroxyl or methoxyl group；
In Formulas IFor
Ar is phenyl or benzothiazolyl；R5For hydrogen, halogen, trifluoromethyl, trifluoromethoxy, the alkane of amino or C1-C4
Base.
7. a kind of coumarin derivatives as caspase-3 activator according to claim 6, it is characterised in that：
The coumarin derivatives as caspase-3 activator are selected from following compound：
N- [2- (6- (Diethylaminomethyl) benzo [d] thiazolyl)] -8- hydroxyl -2- oxo -2H- chromene -3- formamides,
N- [2- (6- (Diethylaminomethyl) benzo [d] thiazolyl)] -8- methoxyl group -2- oxo -2H- chromene -3- formyls
Amine,
N- [2- (6- (4- methyl piperidines ylmethyl) benzo [d] thiazolyl)] -8- hydroxyl -2- oxo -2H- chromene -3- first
Amide,
N- [2- (6- (4- methyl piperidines ylmethyl) benzo [d] thiazolyl)] -8- methoxyl group -2- oxo -2H- chromenes -3-
Formamide,
N- [2- (6- (dimethylaminomethyl) benzo [d] thiazolyl)] -8- hydroxyl -2- oxo -2H- chromene -3- formyls
Amine,
N- [2- (6- (dimethylaminomethyl) benzo [d] thiazolyl)] -8- methoxyl group -2- oxo -2H- chromene -3- first
Amide,
N- [4- (4- methyl piperidines ylmethyl) phenyl] -8- hydroxyl -2- oxo -2H- chromene -3- formamides,
N- [4- (4- methyl piperidines ylmethyl) phenyl] -8- methoxyl group -2- oxo -2H- chromene -3- formamides,
N- [4- (diethylin methyl) phenyl] -8- hydroxyl -2- oxo -2H- chromene -3- formamides,
N- [4- (diethylin methyl) phenyl] -8- methoxyl group -2- oxo -2H- chromene -3- formamides,
N- [4- (dimethylamino methyl) phenyl] -8- hydroxyl -2- oxo -2H- chromene -3- formamides,
N- [4- (dimethylamino methyl) phenyl] -8- methoxyl group -2- oxo -2H- chromene -3- formamides,
N- [4- (diethylin methyl) phenyl] -2- (8- hydroxyl -2- oxo -2H- chromene -3- carbonyls) hydrazine -1- formamides,
N- [4- (diethylin methyl) phenyl] -2- (8- methoxyl group -2- oxo -2H- chromene -3- carbonyls) hydrazine -1- formyls
Amine,
N- [4- (4- methyl piperidines ylmethyl) phenyl] -2- (8- hydroxyl -2- oxo -2H- chromene -3- carbonyls) hydrazine -1- first
Amide,
N- [4- (4- methyl piperidines ylmethyl) phenyl] -2- (8- methoxyl group -2- oxo -2H- chromene -3- carbonyls) hydrazine -1-
Formamide,
N- [4- (dimethylamino methyl) phenyl] -2- (8- hydroxyl -2- oxo -2H- chromene -3- carbonyls) hydrazine -1- formamides,
N- [4- (dimethylamino methyl) phenyl] -2- (8- methoxyl group -2- oxo -2H- chromene -3- carbonyls) hydrazine -1- formyls
Amine,
N- [6- (diethylin methyl) benzothiazole -2- bases] -2- (8- hydroxyl -2- oxo -2H- chromene -3- carbonyls) hydrazine -
1- formamides,
N- [6- (diethylin methyl) benzothiazole -2- bases] -2- (8- methoxyl group -2- oxo -2H- chromene -3- carbonyls)
Hydrazine -1- formamides,
N- [6- (4- methyl piperidines ylmethyl) benzothiazole -2- bases] -2- (8- hydroxyl -2- oxo -2H- chromene -3- carbonyls
Base) hydrazine -1- formamides,
N- [6- (4- methyl piperidines ylmethyl) benzothiazole -2- bases] -2- (8- methoxyl group -2- oxo -2H- chromene -3- carbonyls
Base) hydrazine -1- formamides,
N- [6- (dimethylamino methyl) benzothiazole -2- bases] -2- (8- hydroxyl -2- oxo -2H- chromene -3- carbonyls) hydrazine -
1- formamides,
Or N- [6- (dimethylamino methyl) benzothiazole -2- bases] -2- (8- methoxyl group -2- oxo -2H- chromene -3- carbonyls
Base) hydrazine -1- formamides.
8. a kind of Coumarins as caspase-3 activator as described in any one of claim 1~7 claim spread out
Application of the biology in preparing treatment and/or the drug of pre- anti-cancer and other proliferative diseases.
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