CN108715589B - Coumarin derivative used as caspase-3 activator and application thereof - Google Patents
Coumarin derivative used as caspase-3 activator and application thereof Download PDFInfo
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Abstract
The invention discloses a coumarin derivative used as a caspase-3 activator, similar structural design and use are not seen in similar products, and the coumarin derivative has a remarkable caspase-3 activation effect and can be used for treating caspase-related diseases. The invention also aims to provide the application of the coumarin derivative in preparing medicaments for treating and/or preventing cancers and other proliferative diseases.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a coumarin derivative used as a caspase-3 activator and application thereof in preparing medicines for treating and/or preventing cancers and other proliferative diseases.
Background
Tumor is a disease seriously threatening human life and health, and in recent years, the incidence and death rate of tumor have a trend to rise year by year. Cytotoxic drugs can kill tumor cells, but lack selectivity to cancer cells and normal cells, so the cytotoxic drugs have strong toxic and side effects, and the search for targeting antitumor drugs which can selectively kill cancer cells and have no influence on normal proliferating cells has become an important direction for the research and development of novel antitumor drugs.
Apoptosis is an autonomous and ordered death process in cells regulated by genes, and is generally considered to be caused by uncontrolled growth and hyperproliferation of malignant transformed tumor cells, and is considered to be the result of inhibition of the apoptosis mechanism of tumors and failure of normal cell death and clearance from the viewpoint of apoptosis. A series of oncogenes and proto-oncogenes are activated in tumor cells and show an over-expression state. There is a very close relationship between the activation of these genes and the development of tumors. After many kinds of oncogenes are expressed, the apoptosis process of tumor cells is blocked, so that the number of tumor cells is increased. Therefore, the method for designing the treatment of the tumor through the apoptosis angle and mechanism is to reconstruct the apoptosis signal transfer system of the tumor cell, namely to inhibit the expression of the survival gene of the tumor cell and activate the expression of the death gene.
The Caspase family belongs to the Caspase family and plays a key role in the apoptotic process in multicellular organisms. In humans, 14 caspases have been found to exist, only a part of which is involved in the process of apoptosis, with Caspase-3, the most important member of the Caspase family, being in the common pathway of apoptosis, being one of the key performers of apoptosis. Caspase-3 normally exists in cytoplasm in an inactive zymogen form (procaspase-3), and only when an external apoptosis signal activates caspase-3 to be active, key proteases of cytoplasm, nucleus and cell framework are inactivated, so that apoptosis is caused. Caspase-3 is inhibited in tumor cells, and if caspase-3 can be reactivated, apoptosis will be restarted, thereby inhibiting tumor cell proliferation.
Currently, studies have demonstrated that procaspase-3 is highly expressed in many tumor cells due to caspase-3 inhibition, such as: lymphoma; leukemia; melanoma; neuroblastoma; liver cancer; lung cancer; breast and colon cancer. It is more worth mentioning that procaspase-3 belongs to a downstream protein in an apoptosis signal pathway, and if the cancer is caused by mutation of the downstream protein, an upstream apoptosis signal cannot be correctly transmitted to the downstream protein, so that an anti-tumor drug acting on the intermediate/upstream apoptosis signal cannot play a role in inhibiting tumor cell growth. Therefore, designing and synthesizing a small molecular compound for directly activating caspase-3, and then catalyzing and hydrolyzing a plurality of protein substrates to induce tumor cell apoptosis can be a novel method for safely and effectively searching antitumor drugs.
PAC-1 is the first small molecule compound reported to act directly on caspase-3-proenzyme procaspase-3, activating it to active caspase-3. Experiments show that PAC-1 directly activates procaspase-3 to become caspase-3, so as to induce tumor cell apoptosis, catalyze and hydrolyze various protein substrates, and finally play a role in inhibiting tumor cell proliferation; PAC-1 is currently in the first phase of clinical research with orphans being awarded in 2016.
1541A series of coumarin derivatives with novel structure are obtained by high throughput screening of 6200 compounds, wherein compounds 1541, 1541B, 1541C and 1541D exhibit outstanding activation activity on procaspase-3, compound 1541B has strongest activity, and EC thereof is50At 1.3. mu.M. Research shows that 1541B forms fiber molecules through self-assembly to activate procaspase-3 to become caspase-3, so as to induce tumor cell apoptosis.
The inventor conducts extensive research on coumarin compounds, and synthesizes a series of aryl-containing coumarin derivatives with novel structures by modifying and reconstructing a plurality of structural sites. The compounds are found to have obvious caspase-3 activation effect by testing the activation activity of caspase-3.
Disclosure of Invention
The invention aims to provide coumarin derivatives used as caspase-3 activators, and the compounds have obvious caspase-3 activating effect.
The invention also aims to provide the application of the coumarin derivative in preparing medicaments for treating and/or preventing cancers and other proliferative diseases.
In order to achieve the above purpose, the solution of the invention is:
coumarin derivatives used as caspase-3 activator have a structural formula shown in I,
wherein X is CH2O, S, NH or NHCONH; n is an integer between 1 and 6; r1H or 1 to 3 substituents selected from hydroxyl, halogen, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkyl or C1-C6 alkoxy substituted by hydroxyl, amino or halogen or C1-C6 alkylthio, amino substituted by single or two C1-C6 alkyl, C1-C6 alkylamido, free, salified, esterified and amidated carboxyl, C1-C6 alkylsulfinyl, C1-C6 sulfonyl, C1-C6 alkylacyl, carbamoyl substituted by single or two C1-C6 alkyl, C1-C3 alkylenedioxy;
R2and R3Identical or different, R2And R3Each independently selected from hydrogen, C1-C10 alkyl, C3-C7 cycloalkyl, C2-C10 alkenyl or C2-C10 alkynyl;
or R2、R3And R2、R3The nitrogen atoms to which they are bonded form a 5-to 10-membered heterocyclic group or a 5-to 10-membered heteroaryl group, and R2、R3The heterocyclic group or heteroaryl group of (A) has 1 to 3 same or different substituents R4，R4Is benzyl, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, carboxyl or ester group;
ar is C6-C10 aryl or 5-10-membered heteroaryl, wherein the heteroaryl of Ar contains 1-3 heteroatoms selected from N, O and/or S.
Preferably, said R is2、R3With exception of heterocyclic or heteroaryl groups of R2And R3The nitrogen atom is connected with 1-4 hetero atoms selected from N, O and S, and R2、R3The heterocyclic group of (A) contains 1-2 carbon-carbon double bonds or 1-2 carbon-carbon triple bondsA bond, wherein the heteroaryl group of Ar contains 1 to 3 same or different substituents R5；R5Hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkyl or C1-C6 alkoxy substituted by hydroxy, amino or halogen, amino substituted by one or two C1-C6 alkyl, C1-C6 alkylamido, free, salified, esterified and amidated carboxy, C1-C6 alkylsulfinyl, C1-C6 sulfonyl, C1-C6 alkylacyl, carbamoyl substituted by one or two C1-C6 alkyl, C1-C3 alkylenedioxy.
Preferably, X is O, S, NH or nhconh; n is an integer between 1 and 4; r1H or 1 to 3 substituents selected from hydroxyl, halogen, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkyl or C1-C6 alkoxy substituted by hydroxyl, amino or halogen or C1-C6 alkylthio, amino substituted by single or two C1-C6 alkyl, C1-C6 alkylamido, free, salified, esterified and amidated carboxyl, C1-C6 alkylsulfinyl, C1-C6 sulfonyl, C1-C6 alkylacyl, carbamoyl substituted by single or two C1-C6 alkyl, C1-C3 alkylenedioxy;
R2and R3Identical or different, R2And R3Each independently selected from hydrogen, C1-C10 alkyl, C3-C7 cycloalkyl, C2-C10 alkenyl or C2-C10 alkynyl;
or R2、R3And R2、R3The nitrogen atoms to which they are bonded form a 5-to 10-membered heterocyclic group or a 5-to 10-membered heteroaryl group, and R2、R3The heterocyclic group or heteroaryl group of (A) has 1 to 3 same or different substituents R4，R4Is benzyl, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, carboxyl or ester group;
ar is C6-C10 aryl or 5-10-membered heteroaryl, wherein the heteroaryl of Ar contains 1-3 heteroatoms selected from N, O and/or S.
Preferably, X is O, NH or nhconh; n is an integer between 1 and 4; r1Is H or 1-3 substituents selected from hydroxyl, halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl and trifluoromethoxy;
R2and R3Identical or different, R2And R3Each independently selected from C1-C6 alkyl or C3-C6 cycloalkyl;
or R2、R3And R2、R3The nitrogen atoms to which they are bonded together form a 5-to 6-membered heterocyclic group, and R2、R3The heterocyclic group of (A) contains 1 to 3 same or different substituents R4，R4Is benzyl, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, carboxyl or ester group;
ar is phenyl, naphthyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyrimidinyl, benzopyrazinyl, thienopyrimidinyl, pyrrolopyrimidinyl, thienopyridyl, or thienopyridyl; r5Is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, amino, nitro, alkyl of C1-C4, alkynyl of C1-C4, alkoxy of C1-C4 or alkylthio of C1-C4.
Preferably, X is NH or NHNHCONH; n is 1; r1Is hydroxy or methoxy;
R2and R3Taking the same substituent, R2And R3Are respectively selected from alkyl of C1-C6;
or R2、R3And R2、R3The nitrogen atoms to which they are bonded together form a 5-to 6-membered heterocyclic group, and R2、R3The heterocyclic group of (A) contains 1 to 3 same or different substituentsR4，R4Is C1-C4 alkyl;
ar is phenyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl, benzopyrimidinyl or thienopyrimidyl; r5Is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, amino or C1-C4 alkyl.
Preferably, X is NH or NHNHCONH; n is 1; r1Is hydroxy or methoxy;
in formula I
Is composed of
Or
Ar is phenyl or benzothiazolyl; r5Is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, amino or C1-C4 alkyl.
Preferably, the coumarin derivatives used as caspase-3 activators are selected from the group consisting of:
n- [2- (6- (diethylaminomethyl) benzo [ d ] thiazolyl) ] -8-hydroxy-2-oxo-2H-benzopyran-3-carboxamide,
n- [2- (6- (diethylaminomethyl) benzo [ d ] thiazolyl) ] -8-methoxy-2-oxo-2H-benzopyran-3-carboxamide,
n- [2- (6- (4-methylpiperidinylmethyl) benzo [ d ] thiazolyl) ] -8-hydroxy-2-oxo-2H-benzopyran-3-carboxamide,
n- [2- (6- (4-methylpiperidinylmethyl) benzo [ d ] thiazolyl) ] -8-methoxy-2-oxo-2H-benzopyran-3-carboxamide,
n- [2- (6- (dimethylaminomethyl) benzo [ d ] thiazolyl) ] -8-hydroxy-2-oxo-2H-benzopyran-3-carboxamide,
n- [2- (6- (dimethylaminomethyl) benzo [ d ] thiazolyl) ] -8-methoxy-2-oxo-2H-benzopyran-3-carboxamide,
n- [4- (4-methylpiperidinylmethyl) phenyl ] -8-hydroxy-2-oxo-2H-benzopyran-3-carboxamide,
n- [4- (4-methylpiperidinylmethyl) phenyl ] -8-methoxy-2-oxo-2H-benzopyran-3-carboxamide,
n- [4- (diethylaminomethyl) phenyl ] -8-hydroxy-2-oxo-2H-benzopyran-3-carboxamide,
n- [4- (diethylaminomethyl) phenyl ] -8-methoxy-2-oxo-2H-benzopyran-3-carboxamide,
n- [4- (dimethylaminomethyl) phenyl ] -8-hydroxy-2-oxo-2H-benzopyran-3-carboxamide,
n- [4- (dimethylaminomethyl) phenyl ] -8-methoxy-2-oxo-2H-benzopyran-3-carboxamide,
n- [4- (diethylaminomethyl) phenyl ] -2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
n- [4- (diethylaminomethyl) phenyl ] -2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
n- [4- (4-methylpiperidinylmethyl) phenyl ] -2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
n- [4- (4-methylpiperidinylmethyl) phenyl ] -2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
n- [4- (dimethylaminomethyl) phenyl ] -2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
n- [4- (dimethylaminomethyl) phenyl ] -2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
n- [6- (diethylaminomethyl) benzothiazol-2-yl ] -2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
n- [6- (diethylaminomethyl) benzothiazol-2-yl ] -2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
n- [6- (4-methylpiperidinylmethyl) benzothiazol-2-yl ] -2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
n- [6- (4-methylpiperidinylmethyl) benzothiazol-2-yl ] -2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
n- [6- (dimethylaminomethyl) benzothiazol-2-yl ] -2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
or N- [6- (dimethylaminomethyl) benzothiazol-2-yl ] -2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have poor or no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "alkylene" refers to straight or branched chain alkylene; "aryl" refers to phenyl with no substituents or with substituents; "heteroaryl" means a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, the ring system being aromatic, such as thiazolyl, imidazolyl, pyridyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, furyl, thienyl, pyrrolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl and the like.
A process for the preparation of coumarin derivatives useful as caspase-3 activators, by reaction of the corresponding intermediate A with the corresponding intermediate B according to scheme 1, to obtain the compounds of formula I:
wherein the intermediate A is prepared as shown in scheme 2, and the substituent R1As defined above:
when X is NH, Ar is phenyl and n is 1, intermediate B-1 is prepared as in scheme 3, substituent R2And R3As defined above:
when X is NH, Ar is benzothiazolyl and n is 1, intermediate B-2 is prepared as in scheme 4, substituent R2And R3As defined above:
when X is NHCONH, Ar is phenyl and n is 1, intermediate B-3 is prepared as shown in scheme 5, substituent R2And R3As defined above:
when X is NHCONH, Ar is benzothiazolyl and n is 1, intermediate B-4 is prepared as shown in scheme 6, substituent R2And R3As defined above:
the coumarin derivatives used as caspase-3 activators are used in the preparation of medicaments for treating and/or preventing cancers and other proliferative diseases.
After the technical scheme is adopted, the coumarin derivative used as the caspase-3 activator does not have similar structural design and use in similar products, has a remarkable caspase-3 activation effect, and has an application prospect in the field of preparing medicaments for treating and/or preventing cancers and other proliferative diseases.
Detailed Description
In order to further explain the technical solution of the present invention, the present invention is explained in detail by the following specific examples.
First, synthesis example:
the reagents used in each example were either analytically or chemically pure, and the NMR spectra of the synthesized compounds were determined using Bruker ARX-400 and the mass spectra were determined using Agilent 1100 LC/MSD.
Example 1
Step A, preparation of 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid:
adding 0.1mol of 2, 3-dihydroxy benzaldehyde and 0.11mol of Meldrum's acid into 80ml of water, reacting at 80 ℃ for 2H, cooling after the reaction is finished, and performing suction filtration to obtain a product intermediate A, wherein the yield is 92.5%, and 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, N preparation of Ethyl-N- (4-nitrobenzyl) ethylamine (1)
20g of p-nitrobenzyl bromide (0.092mol) and 14.14g of diethylamine (0.19mol) are added into 80ml of acetonitrile, stirred for 5H at room temperature, after the reaction is finished, 200ml of water and 200ml of dichloromethane are added into the reaction solution, extraction is carried out to obtain an organic layer, anhydrous sodium sulfate is dried, the solvent is evaporated to dryness, the yield is 73.1 percent, MS (ESI) M/z (%): 208.4[ M + H%]+；1H NMR(400MHz,CDCl3)δ8.21–8.13(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, preparation of 4- (diethylaminomethyl) aniline (B-1):
20g of N-ethyl-N- (4-nitrobenzyl) ethylamine (0.096mol) are dissolved in 80mL of 90% ethanol, the temperature is raised to 60 ℃ with stirring, and 6.07g of trichloro chloride hexahydrate are addedFerric oxide (0.022mol) and trace active carbon, 53.5g hydrazine hydrate (1.05mol) are dripped in, after the reaction is finished, the temperature is raised to 80 ℃, reflux reaction is carried out, after the reaction is finished, the hot reaction solution is filtered, 250ml water is added into the filtrate, 100ml dichloromethane is added into the filtrate, extraction is carried out twice, the dichloromethane layer is added into saturated sodium chloride for extraction, then drying is carried out by using anhydrous sodium sulfate, the solvent is evaporated, the yield is 66.2%, MS (ESI) M/z (%): 178.6[ M + H%]+；1H NMR(400MHz,CDCl3)δ7.13(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, preparation of 6- (diethylaminomethyl) benzo [ D ] thiazol-2-amine (B-2):
dissolving 6.5g 4- (diethylaminomethyl) aniline (0.036mol) and 13.9g ammonium thiocyanate (0.182mol) in 50ml acetic acid, stirring for 0.5H, cooling to below 10 deg.C, slowly adding 2.25ml bromine in acetic acid dropwise, reacting at room temperature for 5H, pouring the reaction solution into 200ml water, adjusting pH to alkalinity with NaOH solution, vacuum filtering to remove insoluble substances, adjusting pH of the filtrate to 10 with NaOH solution, precipitating solid, vacuum filtering to obtain yellow solid with yield of 58.9%, MS (ESI) M/z (%) (236.0 [ M + H)]+；1H NMR(400MHz,DMSO)δ7.55(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 preparation of- [2- (6- (diethylaminomethyl) benzo [ d ] thiazolyl) ] -8-hydroxy-2-oxo-2H-benzopyran-3-carboxamide:
2.9g of 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid (0.009mol), 0.16ml of DIPEA and 6.9g of HATU (0.018mol) are dissolved in 20ml of DMF and, after stirring for 2H, 1.6g of 6- (diethylaminomethyl) -benzo [ d ] is added]Thiazole-2-amine (0.009mol) reacts at room temperature for 1h, after the reaction is finished, the reaction solution is poured into 30ml of water, solid is separated out, the mixture is stirred at room temperature for 2h and is filtered, the filter cake is washed by methanol, and the mixture is stirred for 4h and is filtered to obtain yellow solid, the structure is shown in table 1, and the yield is as follows: 45.1 percent; 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。
Example 2
Referring to step A of example 1, 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared in 88.7% yield using 2-hydroxy 3-methoxybenzaldehyde as the starting material, MS (ESI) M/z (%) 219.1[ M-H-Z ]]-；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)。
Referring to step B, step C and step D in example 1, 6- (diethylaminomethyl) benzo [ D ] was prepared]Thiazol-2-amine (B-2), finally referring to step E in example 1, starting with 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid and 6- (diethylaminomethyl) benzo [ d ]]Taking thiazole-2-amine (B-2) as a raw material to prepare N- [2- (6- (diethylaminomethyl) benzo [ d ]]Thiazolyl)]-8-methoxy-2-oxo-2H-benzopyran-3-carboxamide, structure shown in table 1, yield: 46.2 percent; 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)。
Example 3
Referring to step A in example 1, 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
With reference to step B of example 1, p-nitrobenzyl bromide and 4-methylpiperidine as starting materials, 4-methyl-1- (4-nitrophenyl) piperidine (1) was prepared, with reference to step C of example 1, 4-methyl-1- (4-nitrophenyl) piperidine as starting material, 4- (4-methylpiperidinylmethyl) aniline (B-1) was prepared, and with reference to the method of step D of example one, 4- (4-methylpiperidinylmethyl) aniline as starting material, 6- (4-methylpiperidinylmethyl) benzo [ D]Thiazol-2-amine (B-2), yield: 85.3 percent; 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)。
Finally, with reference to step E in example 1, with 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid and 6- (4-methylpiperidinylmethyl) benzo [ d]Taking thiazole-2-amine (B-2) as a raw material to prepare N- [2- (6- (4-methylpiperidinylmethyl) benzo [ d ]]Thiazolyl)]-8-hydroxy-2-oxo-2H-benzopyran-3-carboxamide, structure shown in table 1, yield: 55.7 percent; MS (ESI) M/z (%) 450.2[ M + H]+；1H NMR(400MHz,DMSO)δ9.00(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。
Example 4
Referring to step A of example 1, 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared starting from 2-hydroxy 3-methoxybenzaldehyde.
With reference to step B, step C and step D in example 3, 6- (4-methylpiperidinylmethyl) benzo [ D ] was prepared]Thiazol-2-amine (B-2), finally referring to step E in example 1, starting with 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid and 6- (4-methylpiperidinylmethyl) benzo [ d []Taking thiazole-2-amine (B-2) as a raw material to prepare N- [2- (6- (4-methylpiperidinylmethyl) benzo [ d ]]Thiazolyl)]-8-methoxy-2-oxo-2H-benzopyran-3-carboxamide, structure shown in table 1, yield: 61.3 percent; 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)。
Example 5
Referring to step A in example 1, 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
With reference to step B of example 1, N-methyl-N- (4-nitrobenzyl) methylamine (1) was prepared from p-nitrobenzyl bromide and dimethylamine, with reference to step C of example 1, 4- (dimethylaminomethyl) aniline (B-1) was prepared from N-methyl-N- (4-nitrobenzyl) methylamine, and with reference to step D of example 1, 6- (dimethylaminomethyl) benzo [ D ] was prepared from 4- (dimethylaminomethyl) aniline]Thiazol-2-amine (B-2), finally referring to step E in example 1, starting with 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid and 6- ((dimethylamino) methyl) benzo [ d []Taking thiazole-2-amine (B-2) as a raw material to prepare N- [2- (6- (dimethylaminomethyl) benzo [ d ]]Thiazolyl)]-8-hydroxy-2-oxo-2H-benzopyran-3-carboxamide, structure shown in table 1, yield: 51.1 percent; MS (ESI) M/z (%): 396.1[ M + H]+；1H NMR(400MHz,DMSO)δ9.01(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。
Example 6
Referring to step A of example 1, 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared starting from 2-hydroxy 3-methoxybenzaldehyde.
With reference to step B, step C and step D in example 5, 6- (dimethylaminomethyl) benzo [ D ] was prepared]Thiazol-2-amine (B-2), finally referring to step E in example 1, starting with 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid and 6- (dimethylaminomethyl) benzo [ d ]]Taking thiazole-2-amine (B-2) as a raw material to prepare N- [2- (6- (dimethylaminomethyl) benzo [ d ]]Thiazolyl)]-8-methoxy-2-oxo-2H-benzopyran-3-carboxamide, structure shown in table 1, yield: 53.2 percent; 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)δ161.24,160.52,158.42,149.77,149.56,146.89,143.92,132.50,129.76,126.93,125.99,125.15,122.06,121.50,119.34,118.27,117.60,60.03,56.84,42.16。
Example 7
Referring to step A in example 2, 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
4- (4-Methylpiperidylmethyl) aniline (B-1) was prepared according to Steps B and C of example 3, and N- [4- (4-Methylpiperidylmethyl) phenyl ] amine (B-1) was prepared from 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid and 4- (4-Methylpiperidylmethyl) aniline (B-1) according to step E of example 1]-8-methoxy-2-oxo-2H-benzopyran-3-carboxamide, structure shown in table 1, yield: 61.4 percent; 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)。
Example 8
Referring to step A in example 1, 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
4- (4-Methylpiperidylmethyl) aniline (B-1) was prepared according to Steps B and C of example 3, and N- [4- (4-Methylpiperidylmethyl) phenyl ] amine (B-1) was prepared from 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid and 4- (4-Methylpiperidylmethyl) aniline (B-1) as starting materials according to step E of example 1]-8-hydroxy-2-oxo-2H-benzopyran-3-carboxamide, structure shown in table 1, yield: 55.7 percent; MS (ESI) M/z (%): 450.1[ M + H]+；1H NMR(400MHz,DMSO)δ9.00(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。
Example 9
Referring to step A in example 2, 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
Referring to the steps B and C of example 1, 4- (diethylaminomethyl) aniline (B-1) was prepared, and referring to the step E of example 1, N- [4- (diethylaminomethyl) phenyl ] aniline (B-1) was prepared from 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid and 4- (diethylaminomethyl) aniline (B-1)]-8-methoxy-2-oxo-2H-benzopyran-3-carboxamide, structure 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。
Example 10
Referring to step A in example 1, 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
4- (diethylaminomethyl) aniline (B-1) was prepared according to steps B and C of example 1, and N- [4- (diethylaminomethyl) phenyl ] aniline (B-1) was prepared from 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid and 4- (diethylaminomethyl) aniline (B-1) as starting materials according to step E of example 1]-8-hydroxy-2-oxo-2H-benzopyran-3-carboxamide, structure 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)。
Example 11
Referring to step A in example 1, 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
Referring to step B, step C of example 5 to prepare 4- (dimethylaminomethyl) aniline (B-1), and referring to step E of example 1, starting from 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid and 4- (dimethylaminomethyl) aniline (B-1), N- [4- (dimethylaminomethyl) phenyl ] aniline was prepared]-8-hydroxy-2-oxo-2H-benzopyran-3-carboxamide, structure 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)。
Example 12
Referring to step A in example 2, 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
Referring to step B and step C of example 5, 4- (dimethylaminomethyl) aniline (B-1) was prepared, and referring to step E of example 1, N- [4- (dimethylaminomethyl) phenyl ] aniline (B-1) was prepared from 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid and 4- (dimethylaminomethyl) aniline (B-1)]-8-methoxy-2-oxo-2H-benzopyran-3-carboxamide, structure 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)δ160.62,160.58,148.27,146.84,143.72,139.49,132.67,125.78,121.71,120.48,119.49,116.89,59.33,56.77,52.12,31.28,28.58,21.53。
Example 13
Referring to step A in example 1, 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
Step F, N preparation of phenyl- [4- (diethylaminomethyl) phenyl ] carbamate (2):
dissolving 5g of 4- (diethylaminomethyl) aniline (0.02mol) in 20ml of dichloromethane, stirring, adding 4.27ml of pyridine (0.053mol) into the mixture, cooling the mixture to below 0 ℃, dropwise adding 1.94g of phenyl chloroformate (0.028mol), gradually heating the mixture to room temperature after dropwise addition, evaporating the solvent after the reaction is finished, adding water into the mixture, stirring the mixture, and performing suction filtration to obtain a solid product, wherein the yield is 70.1%, and MS (ESI) M/z (%) is 298.9[ M + H ], (298.]+。
Step G, N preparation of- [4- (diethylaminomethyl) phenyl ] carbamoylhydrazine (B-3):
5g of N- [4- (diethylaminomethyl) phenyl]Dissolving phenyl carbamate (0.015mol) in 30ml dioxane, stirring and dropwise adding hydrazine hydrate (0.03mol) 1.45ml, heating to 80 ℃ for reaction for 5H, stopping heating after the reaction is finished, cooling, evaporating the solvent, adding diethyl ether, stirring for 2H, and filtering to obtain white solid with the yield of 55.2%, wherein MS (ESI) M/z (%) is 236.8[ M + H ]]+。
The method according to step E, using 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid and the N- [4- (diethylaminomethyl) phenyl group obtained in step G]Carbamyl hydrazine is used as raw material to prepare N- [4- (diethylaminomethyl) phenyl]-2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide, structure shown in table 1, yield: 49.9 percent; MS (ESI) M/z (%): 425.2[ M + H)]+。
Example 14
Referring to step A in example 2, 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
Preparation of N- [4- (diethylaminomethyl) phenyl ] was carried out in the same manner as in step F and step G of example 13]Carbamoyl hydrazine (B-3), finally according to step E of example 1, starting with 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid and N- [4- (diethylaminomethyl) phenyl]Carbamyl hydrazine (B-3) is used as a raw material to prepare N- [4- (diethylaminomethyl) phenyl]-2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide, yield: 58.9 percent; MS (ESI) M/z (%): 439.0[ M + H]+The structure is shown in Table 1.
Example 15
Referring to step A in example 1, 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
4- (4-Methylpiperidylmethyl) aniline (B-1) was prepared according to steps B and C of example 3, and N- [4- (4-Methylpiperidylmethyl) phenyl ] amine (B-1) was prepared from 4- (4-Methylpiperidylmethyl) aniline (B-1) according to step F of example 13]Phenyl carbamate (2), see step G in example 13, as N- [4- (4-methylpiperidinylmethyl) phenyl]Phenyl carbamate (2) is used as a raw material to prepare N- [4- (4-methylpiperidinylmethyl) phenyl]Carbamoyl hydrazine (B-3), finally according to step E of example 1, starting with 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid and N- [4- (4-methylpiperidinylmethyl) phenyl]Carbamyl hydrazine (B-3) is used as a raw material to prepare N- [4- (4-methylpiperidinylmethyl) phenyl]-2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide, structure shown in table 1, yield: 62.1 percent; MS (ESI) M/z (%): 451.1[ M + H]+。
Example 16
Referring to step A in example 2, 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
With reference to step B, step C, step F and step G in example 15, N- [4- (4-methylpiperidylmethyl) phenyl ] was prepared]Carbamoyl hydrazine (B-3), finally according to step E of example 1, starting with 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid and N- [4- (4-methylpiperidinylmethyl) phenyl]Carbamyl hydrazine (B-3) is used as a raw material to prepare N- [4- (4-methylpiperidinylmethyl) phenyl]-2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide, structure shown in table 1, yield: 68.2 percent; MS (ESI) M/z (%): 465.1[ M + H]+。
Example 17
Referring to step A in example 1, 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
4- (dimethylaminomethyl) aniline (B-1) was prepared according to steps B and C in example 5, and N- [4- (dimethylaminomethyl) phenyl ] was prepared from 4- (dimethylaminomethyl) aniline (B-1) according to step F in example 13]Phenyl carbamate (2) as N- [4- (dimethylaminomethyl) phenyl ester according to step G of example 13]Benzoic acid carbamateThe ester (2) is used as a raw material to prepare the N- [4- (dimethylamino methyl) phenyl]Carbamoyl hydrazine (B-3), finally according to step E of example 1, starting with 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid and N- [4- (dimethylaminomethyl) phenyl]Carbamyl hydrazine (B-3) is used as a raw material to prepare N- [4- (dimethylamino methyl) phenyl]-2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide, structure shown in table 1, yield: 50.2 percent; MS (ESI) M/z (%): 397.0[ M + H)]+。
Example 18
Referring to step A in example 2, 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
4- (dimethylaminomethyl) aniline (B-1) was prepared according to steps B and C in example 5, and N- [4- (dimethylaminomethyl) phenyl ] was prepared from 4- (dimethylaminomethyl) aniline (B-1) according to step F in example 13]Phenyl carbamate (2) as N- [4- (dimethylaminomethyl) phenyl ester according to step G of example 13]Phenyl carbamate (2) is used as a raw material to prepare N- [4- (dimethylaminomethyl) phenyl]Carbamoyl hydrazine (B-3), finally according to step E of example 1, starting with 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid and N- [4- (dimethylaminomethyl) phenyl]Carbamyl hydrazine (B-3) is used as a raw material to prepare N- [4- (dimethylamino methyl) phenyl]-2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide, structure shown in table 1, yield: 62.1 percent; MS (ESI) M/z (%): 411.0[ M + H]+。
Example 19
Referring to step A in example 1, 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
Referring to step B, step C and step D in example 1, 6- (diethylaminomethyl) benzo [ D ] thiazol-2-amine (B-2) was prepared.
Step H, N preparation of phenyl (6- (diethylaminomethyl) benzo [ d ] thiazole-2-amino) carboxylate (3):
5g of 6- (diethylaminomethyl) benzo [ d ]]Thiazole-2-amine (0.02mol) was dissolved in 20ml of dichloromethane, 4.27ml of pyridine (0.053mol) was added with stirring, the temperature was reduced to below 0 ℃ and 1.9 g of pyridine was added dropwise4g phenyl chloroformate (0.028mol), gradually heating to room temperature after dropwise addition, evaporating to dryness, adding water, stirring, and vacuum filtering to obtain solid product with yield of 82.4%, MS (ESI) M/z (%) of 335.8[ M + H ]]+。
Step I, N preparation of- [6- (diethylaminomethyl) benzo [ d ] thiazole-2-amino ] carbohydrazide (B-4):
5g of N- (6- (diethylaminomethyl) benzo [ d ]]Dissolving thiazole-2-amino) phenyl formate (0.015mol) in 30ml dioxane, stirring and dropwise adding hydrazine hydrate (0.03mol) 1.45ml, heating to 80 ℃ for reaction for 5H, stopping heating after the reaction is finished, cooling, evaporating the solvent, adding diethyl ether, stirring for 2H, and performing suction filtration to obtain a white solid, wherein the yield is 64.5%, and MS (ESI) M/z (%): 294.8[ M + H)]+。
Referring to step E of example 1, N- [6- (diethylaminomethyl) benzo [ d ] prepared from 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid and step I]Thiazol-2-amino]Using formylhydrazine as raw material to prepare N- [6- (diethylaminomethyl) benzothiazole-2-yl]-2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide, structure shown in table 1, yield: 49.9 percent; MS (ESI) M/z (%): 482.1[ M + H ]]+。
Example 20
Referring to step A in example 2, 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
With reference to step B, step C, step D, step H and step I in example 19, N- [6- (diethylaminomethyl) benzo [ D ] was prepared]Thiazol-2-amino]Formyl hydrazine (B-4), finally, according to step E of example 1, starting from 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid and N- [6- (diethylaminomethyl) benzo [ d ]]Thiazol-2-amino]Using formylhydrazine (B-4) as raw material to prepare N- [6- (diethylaminomethyl) benzothiazole-2-yl]-2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide, yield: 55.7 percent; MS (ESI) M/z (%): 496.9[ M + H]+The structure is shown in Table 1.
Example 21
Referring to step A in example 1, 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
With reference to step B, step C and step D in example 3, 6- (4-methylpiperidinylmethyl) benzo [ D ] was prepared]Thiazol-2-amine (B-2), reference step H in example 19, with 6- (4-methylpiperidylmethyl) benzo [ d]Taking thiazole-2-amine (B-2) as a raw material to prepare N- (6- (4-methylpiperidinylmethyl) benzo [ d]Phenyl thiazole-2-amino) carboxylate (3), according to step I in example 19, was synthesized as N- (6- (4-methylpiperidinylmethyl) benzo [ d]Taking thiazole-2-amino) phenyl formate as a raw material to prepare N- [6- (4-methylpiperidinylmethyl) benzo [ d]Thiazol-2-amino]Formyl hydrazine (B-4), finally, according to step E of example 1, starting from 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid and N- [6- (4-methylpiperidinylmethyl) benzo [ d]Thiazol-2-amino]Using formyl hydrazine (B-4) as raw material to prepare N- [6- (4-methylpiperidinylmethyl) benzothiazole-2-yl]-2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide, yield: 45.9 percent; MS (ESI) M/z (%): 508.9[ M + H]+The structure is shown in Table 1.
Example 22
Referring to step A in example 2, 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
With reference to step B, step C, step D, step H and step I in example 21, N- [6- (4-methylpiperidylmethyl) benzo [ D ] was prepared]Thiazol-2-amino]Formyl hydrazine (B-4), final reference to step E in example 1, starting from 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid and N- [6- (4-methylpiperidinylmethyl) benzo [ d]Taking thiazole-2-carbamyl hydrazine (B-4) as a raw material to prepare N- [6- (4-methylpiperidinylmethyl) benzothiazole-2-yl]-2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide, yield: 51.6 percent; MS (ESI) M/z (%): 522.8[ M + H]+The structure is shown in Table 1.
Example 23
Referring to step A in example 1, 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
With reference to step B, step C and step D in example 5, 6- (dimethylaminomethyl) benzo [ D ] was prepared]Thiazol-2-amine (B-2), reference step H in example 19, with 6- (dimethylaminomethyl) benzo [ d]Thiazole-2-amine (B-2) as a starting materialPreparing to obtain N- (6- (dimethylaminomethyl) benzo [ d]Phenyl thiazole-2-amino) carboxylate (3), according to step I in example 19, with N- (6- (dimethylaminomethyl) benzo [ d]Taking thiazole-2-amino) phenyl formate (3) as a raw material to prepare N- [6- (dimethylaminomethyl) benzo [ d ]]Thiazol-2-amino]Formyl hydrazine (B-4), finally, according to step E of example 1, starting from 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid and N- [6- (dimethylaminomethyl) benzo [ d ]]Thiazol-2-amino]Using formylhydrazine (B-4) as raw material to prepare N- [6- (dimethylaminomethyl) benzothiazole-2-yl]-2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide, yield: 43.1%; MS (ESI) M/z (%): 454.8[ M + H]+The structure is shown in Table 1.
Example 24
Referring to step A in example 2, 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid was prepared.
With reference to step B, step C, step D, step H and step I in example 23, N- [6- (dimethylaminomethyl) benzo [ D ] was prepared]Thiazol-2-amino]Formyl hydrazine (B-4), finally, according to step E of example 1, starting from 8-methoxy-2-oxo-2H-benzopyran-3-carboxylic acid and N- [6- (dimethylaminomethyl) benzo [ d ]]Thiazol-2-amino]Using formylhydrazine (B-4) as raw material to prepare N- [6- (dimethylaminomethyl) benzothiazole-2-yl]-2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide, yield: 50.9 percent; MS (ESI) M/z (%): 468.8[ M + H]+The structure is shown in Table 1.
TABLE 1 chemical name and structural formula of each example
Secondly, the compound with the structure shown in the formula I prepared in the embodiment 1-24 is subjected to an in vitro caspase-3 activation activity screening test, and the specific process is as follows.
U-937 suspension cell culture in phenol Red-free RPMI-1640 complete Medium (50000 cells/well), 100. mu. L U937 cell suspensions were seeded separately in two 96-well plates and then incubated at 37 ℃ in 5% CO2The culture was carried out in an incubator for 15 hours. Each compound (including the compounds of examples 1-24, PAC-1) was individually configured to a 3 final concentration (3% DMSO as a blank) using complete media, while 50 μ L of compound was added to corresponding wells in two 96-well plates, each compound set up in six replicates. To the first 96 well plate, 50 μ L of bifunctional cell lysis/caspase activity buffer was added, and the fluorescence intensity (ex.400nm, em.505nm) was read every 2 minutes using a microplate reader for 1 hour with a slope representing caspase-3 activity, which is the caspase activity of U937 cells prior to compound treatment. Second 96-well plate at 37 ℃ with 5% CO2Under the environment, the incubation is continued for 15 hours, then 50 μ L of bifunctional cell lysis/caspase activity buffer is added, the fluorescence intensity (ex.400nm, em.505nm) is also read every 2 minutes, the reading is continued for 1 hour, the caspase activity of U937 cells before compound treatment is subtracted, finally, the caspase activity of the cells after compound treatment for 16 hours is calculated, the caspase activity of a positive control PAC-1 is taken as 100%, and finally, the activation rate percentage of each compound relative to the PAC-1 is calculated, and the result is shown in Table 2, wherein, + represents that the activation degree of caspase-3 is between 10% and 50%, + represents that the activation degree of caspase-3 is between 50% and 70%, and, + represents that the activation degree of caspase-3 is between 70% and 100%.
TABLE 2 in vitro caspase-3 activation Activity test results for Compounds having the Structure of formula I
As is clear from the above test results, the compounds of formula I as claimed in the present invention have significant caspase-3 activating activity, comparable or superior to that of the control drug PAC-1.
The above embodiments are not intended to limit the form and style of the present invention, and any suitable changes or modifications made by those skilled in the art should be considered as not departing from the scope of the present invention.
Claims (2)
1. A coumarin derivative useful as a caspase-3 activator, characterized by: the coumarin derivative used as the caspase-3 activator is selected from the following compounds:
N- [2- (6- (diethylaminomethyl) benzo [ d ]]Thiazolyl)]-8-hydroxy-2-oxo-2H-a benzopyran-3-carboxamide having a structure,
N- [2- (6- (diethylaminomethyl) benzo [ d ]]Thiazolyl)]-8-methoxy-2-oxo-2H-a benzopyran-3-carboxamide having a structure,
N- [2- (6- (4-methylpiperidinylmethyl) benzo [ d ]]Thiazolyl)]-8-hydroxy-2-oxo-2H-a benzopyran-3-carboxamide having a structure,
N- [2- (6- (4-methylpiperidinylmethyl) benzo [ d ]]Thiazolyl)]-8-methoxy-2-oxo-2H-a benzopyran-3-carboxamide having a structure,
N- [2- (6- (dimethylaminomethyl) benzo [ d ]]Thiazolyl)]-8-hydroxy-2-oxo-2H-a benzopyran-3-carboxamide having a structure,
N- [2- (6- (dimethylaminomethyl) benzo [ d ]]Thiazolyl)]-8-methoxy-2-oxo-2H-a benzopyran-3-carboxamide having a structure,
N- [6- (diethylaminomethyl) benzothiazol-2-yl group]-2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
N- [6- (diethylaminomethyl) benzothiazol-2-yl group]-2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
N- [6- (4-Methylpiperidylmethyl) benzothiazol-2-yl]-2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
N- [6- (4-Methylpiperidylmethyl) benzothiazol-2-yl]-2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
N- [6- (dimethylaminomethyl) benzothiazol-2-yl]-2- (8-hydroxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide,
orN- [6- (dimethylaminomethyl) benzothiazol-2-yl]-2- (8-methoxy-2-oxo-2H-benzopyran-3-carbonyl) hydrazine-1-carboxamide.
2. Use of a coumarin derivative as claimed in claim 1 as a caspase-3 activator in the manufacture of a medicament for the treatment and/or prophylaxis of cancer and other proliferative disorders.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1516700A (en) * | 2001-05-16 | 2004-07-28 | ά | Substituted 4H-chromenes and analogs as activators ofgasp ases and inducers of apoptosis and use thereof |
| CN1668609A (en) * | 2002-05-16 | 2005-09-14 | 西托维亚公司 | Substituted 4-aryl-4H-pyrrolo[2,3-H]chromenes and analogs as activators of caspases and inducers of apoptosis and the use thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1516700A (en) * | 2001-05-16 | 2004-07-28 | ά | Substituted 4H-chromenes and analogs as activators ofgasp ases and inducers of apoptosis and use thereof |
| CN1668609A (en) * | 2002-05-16 | 2005-09-14 | 西托维亚公司 | Substituted 4-aryl-4H-pyrrolo[2,3-H]chromenes and analogs as activators of caspases and inducers of apoptosis and the use thereof |
| CN101421260A (en) * | 2006-04-12 | 2009-04-29 | 诺瓦提斯公司 | Chromen-2-one derivatives |
Non-Patent Citations (2)
| Title |
|---|
| "Design, synthesis and biological evaluation of coumarin derivatives as novel acetylcholinesterase inhibitors that attenuate H2O2-induced apoptosis in SH-SY5Y cells";Dahong Yao et al.;《Bioorganic Chemistry》;20160727;第68卷;第112-123页 * |
| Aurora Fine Chemicals等提供的产品目录;来源：;《数据库REGISTRY（在线）》;20160511;CAS登记号: 1908294-14-3等 * |
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