CN109824640A - A kind of coumarin kind compound and its pharmaceutical composition, preparation method and application - Google Patents
A kind of coumarin kind compound and its pharmaceutical composition, preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of coumarin kind compound with BRD4 albumen inhibiting effect, which includes: the compound and its pharmaceutically acceptable salt of structure shown in lower formula (I)；The compound for containing the brand new of cumarin parent nucleus can inhibit in various degree BRD4 albumen, it can be used for preparing BRD4 protein inhibitor, it can also be used to prevent and treat disease relevant to BRD4 protein active, related disease type is extremely more, therefore its application range is extremely wide.The invention also discloses the preparation method of the coumarin kind compound, raw material sources are wide, easy to operate, mild condition, at low cost, are fully compatible for industrialization large-scale production.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to coumarin derivatives, they preparation method, contain these
The Pharmaceutical composition of compound and their medicinal usage, especially as the purposes of BRD4 protein inhibitor.
Background technique
In recent years, tumour becomes one of the main reason for leading to human death in global range.Tumour generally has totality
The features such as cure rate is low and high recurrence rate, therefore prevent, treat and inhibit tumor recurrence that there is important scientific research value, it realizes
The prevention and healing of tumour have comparable urgent and challenge.
The exception of epigenetic regulation is to lead to one of tumorigenic key factor.Current research discovery, BRD4 albumen
The epigenetic of mediation is abnormal closely related with the overexpression of oncogene and in close relations with the growing multiplication of cancer cell.BRD4
It is a member of Bromodomain and extra C-terminal domain (BET) protein family, due in anti-tumor aspect
Potential value, cause the very big concern of major drugmaker and scientific research institution.
BET albumen is also referred to as epigenetic identification albumen, can identify that the epigenetics information in cellular histone becomes
Change, and transmit activated cell division etc. signal.By taking leukaemia as an example, the gene mutation of BET albumen can interfere this in haemocyte
Kind signal transmission, causes sick cell uncontrollably to divide, thus insulting histoorgan.BRD3/BRD4's
The code area Bromodomain and NUT (nucleoprotein in testis) gene chromosomal translocation form BRD-NUT pattern of fusion proto-oncogene
It is the pathogenesis place of center line cancer, and BRD4 albumen participates in the positive evidence of tumor invasion process at present.
Research simultaneously is, it was also found that include AML in haematopoietic cancer, Burkitt lymthoma, Huppert's disease and
In the model of B cell acute lymphatic leukemia, by combination of the interference BRD4 on the site MYC directly by MYC silencing.By
In the important regulatory factor that the isomers of known various MYC is cell Proliferation and survival, and MYC is excessive in many cancers
One possible oncogene of expression, therefore tumour generation of the Bromodomain Antagonism also for the first time to drive for MYC provides
One effect chance.
These results of study illustrate that BRD4 and kinds of tumors exist and maintain close ties with, especially be difficult to cure so far some or
It there is no and play a significant role in the tumour of effective treatment means, the research with relation between tumor provides new plan for oncotherapy
Slightly.By acting on the small molecule compound of BRD4 protein B romodomain structural domain, interference Bromodomain structural domain with
The specific binding of acetylated lysine influences transcriptional regulatory and other cell processes in tumour cell, may be implemented to swollen
The targeted therapy of tumor.
Therefore, BRD4 albumen is a very promising epigenetic novel targets, and acts on BRD4 albumen
The micromolecular inhibitor of Bromodomain structural domain also has broad application prospects in tumor research, and be possible to from
In develop new type antineoplastic medicine.
The selective depressant JQ1 and IBET151 of reported BRD4 albumen, crystal complex show this micromolecular
Inhibitor is just being incorporated in the acetylated lysine identification pocket of Bromodomain structural domain, to block
The acetylation regulation that Bromodomain structural domain mediates, therapeutic effect of these inhibitor in several cancers have been obtained
It confirms.
Currently, the micromolecular inhibitor structure type of BRD4 albumen is few and selectivity is prominent not enough, people couple are limited
The biological function of the domain protein containing Bromodomain and its carry out in-depth study in terms of antitumor potentiality.In addition, existing
BRD4 protein inhibitor function and effect wait to improve, mechanism needs to be furtherd elucidate, and therefore, find efficient, highly selective new
Type small molecule BRD4 protein inhibitor is a hot spot of the antitumor research of epigenetic.
Summary of the invention
The object of the present invention is to provide a kind of coumarin kind compound containing cumarin parent nucleus, the Coumarins
Closing object has good BRD4 protein inhibiting activity and good anti-tumor activity, can be applied to preparation BRD4 protein inhibitor
In, it can also further apply and prepare in anticancer drug, have a very broad application prospects.
A kind of coumarin kind compound with BRD4 albumen inhibiting effect, comprising: the chemical combination of structure shown in following formula (I)
Object and its pharmaceutically acceptable salt；
In formula (I), R is selected from C1~C6Alkyl, C3~C6Naphthenic base, 2,3- dihydro benzo furyl, is not taken thienyl
Generation or the phenyl and naphthalene being substituted with a substituent；The substituent group is halogen, cyano, hydroxyl, amino, sulfydryl, C1~C6Alkyl,
C1~C6Alkoxy, C1~C6Alkylamino or C1~C6Halogenated alkoxy.
“C1~C6Alkyl " refers to the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；"C3~C6Naphthenic base ", which refers to, to be had
The cyclic saturated hydrocarbon base of 3-6 carbon atom；" halogen " or " halogen " refers to halogen atom, including fluorine, chlorine, bromine, iodine and astatine；" alkoxy "
It (is defined as above) for-O- alkyl；" alkylamino " is-NH- alkyl (being defined as above)；" halogenated alkoxy " refers to hydrogen atom by halogen atom
Substituted alkoxy.
The present invention has been designed and synthesized a series of containing cumarin parent nucleus by the crystal structure model of research BRD4 albumen
Brand new compound, and there is the compound shown by pharmacological tests good BRD4 albumen to inhibit to live
Property and good anti-tumor activity, have a very broad application prospects.
Preferably, R base is n-propyl, normal-butyl, phenyl, cyclopenta, cyclohexyl, 2- thienyl, 2- methoxyphenyl, 4-
The chloro- 2- methoxy of chlorphenyl, 2- chlorphenyl, 4- methoxyphenyl, 4- tert-butyl-phenyl, 3- cyano-phenyl, 2,4 dichloro benzene base, 4-
Base phenyl, 2- naphthalene or 2,3- Dihydrobenzofuranes -5- base.
The concrete structure formula of R base as shown in the table below:
The particular compound title of above-mentioned preferred compound number 1~16 are as follows:
N- (2- oxo -2H- chromene -6- base) benzsulfamide (1)；
N- (2- oxo -2H- chromene -6- base) hexamethylene sulfonamide (2)；
Penta sulfonamide (3) of N- (2- oxo -2H- chromene -6- base) ring；
N- (2- oxo -2H- chromene -6- base) third sulfonamide (4)；
N- (2- oxo -2H- chromene -6- base) fourth sulfonamide (5)；
The chloro- N- of 4- (2- oxo -2H- chromene -6- base) benzsulfamide (6)；
4- methoxyl group-N- (2- oxo -2H- chromene -6- base) benzsulfamide (7)；
4- tert-butyl-n-(2- oxo -2H- chromene -6- base) benzsulfamide (8)；
3- cyano-N- (2- oxo -2H- chromene -6- base) benzsulfamide (9)；
The chloro- N- of 2- (2- oxo -2H- chromene -6- base) benzsulfamide (10)；
2- methoxyl group-N- (2- oxo -2H- chromene -6- base) benzsulfamide (11)；
The chloro- N- of 2,4- bis- (2- oxo -2H- chromene -6- base) benzsulfamide (12)；
The chloro- N- of 2- methoxyl group -4- (2- oxo -2H- chromene -6- base) benzsulfamide (13)；
N- (2- oxo -2H- chromene -6- base) thiophene -2- sulfonamide (14)；
N- (2- oxo -2H- chromene -6- base) naphthalene -2- sulfonamide (15)；
N- (2- oxo -2H- chromene -6- base) -2,3- Dihydrobenzofuranes -5- sulfonamide (16).
The BRD4 albumen rejection ability of above-mentioned preferred compound is stronger, is particularly suited for preparation BRD4 protein inhibitor.
The compound pharmaceutically acceptable salt include: formula (I) compound and acid formed acid salt and with it is inorganic
The basic salt that alkali is formed.
The acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, naphthalene sulfonic acids, lemon
Acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or tussol；It is described
Inorganic base be contain alkali metal cations, alkaline earth metal cation or ammonium cation salt.
Invention additionally discloses a kind of preparation methods of above-mentioned formula (I) compound, include the following steps:
Include the following steps:
Wherein, R is consistent with definition described in formula (I)；
Step a is mixed acid nitrification, and step b is nitro reduction, and step c is sulfonamide reaction.
Method particularly includes: using formula (A) compound represented as raw material, in HNO3/H2SO4Nitration mixture under the conditions of nitrified,
Intermediate (C) is obtained after nitro reduction,
Intermediate (C) progress sulfonamide reaction is finally obtained into target product.Above-mentioned steps a's, step b and step c
Reaction is all made of conventional method progress, and the preparation of the compounds of this invention is selected according to the difference of substituent group and the different of substituting group position
With corresponding raw material.
The invention also discloses a kind of pharmaceutical compositions, contain above compound and pharmaceutically acceptable auxiliary material, tool
Body includes: formula (I) compound or pharmaceutically acceptable salt and pharmaceutically acceptable carrier or figuration of therapeutically effective amount
Agent.
The present invention evaluates the BRD4 protein binding capacity of compound, it is found that compound provided by the invention can be not
Inhibit BRD4 albumen with degree, can be used for preparing BRD4 protein inhibitor.
Compound provided by the invention, which can be used for preparing prevention or/and treatment, the drug of related disorders, describedization with BRD4
Closing object can also be used in the drug of preparation treatment Bromodomain dependence disease.By acting on BRD4 protein B romodomain
The small molecule compound of structural domain interferes the specific binding of Bromodomain structural domain and acetylated lysine, influences tumour
Intracellular transcriptional regulatory and other cell processes, may be implemented the targeted therapy to tumour.
The disease includes: melanoma, Papillary thyroid carcinoma, cholangiocarcinoma, colon cancer, oophoroma, center line cancer, non-
Small Cell Lung Cancer, malignant lymphatic tumor, liver cancer, kidney, lung cancer, cancer of pancreas, bladder cancer, prostate cancer, breast cancer, cancer of pancreas,
Thyroid cancer, cutaneum carcinoma, colorectal cancer, cancer of pancreas, oophoroma, breast cancer, carcinoma of testis, osteocarcinoma, the cancer of the brain, the cancer of the esophagus, stomach and intestine
Road cancer, soft-tissue tumor, leukemia, lymph cancer.
BRD4 albumen external activity test shows that compound provided by the present invention has significant BRD4 protein binding energy
Power, since BRD4 has key effect in growth of tumour cell proliferation and has external protein inhibiting activity experiment to support, this
Compound provided by inventing can be used for preventing or treating in the drug of disease related with BRD4 inhibitor, especially tumour
Drug in.
Compared with the existing technology, the beneficial effects of the present invention are embodied in: the present invention provides one kind contain cumarin parent nucleus
Compound, the compound can in various degree inhibit BRD4 albumen, can be used for preparing BRD4 protein inhibitor, for prevent and
Disease related with BRD4 protein inhibitor is treated, good anti-tumor activity, the kinds of Diseases are extremely more, therefore it applies model
It encloses extremely wide.In addition, the raw material sources of preparation method of the present invention are wide, easy to operate, mild condition, at low cost, it is fully compatible for work
Industryization large-scale production.
Specific embodiment
1HNMR、13CNMR uses Waters with BRUKER ACF-400 type Nuclear Magnetic Resonance, high resolution mass spectrum (HRMS)
The measurement of Synapt G2 type mass spectrograph.Further invention is made to the present invention below with reference to specific embodiment, but is limited of the invention
Protection scope.
Embodiment 1
(1) 6- nitro -2H- chromen-2-one (II) is synthesized:
HNO is added in 250mL three-necked bottle3(1.3g, 20.1mmol) and H2SO410mL is placed under the conditions of ice salt bath and stirs
It mixes, maintains 0 DEG C of temperature, the H dissolved with cumarin (2.9g, 20mmol) is added dropwise by constant pressure funnel2SO4Then 2mL is maintained
0 DEG C of temperature reaction about 2h, TLC detection fully reacting, reaction solution is poured into 300mL mixture of ice and water, stirring while adding, ice melts
There is solid precipitation after change, filter, filter cake vacuum drying obtains yellow solid, yield 64.8%.
(2) 6- amino -2H- chromen-2-one (III):
Iron powder (1.7g, 31mmol) and NH are added in the eggplant-shape bottle of 100mL4Cl (0.8g, 15mmol), adds ethyl alcohol
(30mL), water (10mL) 6- nitro -2H- chromen-2-one (II) (1.5g, 7.8mmol) is added in above-mentioned system, 80
It DEG C reaction 2 hours, filters, distillation under pressure removes solvent, and column chromatography for separation obtains 6- amino -2H- chromen-2-one (III)
(1.04g, 86.7%), white solid.
1H NMR (400MHz, DMSO) δ 10.34 (s, 2H), 8.19 (d, J=9.6Hz, 1H), 7.77 (s, 1H), 7.66
(dd, J=8.8,2.2Hz, 1H), 7.52 (d, J=8.9Hz, 1H), 6.58 (d, J=9.7Hz, 1H)13C NMR(101MHz,
DMSO)δ159.98,152.78,143.91,129.03,127.01,122.82,119.74,118.16,117.81.HRMS
(ESI)calcd.for C9H8NO2([M+H]+)162.0555,found 162.0560.
(3) synthesis of N- (2- oxo -2H- chromene -6- base) benzsulfamide (1):
6- amino -2H- chromen-2-one (III) (80mg, 0.5mmol) and benzene sulfonyl chloride (0.5mmol) are dissolved in two
In chloromethanes (5mL), then the drop of pyridine 3 is added dropwise, after room temperature reaction 2 hours, reaction is also added in water, ethyl acetate extraction,
Column chromatography for separation obtains N- (2- oxo -2H- chromene -6- base) benzsulfamide (1), yield 89.3%.
1H NMR (400MHz, DMSO) δ 10.49 (s, 1H), 8.05 (d, J=9.6Hz, 1H), 7.80 (d, J=7.6Hz,
2H), 7.60 (dt, J=26.7,7.3Hz, 3H), 7.47 (s, 1H), 7.31 (s, 2H), 6.48 (d, J=9.6Hz, 1H)13C
NMR(101MHz,DMSO)δ160.18,150.79,144.30,139.61,134.39,133.51,129.79,127.14,
125.19,119.92,119.55,117.70,117.33.HRMS(ESI)calcd.for C11H8N7O2S([M+H]+)
302.0460,found 302.0480.
Embodiment 2
The synthesis of N- (2- oxo -2H- chromene -6- base) hexamethylene sulfonamide (2): specific the preparation method is the same as that of Example 1,
Obtained yield 92.3%.
1H NMR (400MHz, DMSO) δ 9.97 (s, 1H), 8.09 (d, J=9.6Hz, 1H), 7.56 (d, J=2.4Hz,
1H), 7.45 (dd, J=8.9,2.5Hz, 1H), 7.39 (d, J=8.9Hz, 1H), 6.50 (d, J=9.6Hz, 1H), 3.03 (t, J
=10.2Hz, 1H), 2.05 (d, J=11.5Hz, 2H), 1.76 (d, J=12.9Hz, 2H), 1.59 (d, J=12.0Hz, 1H),
1.43(m,2H),1.18(m,3H).13C NMR(101MHz,DMSO)δ160.31,150.34,144.55,135.38,124.39,
119.63,118.65,117.74,117.23,59.50,26.45,25.19,24.77.HRMS(ESI)calcd.for
C15H18NO4S([M+H]+)308.0957,found 308.0952.
Embodiment 3
The synthesis of penta sulfonamide (3) of N- (2- oxo -2H- chromene -6- base) ring: specific the preparation method is the same as that of Example 1,
Obtained yield 85.9%.
1H NMR (400MHz, DMSO) δ 9.95 (s, 1H), 8.10 (d, J=9.6Hz, 1H), 7.57 (d, J=2.3Hz,
1H), 7.48-7.37 (m, 2H), 6.50 (d, J=9.7Hz, 1H), 3.64-3.49 (m, 1H), 1.94-1.85 (m, 4H), 1.65
(m,4H),1.55(m,4H).13C NMR(101MHz,DMSO)δ160.31,150.53,144.52,135.20,124.93,
119.63,119.25,117.73,117.23,60.21,27.77,25.87.HRMS(ESI)calcd.for C14H16NO4S([M+
H]+)294.0800,found 294.0794.
Embodiment 4
The synthesis of N- (2- oxo -2H- chromene -6- base) third sulfonamide (4): specific the preparation method is the same as that of Example 1, produces
Rate is 88.4%.
1H NMR (400MHz, DMSO) δ 9.98 (s, 1H), 8.10 (d, J=9.5Hz, 1H), 7.55 (s, 1H), 7.42 (q,
J=8.9Hz, 2H), 6.51 (d, J=9.5Hz, 1H), 3.23-3.00 (m, 2H), 1.72 (m, 2H), 0.96 (t, J=7.3Hz,
3H)13C NMR(101MHz,DMSO)δ160.31,150.51,144.51,135.14,124.68,119.65,118.96,
117.78,117.25,52.86,17.30,12.99.HRMS(ESI)calcd.for C12H14NO4S([M+H]+)268.0644,
found 268.0635.
Embodiment 5
The synthesis of N- (2- oxo -2H- chromene -6- base) fourth sulfonamide (5): specific the preparation method is the same as that of Example 1, produces
Rate is 93.1%.
1H NMR (400MHz, DMSO) δ 9.99 (s, 1H), 8.10 (d, J=9.6Hz, 1H), 7.56 (s, 1H), 7.42 (q,
J=9.0Hz, 2H), 6.51 (d, J=9.6Hz, 1H), 3.18-3.07 (m, 2H), 1.75-1.61 (m, 2H), 1.45-1.30 (m,
2H), 0.85 (t, J=7.3Hz, 3H)13C NMR(101MHz,DMSO)δ160.29,150.50,144.49,135.13,
124.66,119.64,118.96,117.76,117.24,50.85,25.57,21.12,13.88.HRMS(ESI)calcd.for
C13H16NO4S([M+H]+)282.0800,found 282.0792.
Embodiment 6
The synthesis of the chloro- N- of 4- (2- oxo -2H- chromene -6- base) benzsulfamide (6): specific preparation method is the same as implementation
Example 1, yield 86.2%.
1H NMR (400MHz, DMSO) δ 10.55 (s, 1H), 8.06 (d, J=9.6Hz, 1H), 7.76 (d, J=8.5Hz,
2H), 7.64 (d, J=8.5Hz, 2H), 7.46 (s, 1H), 7.31 (m 2H), 6.49 (d, J=9.6Hz, 1H)13C NMR
(101MHz,DMSO)δ160.16,151.00,144.31,138.42,134.03,129.98,129.10,125.53,120.36,
119.63,117.81,117.37.HRMS(ESI)calcd.for C15H11NO4SCl([M+H]+)336.0097,found
336.0085.
Embodiment 7
The synthesis of 4- methoxyl group-N- (2- oxo -2H- chromene -6- base) benzsulfamide (7): specific preparation method is same
Embodiment 1, yield 72.8%.
1H NMR (400MHz, DMSO) δ 10.34 (s, 1H), 8.05 (d, J=9.6Hz, 1H), 7.71 (d, J=8.7Hz,
2H), 7.46 (s, 1H), 7.35-7.21 (m, 2H), 7.06 (d, J=8.7Hz, 2H), 6.47 (d, J=9.6Hz, 1H), 3.80
(s,3H).13C NMR(101MHz,DMSO)δ162.98,160.21,150.66,144.37,134.69,131.20,129.39,
125.01,119.57,117.66,117.28,114.90,56.00.HRMS(ESI)calcd.for C16H14NO5S([M+H]+)
332.0593,found 332.0586.
Embodiment 8
The synthesis of 4- tert-butyl-n-(2- oxo -2H- chromene -6- base) benzsulfamide (8): specific preparation method is same
Embodiment 1, yield 85.3%.
1H NMR (400MHz, DMSO) δ 10.48 (s, 1H), 8.04 (d, J=9.6Hz, 1H), 7.72 (d, J=8.3Hz,
2H), 7.57 (d, J=8.4Hz, 2H), 7.48 (s, 1H), 7.31 (s, 2H), 6.47 (d, J=9.6Hz, 1H), 1.25 (s, 9H)
.13C NMR(101MHz,DMSO)δ160.19,156.48,150.60,144.36,137.03,134.62,127.03,126.65,
124.70,119.50,119.29,117.73,117.33,35.32,31.16.HRMS(ESI)calcd.for C19H20NO4S([M
+H]+)358.1113,found 358.1109.
Embodiment 9
The synthesis of 3- cyano-N- (2- oxo -2H- chromene -6- base) benzsulfamide (9): specific preparation method is the same as real
Apply example 1, yield 87.9%.
1H NMR (400MHz, DMSO) δ 10.67 (s, 1H), 8.23 (s, 1H), 8.18-8.00 (m, 3H), 7.80 (t, J=
7.9Hz, 1H), 7.49 (d, J=2.2Hz, 1H), 7.31 (dt, J=8.9,5.6Hz, 2H), 6.50 (d, J=9.6Hz, 1H)13C
NMR(101MHz,DMSO)δ160.14,151.14,144.27,140.80,137.18,133.61,131.57,131.35,
130.72,125.68,120.59,119.68,117.87,117.39,113.08.HRMS(ESI)calcd.for C16H11N2O4S
([M+H]+)327.0440,found 327.0429.
Embodiment 10
The synthesis of the chloro- N- of 2- (2- oxo -2H- chromene -6- base) benzsulfamide (10): specific preparation method is the same as implementation
Example 1, yield 91.0%.
1H NMR (400MHz, DMSO) δ 10.86 (s, 1H), 8.07 (m, 2H), 7.70-7.60 (m, 2H), 7.53 (t, J=
6.1Hz, 1H), 7.48 (s, 1H), 7.35 (m, 2H), 6.47 (d, J=9.6Hz, 1H)13C NMR(101MHz,DMSO)δ
160.13,150.63,144.19,136.68,135.21,133.78,132.36,132.08,131.21,128.21,124.37,
119.55,118.98,117.76,117.40.HRMS(ESI)calcd.for C11H7N7O2SCl([M+H]+)336.0070,
found 336.0091.
Embodiment 11
The synthesis of 2- methoxyl group-N- (2- oxo -2H- chromene -6- base) benzsulfamide (11): specific preparation method is same
Embodiment 1, yield 84.9%.
1H NMR (400MHz, DMSO) δ 10.20 (s, 1H), 8.01 (d, J=9.6Hz, 1H), 7.78 (d, J=7.8Hz,
1H), 7.56 (t, J=7.9Hz, 1H), 7.42 (s, 1H), 7.31 (m, 2H), 7.18 (d, J=8.4Hz, 1H), 7.03 (t, J=
7.6Hz, 1H), 6.44 (d, J=9.6Hz, 1H), 3.90 (s, 3H)13C NMR(101MHz,DMSO)δ160.22,156.81,
150.43,144.33,135.68,134.70,130.73,126.50,124.63,120.59,119.37,119.10,117.48,
117.24,113.32.HRMS(ESI)calcd.for C16H14N O5S([M+H]+)332.0593,found 332.0587.
Embodiment 12
The synthesis of the chloro- N- of 2,4- bis- (2- oxo -2H- chromene -6- base) benzsulfamide (12): specific preparation method is same
Embodiment 1, yield 83.1%.
1H NMR (400MHz, DMSO) δ 10.92 (s, 1H), 8.05 (d, J=8.8Hz, 2H), 7.87 (s, 1H), 7.61
(d, J=10.4Hz, 1H), 7.45 (s, 1H), 7.33 (s, 2H), 6.48 (d, J=9.6Hz, 1H)13C NMR(101MHz,
DMSO)δ180.07,150.82,144.22,139.20,135.73,133.45,133.38,132.45,131.90,128.47,
124.68,119.82,119.38,117.86,117.45.HRMS(ESI)calcd.for C15H10NO4SCl2([M+H]+)
369.9708,found 369.9694.
Embodiment 13
The synthesis of the chloro- N- of 2- methoxyl group -4- (2- oxo -2H- chromene -6- base) benzsulfamide (13): specific preparation
Method is the same as embodiment 1, yield 81.9%.
1H NMR (400MHz, DMSO) δ 10.37 (s, 1H), 8.05 (d, J=9.6Hz, 1H), 7.71 (d, J=2.6Hz,
1H), 7.64 (dd, J=8.9,2.5Hz, 1H), 7.44 (s, 1H), 7.31 (s, 2H), 7.24 (d, J=8.9Hz, 1H), 6.46
(d, J=9.6Hz, 1H), 3.91 (s, 3H)13C NMR(101MHz,DMSO)δ160.19,155.71,150.74,144.32,
135.23,134.16,129.72,128.03,124.97,124.15,119.55,117.58,117.33,115.49,
57.09.HRMS(ESI)calcd.for C16H13NO5SCl([M+H]+)366.0203,found 366.0193.
Embodiment 14
The synthesis of N- (2- oxo -2H- chromene -6- base) thiophene -2- sulfonamide (14): specific preparation method is the same as implementation
Example 1, yield 90.5%.
1H NMR (400MHz, DMSO) δ 10.61 (s, 1H), 8.08 (d, J=9.6Hz, 1H), 7.91 (d, J=4.9Hz,
1H), 7.58 (d, J=3.5Hz, 1H), 7.52 (s, 1H), 7.39-7.28 (m, 2H), 7.1-7.09 (m, 1H), 6.49 (d, J=
9.6Hz,1H).13C NMR(101MHz,DMSO)δ160.19,151.04,144.33,139.93,134.11,133.13,
128.18,125.42,120.28,119.57,117.64,117.36.HRMS(ESI)calcd.for C13H10NO4S2([M+H]+)
308.0051,found 308.0044.
Embodiment 15
The synthesis of N- (2- oxo -2H- chromene -6- base) naphthalene -2- sulfonamide (15): the same embodiment of specific preparation method
1, yield 83.5%.
1H NMR (400MHz, DMSO) δ 10.65 (s, 1H), 8.52 (s, 1H), 8.14 (t, J=8.9Hz, 2H), 8.09-
7.97 (m, 2H), 7.85 (d, J=8.7Hz, 1H), 7.68 (m, 2H), 7.55 (s, 1H), 7.34 (m 2H), 6.47 (d, J=
9.6Hz,1H).13C NMR(101MHz,DMSO)δ160.15,150.77,144.24,136.63,134.75,134.37,
132.00,130.00,129.70,129.48,128.54,128.22,125.16,122.44,119.90,119.55,117.70,
117.30.HRMS(ESI)calcd.for C19H14NO4S([M+H]+)352.0644,found 352.0634.
Embodiment 16
The synthesis of N- (2- oxo -2H- chromene -6- base) -2,3- Dihydrobenzofuranes -5- sulfonamide (16): specific
The preparation method is the same as that of Example 1, yield 91.9%.
1H NMR (400MHz, DMSO) δ 10.28 (s, 1H), 8.05 (d, J=9.6Hz, 1H), 7.63 (s, 1H), 7.53
(d, J=9.5Hz, 1H), 7.44 (s, 1H), 7.34-7.24 (m, 2H), 6.86 (d, J=8.5Hz, 1H), 6.46 (d, J=
9.6Hz, 1H), 4.60 (t, J=8.8Hz, 2H), 3.20 (t, J=8.8Hz, 2H)13C NMR(101MHz,DMSO)δ163.7,
160.24,150.54,144.40,134.77,131.21,129.41,128.67,124.87,124.54,119.46,117.65,
117.27,109.55,72.69,28.83.HRMS(ESI)calcd.for C17H14NO5S([M+H]+)344.0593,found
344.0586.
Application examples
(1) BRD4 protein binding capacity is tested
AlphaScreen method:
1) material: BRD4 albumen；HTRF KinEASE (Cisbio, France)；MgCl2,MnCl2,DTT；384 low volumes
Blank (Corning, USA)；Pipette tips (Axygen, USA)；DMSO (Sigma, USA)
2) method: the albumen reaction buffer and peptide substrates of 5 μ L is added in every hole, and 10 μ L of compound is incubated for 30 minutes, mixing
Object is further incubated at room temperature 2 hours, and the stop bath that 5 μ L are added terminates reaction, is detected using EnVision multiple labeling reader
Fluorescence signal ratio, obtained data are analyzed using Graphpad Prism 5.
Reality of compound (1)~(16) that testing example obtains according to the method described above to the 503nhibiting concentration of BRD4 albumen
It is as shown in table 1 below to test result.
Table 1
| Number | Activity (BRD4) IC50(μM) | Number | Activity (BRD4) IC50(μM) |
| 1 | 6.59 | 9 | 5.03 |
| 2 | 19.02 | 10 | 2.21 |
| 3 | 17.9 | 11 | 0.98 |
| 4 | 38.53 | 12 | 1.77 |
| 5 | 30.04 | 13 | 0.93 |
| 6 | 2.97 | 14 | 9.26 |
| 7 | 7.31 | 15 | 12.23 |
| 8 | 5.09 | 16 | 18.42 |
(2) anti-tumor activity is tested
Mtt assay: being made into individual cells suspension with culture solution is obtained containing 10% tire calf serum, thin with every hole 1000-10000
Born of the same parents are inoculated into 96 orifice plates, and every pore volume 200uL adds the drug of respective concentration, cultivate 3-5 days, every hole adds MTT solution (5mg/ml
Prepared with PBS, pH=7.4) 20uL.Continue to be incubated for 4h, terminates culture, careful inhale abandons culture supernatant in hole, thin for suspending
Born of the same parents, which need to inhale again after being centrifuged, abandons culture supernatant in hole.Every hole adds 150uL DMSO, vibrates 10min, melts crystal sufficiently.
490nm wavelength is selected, measures each hole absorbance value on enzyme linked immunological monitor, record is as a result, using the time as abscissa, extinction
Value is that ordinate draws cell growth curve.
And compound (13) is calculated to the 503nhibiting concentration (IC of different tumor cell lines according to cell inhibitory rate50Value),
Concrete outcome is as shown in table 2 below.
Table 2
| Tumor type | Cell strain | IC50(μM) |
| Lung cancer | A549 | 4.63 |
| Liver cancer | HepG2 | 4.75 |
| Cancer of pancreas | PANC-1 | 7.02 |
| Gastric cancer | SGC-7901 | 6.39 |
The above results show that coumarin kind compound provided by the present invention has preferable BRD4 inhibitory effect, and to more
Kind tumour has good inhibiting effect.
Claims (9)
1. a kind of coumarin kind compound with BRD4 albumen inhibiting effect characterized by comprising change shown in formula (I)
Close object and its pharmaceutically acceptable salt；
In formula (I), R is selected from C1~C6Alkyl, C3~C6Naphthenic base, thienyl, 2,3- dihydro benzo furyl, it is unsubstituted or by
The phenyl and naphthalene that substituent group replaces；The substituent group is halogen, cyano, hydroxyl, amino, sulfydryl, C1~C6Alkyl, C1~C6
Alkoxy, C1~C6Alkylamino or C1~C6Halogenated alkoxy.
2. coumarin kind compound according to claim 1, which is characterized in that R base is selected from n-propyl, normal-butyl, phenyl, ring penta
Base, cyclohexyl, 2- thienyl, 2- methoxyphenyl, 4- chlorphenyl, 2- chlorphenyl, 4- methoxyphenyl, 4- tert-butyl-phenyl,
The chloro- 2- methoxyphenyl of 3- cyano-phenyl, 2,4 dichloro benzene base, 4-, 2- naphthalene or 2,3- Dihydrobenzofuranes -5- base.
3. coumarin kind compound according to claim 1, which is characterized in that the pharmaceutically acceptable salt, packet
It includes: the alkali formula of formula (I) compound represented and the acid acid salt formed and logical formula (I) compound represented and inorganic base formation
Salt.
4. the preparation method of coumarin kind compound according to claim 1-3, which is characterized in that including as follows
Step:
Wherein, R is consistent with definition described in formula (I)；
Step a is mixed acid nitrification, and step b is nitro reduction, and step c is sulfonamide reaction.
5. coumarin kind compound preparation method according to claim 4, which is characterized in that method particularly includes: with formula
(A) compound represented is raw material, in HNO3/H2SO4Nitration mixture under the conditions of nitrified, nitro reduction after obtain intermediate
(C), intermediate (C) progress sulfonamide reaction is finally obtained into target product.
6. a kind of pharmaceutical composition, which is characterized in that including the described in any item coumarin kind compounds of claim 1-3 and medicine
Acceptable auxiliary material on.
7. coumarin kind compound according to claim 1-3 is preparing the application in BRD4 protein inhibitor.
8. coumarin kind compound according to claim 1-3 is related with BRD4 in preparation prevention or/and treatment
Application in disease.
9. application according to claim 8, which is characterized in that the disease is melanoma, papillary thyroid is swollen
Tumor, cholangiocarcinoma, colon cancer, oophoroma, center line cancer, non-small cell lung cancer, malignant lymphatic tumor, liver cancer, kidney, lung cancer, pancreas
Cancer, bladder cancer, prostate cancer, breast cancer, cancer of pancreas, thyroid cancer, cutaneum carcinoma, colorectal cancer, cancer of pancreas, oophoroma, cream
Gland cancer, carcinoma of testis, osteocarcinoma, the cancer of the brain, the cancer of the esophagus, gastrointestinal cancer, soft-tissue tumor, leukemia or lymph cancer.
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| CN114146120A (en) * | 2022-02-08 | 2022-03-08 | 首都医科大学附属北京潞河医院 | Composition microcapsule for preventing and treating atrophic gastritis and preparation method thereof |
| WO2023143206A1 (en) * | 2022-01-26 | 2023-08-03 | 南京明德新药研发有限公司 | Coumarin compounds and uses thereof |
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| WO2006083692A2 (en) * | 2005-01-28 | 2006-08-10 | Mount Sinai Schoool Of Medicine | Methods of identifying modulators of bromodomains |
| WO2007005887A2 (en) * | 2005-07-01 | 2007-01-11 | Ligand Pharmaceuticals Incorporated | Androgen receptor modulator compounds, compositions and uses thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023143206A1 (en) * | 2022-01-26 | 2023-08-03 | 南京明德新药研发有限公司 | Coumarin compounds and uses thereof |
| CN114146120A (en) * | 2022-02-08 | 2022-03-08 | 首都医科大学附属北京潞河医院 | Composition microcapsule for preventing and treating atrophic gastritis and preparation method thereof |
| CN114146120B (en) * | 2022-02-08 | 2022-04-22 | 首都医科大学附属北京潞河医院 | Composition microcapsule for preventing and treating atrophic gastritis and preparation method thereof |
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