CN110256346A - Phenanthridines ketone compounds and preparation method and application with BRD4 albumen inhibiting effect - Google Patents
Phenanthridines ketone compounds and preparation method and application with BRD4 albumen inhibiting effect Download PDFInfo
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- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a kind of phenanthridines ketone compounds and preparation method and application with BRD4 albumen inhibiting effect, which includes: the compound and its pharmaceutically acceptable salt of structure shown in formula (I)；The compound for containing the brand new of phenanthridone 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 phenanthridines ketone compounds, 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 phenanthridines ketones derivant, 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 is, it was also found that include AML (leukaemia), Burkitt lymthoma, multiple bone in haematopoietic cancer simultaneously
In the model of myeloma and B cell acute lymphatic leukemia, directly will by combination of the interference BRD4 on the site MYC
MYC silencing.Since the isomers of known various MYC is the important regulatory factor of cell Proliferation and survival, and MYC is in many
A possible oncogene of overexpression in cancer, therefore Bromodomain Antagonism is also swollen to drive for MYC for the first time
Tumor generation provides an 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 phenanthridines ketone compounds with BRD4 albumen inhibiting effect and preparations
Methods and applications, a kind of phenanthridines ketone compounds containing phenanthridone parent nucleus, the phenanthridines ketone compounds have good BRD4
Protein inhibiting activity and good anti-tumor activity can be applied in preparation BRD4 protein inhibitor, can also further apply
In preparing in anticancer drug, have a very broad application prospects.
A kind of phenanthridines ketone compounds with BRD4 albumen inhibiting effect, be formula (I) shown in structure compound 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；C1~C6Alcoxyl
Alkoxy is-O- alkyl (i.e.-O-C in base1~C6Alkyl, C1~C6Alkyl is defined as above)；C1~C6In alkylamino " alkylamino "
For-NH- alkyl (i.e.-NH-C1~C6Alkyl, C1~C6Alkyl is defined as above)；" halogenated alkoxy " refers to that hydrogen atom is taken by halogen atom
The alkoxy in generation.
The present invention has been designed and synthesized a series of containing phenanthridone 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, 5-
Base phenyl, 2- naphthalene or 2,3- Dihydrobenzofuranes -5- base.
The concrete structure formula of R base see the table below shown in 1:
Table 1
The particular compound title of above-mentioned preferred compound number 1~15 are as follows:
N- (6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (1)；
N- (6- oxo -5,6- dihydrophenanthridine -2- base) hexamethylene sulfonamide (2)；
Penta sulfonamide (3) of N- (6- oxo -5,6- dihydrophenanthridine -2- base) ring；
N- (6- oxo -5,6- dihydrophenanthridine -2- base) third sulfonamide (4)；
N- (6- oxo -5,6- dihydrophenanthridine -2- base) fourth sulfonamide (5)；
The chloro- N- of 4- (6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (6)；
4- methoxyl group-N- (6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (7)；
4- tert-butyl-n-(6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (8)；
3- cyano-N- (6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (9)；
The chloro- N- of 2- (6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (10)；
2- methoxyl group-N- (6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (11)；
The chloro- N- of 2- methoxyl group -5- (6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (12)；
N- (6- oxo -5,6- dihydrophenanthridine -2- base) thiophene -2- sulfonamide (13)；
N- (6- oxo -5,6- dihydrophenanthridine -2- base) naphthalene -2- sulfonamide (14)；
N- (6- oxo -5,6- dihydrophenanthridine -2- base) -2,3- Dihydrobenzofuranes -5- sulfonamide (15).
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.
The present invention also provides a kind of preparation methods of the phenanthridines ketone compounds of above-mentioned formula (I) structure, including walk as follows
It is rapid:
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.
A kind of preparation method of the phenanthridines ketone compounds with BRD4 albumen inhibiting effect, comprising the following steps:
1) using formula A structure compound represented as raw material, in HNO3/H2SO4Nitration mixture under the conditions of carry out nitration reaction, obtain
To nitro compound shown in formula B structure；
2) nitro compound shown in formula B structure, obtains intermediate shown in formula C-structure after nitro-reduction reaction；
3) intermediate shown in formula C-structure obtains after sulfonamide reaction with sulfonyl chloride compound shown in formula D structure
To the phenanthridines ketone compounds of structure shown in formula (I).
Wherein, the R in formula D and the R in formula (I) have identical meanings.
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.
In step 1), the condition of the nitration reaction are as follows: in -5~5 DEG C of 1~5h of progress, further preferably, -2~3
DEG C carry out 1.5~2.5h, most preferably, in 0 DEG C of progress 2h.
In step 2), the condition of the nitro-reduction reaction are as follows: iron powder and NH is added4Cl and second alcohol and water, 70
DEG C~90 DEG C react 1~3 hour, further preferably, 75 DEG C~85 DEG C react 1.5~2.5 hours, most preferably, at 80 DEG C
Reaction 2 hours.
In step 3), the condition of the sulfonamide reaction are as follows: in dichloromethane solvent, using pyridine as catalysis
Agent, 15 DEG C~35 DEG C are reacted 1~5 hour, and further preferably, 20 DEG C~30 DEG C are reacted 1~3 hour, most preferably, 25 DEG C of reactions
2 hours.
The preparation of the compounds of this invention selects the corresponding raw material to be according to the difference of substituent group and the differences of substituting group position
It can.
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 a kind of compound containing phenanthridone parent nucleus, which can inhibit in various degree BRD4 egg
It is white, it can be used for preparing BRD4 protein inhibitor, it is good anti-for preventing and treating disease related with BRD4 protein inhibitor
Tumor promotion, the kinds of Diseases are extremely more, therefore its application range is extremely wide.In addition, the raw material sources of preparation method of the present invention
Extensively, easy to operate, mild condition, at low cost, it is fully compatible for industrialization large-scale production.
Detailed description of the invention
Fig. 1 is the nuclear magnetic spectrum of compound 12 in the present invention；
Fig. 2 is the carbon spectrum of compound 12 in the present invention；
Fig. 3 is the high resolution mass spectrum of compound 12 in the present invention.
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.Melting point compound (mp) is measured with BUCHIM-565 type melting point apparatus.Below with reference to specific reality
It applies example and further invention is made to the present invention, but limit the scope of the invention.
Embodiment 1
(1) 2- nitro-phenanthridines -6 (5H) -one (B) is synthesized:
HNO is added in 250mL three-necked bottle31.3g and H2SO410mL is placed under the conditions of ice salt bath and stirs, and maintains temperature 0
DEG C, the H dissolved with (5H) -one of phenanthridines -6 1.85g is added dropwise by constant pressure funnel2SO4Then 2mL maintains 0 DEG C of temperature reaction about
2h, TLC detect fully reacting, and reaction solution is poured into 300mL mixture of ice and water, stirring while adding, there is solid analysis after ice-out
Out, it filters, it is 2- nitro-phenanthridines -6 (5H) -one (B), yield 64.8% that filter cake vacuum drying, which obtains yellow solid,.
(2) 2- amino-phenanthridines -6 (5H) -one (C):
Iron powder 1.7g and NH are added in the eggplant-shape bottle of 100mL4Cl 0.8g adds ethyl alcohol (30mL), water (10mL),
2- nitro-phenanthridines -6 (5H) -one (B) 0.9g is added in above-mentioned system, 80 DEG C are reacted 2 hours, are filtered, and distillation under pressure removes molten
Agent, column chromatography for separation obtain 2- amino-phenanthridines -6 (5H) -one (C) (1.04g, 86.7%), white solid.
mp 286.0-287.4℃.1H NMR (400MHz, DMSO-D6) δ 11.33 (s, 1H), 8.30 (d, J=9.1Hz,
1H), 8.22 (d, J=8.1Hz, 1H), 7.82 (t, J=6.9Hz, 1H), 7.59 (t, J=8.0Hz, 1H), 7.48 (d, J=
2.3Hz, 1H), 7.11 (d, J=8.6Hz, 1H), 6.82 (dd, J=8.6,2.3Hz, 1H), 5.01 (s, 2H) .HRMS m/z:
calcd.for C13H11N2O[M+H]+211.0871,found 211.0874
(3) synthesis of N- (6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (1):
By 2- amino-phenanthridines -6 (5H) -one (C) (80mg, 0.5mmol) and benzene sulfonyl chloride, (0.5mmol, formula D structure, R are
Phenyl) (5mL) is dissolved in methylene chloride, then the drop of pyridine 3 is added dropwise, reaction is also added to water after 25 DEG C of room temperature are reacted 2 hours
In, ethyl acetate extraction, column chromatography for separation obtains N- (2- oxo -2H- chromene -6- base) benzsulfamide (1), and yield is
89.3%.
The characterize data of ideal product is as follows: mp 281.5-282.3 DEG C1H NMR(400MHz,DMSO-D6)δ:
11.66 (s, 1H), 10.29 (s, 1H), 8.32 (d, J=7.7Hz, 1H), 8.17 (d, J=8.1Hz, 1H), 7.98 (s, 1H),
7.89 (d, J=4.1Hz, 0H), 7.88 (s, 1H), 7.79 (d, J=7.2Hz, 2H), 7.65 (d, J=7.5Hz, 1H), 7.63-
7.51(m,3H),7.29–7.20(m,2H)；13C NMR(101MHz,DMSO-D6)δ160.8,139.7,134.2,133.9,
133.4,132.5,129.7,128.8,128.1,127.2,126.3,124.1,122.5,118.2,117.4,116.0；HRMS
m/z:calcd.for C19H15N2O3S[M+H]+351.0803,found 351.0808。
Embodiment 2
The synthesis of N- (6- oxo -5,6- dihydrophenanthridine -2- base) hexamethylene sulfonamide (2): specific preparation method is referring to implementation
Example 1, R is cyclohexyl, obtained yield 79.2% in step (3) Chinese style D structure.
The characterize data of ideal product is as follows: mp 230.2-230.9 DEG C1H NMR(500MHz,DMSO-D6)δ
11.75 (s, 1H), 9.82 (s, 1H), 8.35 (d, J=7.7Hz, 1H), 8.27 (d, J=8.1Hz, 1H), 8.16 (s, 1H),
7.91 (t, J=7.3Hz, 1H), 7.68 (t, J=7.4Hz, 1H), 7.42 (d, J=8.7Hz, 1H), 7.37 (d, J=8.7Hz,
1H), 3.02 (t, J=10.1Hz, 1H), 2.08 (d, J=12.0Hz, 2H), 1.76 (s, 2H), 1.64-1.53 (m, 2H), 1.44
(d, J=10.2Hz, 2H), 1.21 (d, J=12.3Hz, 2H)13C NMR(126MHz,DMSO-D6)δ161.0,134.1,
133.8,133.6,133.3,128.7,128.1,126.4,123.3,122.7,118.36,117.5,114.7,59.4,58.8,
27.8,26.5,25.8,25.5,25.2,24.8.HRMS m/z:calcdfor C19H21N2O3S[M+H]+357.1273,found
357.1264。
Embodiment 3
The synthesis of penta sulfonamide (3) of N- (6- oxo -5,6- dihydrophenanthridine -2- base) ring: specific preparation method is referring to implementation
Example 1, R is cyclopenta, obtained yield 65.3% in step (3) Chinese style D structure.
The characterize data of ideal product is as follows: mp 226.3-226.9 DEG C1H NMR(400MHz,DMSO-D6)δ
11.71 (s, 1H), 9.76 (s, 1H), 8.34 (d, J=7.9Hz, 1H), 8.29 (d, J=8.1Hz, 1H), 8.12 (d, J=
1.9Hz, 1H), 7.91 (t, J=7.6Hz, 1H), 7.68 (t, J=7.5Hz, 1H), 7.37 (dd, J=12.9,5.4Hz, 2H),
1.96–1.85(m,4H),1.71–1.61(m,2H),1.58–1.48(m,2H),1.28–1.15(m,3H).13C NMR
(101MHz,DMSO-D6)δ160.9,134.0,133.9,133.5,133.4,128.8,128.1,126.2,124.0,122.7,
118.4,117.5,115.4,60.1,27.9,25.9.HRMS m/z:calcd.forC18H19N2O3S[M+H]+343.1116,
found 343.1112。
Embodiment 4
The synthesis of N- (6- oxo -5,6- dihydrophenanthridine -2- base) third sulfonamide (4): specific preparation method is referring to embodiment
1, R is n-propyl, yield 80.4% in step (3) Chinese style D structure.
The characterize data of ideal product is as follows: mp 214.6-214.9 DEG C1H NMR(500MHz,DMSO-D6)δ
11.74 (s, 1H), 9.88 (s, 1H), 8.35 (d, J=7.4Hz, 1H), 8.29 (d, J=8.0Hz, 1H), 8.18 (s, 1H),
7.89 (s, 1H), 7.68 (t, J=7.4Hz, 1H), 7.42 (d, J=10.4Hz, 2H), 3.14-3.05 (m, 2H), 1.74 (dd, J
=15.0,7.5Hz, 2H), 0.96 (t, J=7.4Hz, 3H)13C NMR(126MHz,DMSO-D6)δ161.0,134.1,
134.0,133.4,133.34,128.7,128.1,126.3,123.8,122.7,118.4,117.5,115.4,52.7,17.2,
13.1.HRMS m/z:calcd.for C16H17N2O3S[M+H]+317.0960,found 317.0956。
Embodiment 5
The synthesis of N- (6- oxo -5,6- dihydrophenanthridine -2- base) fourth sulfonamide (5): specific preparation method is referring to embodiment
1, R is normal-butyl, yield 93.1% in step (3) Chinese style D structure.
The characterize data of ideal product is as follows: mp 213.7-214.6 DEG C1H NMR(500MHz,DMSO-D6)δ
11.74 (s, 1H), 9.83 (s, 1H), 8.35 (d, J=32.3Hz, 2H), 8.17 (s, 1H), 7.93 (s, 1H), 7.71 (s, 1H),
7.41 (s, 2H), 3.13 (d, J=1.1Hz, 2H), 1.73 (d, J=1.2Hz, 2H), 1.39 (d, J=5.7Hz, 2H), 0.86
(s,3H).13C NMR(126MHz,DMSO-D6)δ161.0,134.1,134.1,133.5,133.3,128.8,128.7,
128.2,126.38,123.8,123.8,122.7,118.4,117.6,115.4,115.3,50.7,25.6,21.2,
14.0.HRMSm/z:calcd.for C17H19N2O3S[M+H]+331.1116,found 331.1107。
Embodiment 6
The synthesis of the chloro- N- of 4- (6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (6): specific preparation method is referring to real
Example 1 is applied, R is 4- chlorphenyl, yield 86.2% in step (3) Chinese style D structure.
The characterize data of ideal product is as follows: mp 268.4-268.9 DEG C1H NMR(500MHz,DMSO-D6)δ:
11.71 (s, 1H), 10.39 (s, 1H), 8.34 (d, J=7.9Hz, 1H), 8.21 (d, J=8.2Hz, 1H), 8.03 (s, 0H),
8.01 (d, J=2.1Hz, 1H), 7.93-7.84 (m, 1H), 7.81-7.73 (m, 2H), 7.71-7.65 (m, 1H), 7.66-7.60
(m, 2H), 7.28 (d, J=8.7Hz, 1H), 7.21 (dd, J=8.7,2.2Hz, 1H)13C NMR(126MHz,DMSO-D6)δ:
160.9,138.2–138.1,134.5,133.9,133.5,132.1,129.9,129.2,128.8,128.1,126.3,
124.4,122.5,118.3,117.5,116.4.HRMS m/z:calcd.forC19H14ClN2O3S[M+H]+385.0414,
found 385.0398。
Embodiment 7
The synthesis of 4- methoxyl group-N- (6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (7): specific preparation method ginseng
According to embodiment 1, R is 4- methoxyphenyl, yield 91.0% in step (3) Chinese style D structure.
The characterize data of ideal product is as follows: mp 285.8-286.7 DEG C1H NMR(500MHz,DMSO-D6)δ:
11.64 (s, 1H), 10.14 (s, 1H), 8.30 (d, J=8.7Hz, 1H), 8.15 (d, J=8.1Hz, 1H), 7.97 (d, J=
1.8Hz, 1H), 7.85 (t, J=7.6Hz, 1H), 7.70 (d, J=8.9Hz, 2H), 7.63 (t, J=7.5Hz, 1H), 7.21
(dt, J=8.7,5.4Hz, 2H), 7.02 (d, J=8.9Hz, 2H), 3.74 (s, 3H)13C NMR(126MHz,DMSO-D6)δ:
162.9,160.9,134.0,133.5,132.8,131.4,129.5,128.7,128.1,126.3,123.9,122.5,
118.1,117.4,115.6,114.8,56.0.HRMS m/z:calcd.for C20H17N2O4S[M+H]+381.0909,found
381.0892。
Embodiment 8
The synthesis of 4- tert-butyl-n-(6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (8): specific preparation method ginseng
According to embodiment 1, R is 4- tert-butyl-phenyl, yield 81.8% in step (3) Chinese style D structure.
The characterize data of ideal product is as follows: mp 267.4-267.7 DEG C1H NMR(500MHz,DMSO-D6)δ
11.67(s,1H),10.28(s,1H),8.33(s,1H),8.11(s,1H),7.96(s,1H),7.86(s,1H),7.70(d,J
=42.4Hz, 3H), 7.56 (s, 2H), 7.28 (s, 2H), 1.22 (s, 9H)13C NMR(126MHz,DMSO-D6)δ161.0,
156.4,137.2,134.1,134.0,133.5,132.7,128.8,128.2,128.2,127.2,126.6,126.3,
124.0,124.0,122.4,122.4,118.2,117.3,117.4,115.7,115.6,35.6,31.9.HRMS m/z:
calcd.for C23H23N2O3S[M+H]+407.1429,found 407.1426。
Embodiment 9
The synthesis of 3- cyano-N- (6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (9): specific preparation method reference
Embodiment 1, R is 3- cyano-phenyl, yield 79.2% in step (3) Chinese style D structure.
The characterize data of ideal product is as follows: mp 290.6-291.3 DEG C1H NMR(500MHz,DMSO-D6)δ
11.78 (d, J=34.8Hz, 1H), 10.54 (d, J=34.4Hz, 1H), 8.45 (s, 1H), 8.42-8.30 (m, 2H), 8.27
(t, J=8.6Hz, 1H), 8.20-8.11 (m, 2H), 8.09 (d, J=7.5Hz, 1H), 8.01 (d, J=6.1Hz, 1H), 7.92
(dd, J=19.4,11.5Hz, 1H), 7.86-7.76 (m, 1H), 7.77-7.66 (m, 1H), 7.44-7.22 (m, 2H)13C NMR
(126MHz,DMSO-D6)δ161.0,161.0,141.1,141.0,137.1,137.0,134.7,134.7,133.6,133.5,
131.8,131.7,131.3,131.3,130.8,130.8,128.9,128.8,128.2,128.1,126.4,126.3,
124.7,124.6,122.7,122.6,118.4,118.4,117.9,117.9,117.6,117.6,117.0,116.9,
113.0,113.0.HRMS m/z:calcd.forC20H14N3O3S[M+H]+376.0756,found 376.0756。
Embodiment 10
The synthesis of the chloro- N- of 2- (6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (10): specific preparation method reference
Embodiment 1, R is 2- chlorphenyl, yield 79.8% in step (3) Chinese style D structure.
The characterize data of ideal product is as follows: mp 275.4-275.8 DEG C1H NMR(500MHz,DMSO-D6)δ
11.72 (s, 1H), 10.72 (s, 1H), 8.32 (d, J=7.9Hz, 1H), 8.16 (d, J=8.1Hz, 1H), 8.10 (dd, J=
7.9,1.4Hz, 1H), 8.04 (d, J=1.9Hz, 1H), 7.90 (dd, J=11.2,4.1Hz, 1H), 7.70-7.64 (m, 2H),
7.63-7.58 (m, 1H), 7.51 (dd, J=11.8,4.5Hz, 1H), 7.29 (dd, J=9.4,7.3Hz, 2H)13C NMR
(126MHz,DMSO-D6)δ160.8,136.9,135.1,134.0,133.8,133.51,132.3,132.1,131.9,
131.3,128.8,128.2,126.31,123.3,122.4,118.2,117.5,114.9.HRMS m/z:calcd.for
C19H14ClN2O3S[M+H]+385.0414,found 385.0406。
Embodiment 11
The synthesis of 2- methoxyl group-N- (6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (11): specific preparation method
Referring to embodiment 1, R is 2- methoxyphenyl, yield 81.3% in step (3) Chinese style D structure.
The characterize data of ideal product is as follows: mp 298.4-299.3 DEG C1H NMR(400MHz,DMSO-D6)δ:
11.61 (s, 1H), 9.98 (s, 1H), 8.34-8.27 (m, 1H), 8.15 (d, J=8.1Hz, 1H), 7.98 (d, J=1.5Hz,
1H), 7.92-7.85 (m, 1H), 7.77 (dd, J=7.8,1.6Hz, 1H), 7.65 (t, J=7.5Hz, 1H), 7.56-7.50 (m,
1H), 7.22 (dd, J=9.8,5.3Hz, 2H), 7.17 (d, J=8.3Hz, 1H), 7.00 (t, J=7.6Hz, 1H), 3.95 (s,
3H)；13CNMR(101MHz,DMSO-D6)δ:160.9,156.8,135.6,133.9,133.5,132.8,130.8,128.7,
128.2,126.6,126.3,123.5,122.3,120.6,118.0,117.2,115.0,113.2,56.6.HRMS m/z:
calcd.for C20H17N2O4S[M+H]+381.0909,found381.0905。
Embodiment 12
The synthesis of the chloro- N- of 2- methoxyl group -5- (6- oxo -5,6- dihydrophenanthridine -2- base) benzsulfamide (12): specific preparation
Method is referring to embodiment 1, and R is the chloro- 2- methoxyphenyl of 5-, yield 72.6% in step (3) Chinese style D structure.
The characterize data of ideal product is as follows: mp 298.4-298.8 DEG C1H NMR(400MHz,DMSO-D6)δ:
11.65 (s, 1H), 10.17 (s, 0H), 10.17 (s, 1H), 8.32 (d, J=7.9Hz, 1H), 8.18 (d, J=8.2Hz, 1H),
7.99 (s, 1H), 7.87 (s, 1H), 7.71 (s, 1H), 7.70 (s, 0H), 7.66 (t, J=7.5Hz, 1H), 7.61 (dd, J=
8.9,2.6Hz, 1H), 7.23 (d, J=9.6Hz, 3H), 3.96 (s, 3H)；13C NMR(101MHz,DMSO-D6)δ:160.9,
155.8,135.1,134.2,133.9,133.6,132.2,129.8,128.8,128.2,126.3,124.2 123.8,
122.3,118.1,117.4,115.5,57.1.HRMS m/z:calcd.for C20H16N2O4S[M+H]+415.0519,found
415.0522。
The nuclear magnetic spectrum of compound 12 is as shown in Figure 1 in the present invention；The carbon spectrum of compound 12 is as shown in Figure 2 in the present invention；
The high resolution mass spectrum of compound 12 is as shown in Figure 3 in the present invention.
Embodiment 13
The synthesis of N- (6- oxo -5,6- dihydrophenanthridine -2- base) thiophene -2- sulfonamide (13): specific preparation method reference
Embodiment 1, R is 2- thienyl, yield 75.5% in step (3) Chinese style D structure.
The characterize data of ideal product is as follows: mp 296.8-297.1 DEG C1H NMR(500MHz,DMSO-D6)δ:
11.81-11.69 (m, 1H), 10.51 (dd, J=21.1,9.9Hz, 1H), 8.34 (d, J=7.4Hz, 1H), 8.20 (d, J=
7.7Hz, 1H), 8.13-8.01 (m, 1H), 7.90 (d, J=6.8Hz, 2H), 7.76-7.65 (m, 1H), 7.60 (d, J=
17.4Hz, 1H), 7.31 (dt, J=21.7,10.7Hz, 2H), 7.21-7.07 (m, 1H)13C NMR(126MHz,DMSO-D6)
δ:161.0,140.2,134.5,134.3,133.6,133.5,133.0,132.3,128.1,126.3,124.4,122.5,
117.4,116.3.HRMS m/z:calcd.for C17H13N2O3S2[M+H]+357.0368,found 357.0366。
Embodiment 14
The synthesis of N- (6- oxo -5,6- dihydrophenanthridine -2- base) naphthalene -2- sulfonamide (14): specific preparation method is referring to real
Example 1 is applied, R is 2- naphthalene, yield 85.9% in step (3) Chinese style D structure.
The characterize data of ideal product is as follows: mp 291.4-292.3 DEG C1H NMR(500MHz,DMSO-D6)δ
11.68 (s, 1H), 10.55 (s, 1H), 8.51 (s, 1H), 8.31 (d, J=7.3Hz, 1H), 8.19 (d, J=7.6Hz, 1H),
8.12 (t, J=8.5Hz, 2H), 8.08 (s, 1H), 8.00 (d, J=7.5Hz, 1H), 7.87 (t, J=8.4Hz, 2H), 7.66
(d, J=7.8Hz, 2H), 7.64-7.60 (m, 1H), 7.26 (d, J=6.5Hz, 2H)13C NMR(126MHz,DMSO-D6)δ
160.9,136.9,134.7,134.2,133.9,133.4,132.5,132.0,129.9,129.7,129.5,128.7,
128.6,128.3,128.1,126.3,124.0,122.7,122.5,118.2,117.4,115.9.HRMSm/z:calcd.for
C23H17N2O3S[M+H]+401.0960,found 401.0968。
Embodiment 15
The synthesis of N- (6- oxo -5,6- dihydrophenanthridine -2- base) -2,3- Dihydrobenzofuranes -5- sulfonamide (15): specific
Preparation method is referring to embodiment 1, and R is 2,3- Dihydrobenzofuranes -5- base, yield 91.9% in step (3) Chinese style D structure.
The characterize data of ideal product is as follows: mp 280.4-280.9 DEG C1H NMR(500MHz,DMSO-D6)δ
11.65 (s, 1H), 10.15 (s, 1H), 8.31 (d, J=7.1Hz, 1H), 8.17 (d, J=6.8Hz, 1H), 7.99 (s, 1H),
7.87 (s, 1H), 7.65 (s, 2H), 7.55 (d, J=7.9Hz, 1H), 7.35-7.17 (m, 2H), 6.84 (d, J=6.7Hz,
1H), 4.67-4.46 (m, 2H), 3.18 (d, J=7.2Hz, 2H)13C NMR(126MHz,DMSO-D6)δ163.7,160.9,
134.0,133.5,132.9,131.5,129.2,128.7,128.2,126.3,124.6,123.8,122.4,118.2,
117.3,115.5,109.8,72.6,28.2.HRMS m/z:calcd.for C21H17N2O4S[M+H]+393.0909,found
393.0899。
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)~(15) that testing example obtains according to the method described above to the 503nhibiting concentration of BRD4 albumen
It is as shown in table 2 below to test result.
Table 2
| Number | Activity (BRD4) IC50(μM) | Number | Activity (BRD4) IC50(μM) |
| 1 | 1.64 | 9 | 1.79 |
| 2 | 5.92 | 10 | 1.25 |
| 3 | 6.17 | 11 | 0.48 |
| 4 | 6.71 | 12 | 0.24 |
| 5 | 5.54 | 13 | 6.74 |
| 6 | 0.79 | 14 | 7.23 |
| 7 | 1.32 | 15 | 13.12 |
| 8 | 1.13 |
(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 3 below.
Table 3
| Tumor type | Cell strain | IC50(μM) |
| Lung cancer | A549 | 0.75 |
| Liver cancer | HepG2 | 4.83 |
| Cancer of pancreas | PANC-1 | 6.70 |
| Gastric cancer | SGC-7901 | 5.35 |
The above results show that phenanthridines ketone compounds provided by the present invention have good BRD4 inhibitory effect, and to more
Kind tumour has good inhibiting effect.
Claims (10)
1. a kind of phenanthridines ketone compounds with BRD4 albumen inhibiting effect, which is characterized in that be formula (I) compound represented
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. the phenanthridines ketone compounds according to claim 1 with BRD4 albumen inhibiting effect, which is characterized in that change
Close object 1~15；
In compound 1, R is
In compound 2, R is
In compound 3, R is
In compound 4, R is
In compound 5, R is
In compound 6, R is
In compound 7, R is
In compound 8, R is
In compound 9, R is
In compound 10, R is
In compound 11, R is
In compound 12, R is
In compound 13, R is
In compound 14, R is
In compound 15, R is
3. the phenanthridines ketone compounds according to claim 1 with BRD4 albumen inhibiting effect, which is characterized in that described
Pharmaceutically acceptable salt, comprising: formula (I) compound represented and acid formed acid salt and logical formula (I) shown in change
Close the basic salt that object and inorganic base are formed.
4. the preparation of described in any item phenanthridines ketone compounds with BRD4 albumen inhibiting effect according to claim 1~3
Method, which comprises the following steps:
1) using formula A structure compound represented as raw material, in HNO3/H2SO4Nitration mixture under the conditions of carry out nitration reaction, obtain formula B
Nitro compound shown in structure；
2) nitro compound shown in formula B structure, obtains intermediate shown in formula C-structure after nitro-reduction reaction；
3) intermediate shown in formula C-structure obtains formula with sulfonyl chloride compound shown in formula D structure after sulfonamide reaction
(I) the phenanthridines ketone compounds of structure shown in.
Wherein, the R in formula D and the R in formula (I) have identical meanings.
5. the preparation method according to claim 4, which is characterized in that in step 1), the condition of the nitration reaction are as follows:
In -5~5 DEG C of 1~5h of progress.
6. the preparation method according to claim 4, which is characterized in that in step 2), the item of the nitro-reduction reaction
Part are as follows: iron powder and NH is added4Cl and second alcohol and water react 1~3 hour at 70 DEG C~90 DEG C.
7. the preparation method according to claim 4, which is characterized in that in step 3), the item of the sulfonamide reaction
Part are as follows: in dichloromethane solvent, using pyridine as catalyst, 15 DEG C~35 DEG C are reacted 1~5 hour.
8. a kind of pharmaceutical composition, which is characterized in that including the described in any item phenanthridines ketone compounds of claims 1 to 3 and
Pharmaceutically acceptable auxiliary material.
9. described in any item phenanthridines ketone compounds are preparing the application in BRD4 protein inhibitor according to claim 1~3.
10. described in any item phenanthridines ketone compounds have in preparation prevention or/and treatment with BRD4 according to claim 1~3
Application in the drug of related disorders, which is characterized in that the disease be 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, testis
Cancer, osteocarcinoma, the cancer of the brain, the cancer of the esophagus, gastrointestinal cancer, soft-tissue tumor, leukemia or lymph cancer.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6277990B1 (en) * | 1999-12-07 | 2001-08-21 | Inotek Corporation | Substituted phenanthridinones and methods of use thereof |
| US20020006927A1 (en) * | 2000-05-19 | 2002-01-17 | Jia-He Li | Sulfonamide and carbamide derivatives of 6(5H)phenanthridinones and their uses |
-
2019
- 2019-07-03 CN CN201910601362.9A patent/CN110256346A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6277990B1 (en) * | 1999-12-07 | 2001-08-21 | Inotek Corporation | Substituted phenanthridinones and methods of use thereof |
| US20020006927A1 (en) * | 2000-05-19 | 2002-01-17 | Jia-He Li | Sulfonamide and carbamide derivatives of 6(5H)phenanthridinones and their uses |
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