CN108947904A - A kind of compound containing seven membered lactams rings and its application - Google Patents
A kind of compound containing seven membered lactams rings and its application Download PDFInfo
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- CN108947904A CN108947904A CN201810885151.8A CN201810885151A CN108947904A CN 108947904 A CN108947904 A CN 108947904A CN 201810885151 A CN201810885151 A CN 201810885151A CN 108947904 A CN108947904 A CN 108947904A
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- 0 *C(C(N(CCCC=C1N)C1=O)=O)=C[C@]1C(*)=C(*)C(*)=C(*)C1 Chemical compound *C(C(N(CCCC=C1N)C1=O)=O)=C[C@]1C(*)=C(*)C(*)=C(*)C1 0.000 description 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D223/08—Oxygen atoms
- C07D223/10—Oxygen atoms attached in position 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
The invention discloses a kind of compound containing seven membered lactams rings, its cis-trans-isomer or its pharmaceutical salts, structure is as shown in logical formula (I):Wherein: R1Selected from hydrogen, halogen；R2、R3、R4It is independently selected from following groups: hydrogen, R5、R6It is independently selected from following groups: hydrogen, low alkyl group or R5With R6Connection forms five-membered ring or hexatomic ring, R when forming five-membered ring or hexatomic ring5、R6It is independently selected from hydrogen, CH, CH2, O, S or NR7；R7Selected from hydrogen, hydroxyl, low alkyl group, naphthenic base, aryl.Compound containing seven membered lactams rings of the invention has anti-tumor activity, the radiotherapeutic response of tumour cell can be improved, they can be used for preparing anti-tumor drug or radiotherapy hypersitization medicine.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of compound containing seven membered lactams rings and its anti-swollen in preparation
Purposes in tumor medicine and radiotherapy hypersitization medicine.
Background technique
Malignant tumour is a kind of common disease, frequently-occurring disease, it has also become seriously threatens one of principal disease of human life and health.
The treatment of tumour includes operative treatment, chemotherapy, radiotherapy etc., with the development of CT images technology, computer technology and radiotherapy apparatus,
Radiotherapy is increasingly valued by people, and has been widely used the treatment of tumour, especially head and neck neoplasm, prostate cancer, food
Pipe cancer, intestinal cancer, lung cancer, cancer of pancreas etc..Radiotherapy technology mainstream includes outside stereotactic radiotherapy and stereo directional radiative at present
Section.Although radiotherapy achieves greater advance in therapeutic field of tumor, higher local recurrence and resistance to spoke can still occur after radiotherapy
It penetrates.Therefore, tumour cell radiosusceptibility is improved by radiotherapy hypersitization medicine, reduces the toxic side effect of radiotherapy, becomes in recent years
Carry out one of the hot spot of tumor radiotherapy research.
Glycididazole sodium is that China develops the small molecule radiosensitizer with obvious curative effects, has in clinic and widely answers
With treatment for nasopharyngeal carcinoma, lung cancer, rhinocarcinoma and head and neck cancer etc..Yu Xinhong etc., which is reported, replaces nitropyridine class compound, tool
There is preferable Apoptosis, and reduces neurotoxicity (Yu Xinhong etc., CN1314346A, radiotherapeutic sensitizer 2- substitution
The preparation method of Amino 3 cyano -5- nitropyridine).Fan Saijun etc. reports Sodium oxamate to be had under nontoxic low concentration
Apparent Apoptosis (Fan Saijun etc., CN102204900A, Sodium oxamate are preparing the application in radiotherapy hypersitization medicine).
Discovery cathepsin L's inhibitor such as Liang Zhongqin can effectively overcome the resistance to radiation of tumour cell, can develop as radiosensitization drug
(qin etc. in beam, CN102423489A, cathepsin L's inhibitor are preparing the application in radiotherapy hypersitization medicine).Gong Zhicheng etc.
The aloperine of plant origin is reported as preparation radiotherapy resistance lung carcinoma cell autophagy level inhibitor and as radio therapy sensitization
The application of agent (Gong Zhicheng etc., CN106880841A, aloperine prepare the application of radiotherapy in lung cancer sensitizer).The report such as Maria Q.
DNA fragmentation small molecule mimetics Dbait has outstanding Apoptosis, can be used as one kind of combined radiotherapy treatment tumour
New strategy (Maria Q., et al., Small-molecule drugs mimicking DNA damage:a new
Strategy for sensitizing tumors to radiotherapy, Clin Cancer Res, 2009,15 (4):
1308-1316)。
So far, clinical radiation therapy hypersitization medicine quantity is relatively fewer, and it is stronger, Small side effects to still need to development sensitization
Novel radioactive sensitizer.
Summary of the invention
The first purpose of the invention is to provide a kind of compounds containing seven membered lactams rings.
A second object of the present invention is to provide the compound containing seven membered lactams rings described in one kind prepare it is antitumor
Purposes in drug and radiotherapy hypersitization medicine.
To achieve the goals above, The technical solution adopted by the invention is as follows:
The first aspect of the present invention, provide a kind of compound containing seven membered lactams rings, its cis-trans-isomer or its
Pharmaceutical salts, structure is as shown in logical formula (I):
Wherein:
R1Selected from hydrogen, halogen；
R2、R3、R4It is independently selected from following groups: hydrogen,
R5、R6It is independently selected from following groups: hydrogen, low alkyl group or R5With R6Connection forms five-membered ring or hexatomic ring,
R when forming five-membered ring or hexatomic ring5、R6It is independently selected from hydrogen, CH, CH2, O, S or NR7；
R7Selected from hydrogen, hydroxyl, low alkyl group, naphthenic base, aryl.
Preferably, in compound shown in the formula (I), R1Selected from hydrogen, halogen；
R2、R3、R4It is independently selected from following groups: hydrogen,
R5、R6It is independently selected from following groups: hydrogen, low alkyl group.
It is furthermore preferred that the compound containing seven membered lactams rings is selected from:
Chloro- 1- cinnamyl -6,7- dihydro -1H- azatropylidene -2 (5H) -one of 3-:
(E)-N- (4- (3- (the chloro- seven ring -1- base of 7- oxo -2,3,4,7- tetrahydro -1H- nitrogen of 6-) -3- oxo propylene -1-
Base) phenyl) acrylamide:
(E) the chloro- N- of -2- (4- (3- (the chloro- seven ring -1- base of 7- oxo -2,3,4,7- tetrahydro -1H- nitrogen of 6-) -3- oxo third
Alkene -1- base) phenyl) acetamide:
In the definition of logical formula (I) given above, collects term used and is generally defined as follows:
Term " rudimentary " related with alkyl refers to the linear chain or branched chain saturated fat hydrocarbyl group containing 1 to 6 carbon atom, example
Such as, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl；Term naphthenic base refers to the ring containing 3 to 7 carbon, for example, cyclopropyl
Base, cyclobutyl, cyclopenta or cyclohexyl.Term aryl refers to that mono-, di- or tricyclic hydrocarbon compound, wherein at least one ring are fragrance
Ring, each ring contains most 7 carbon atoms, for example, phenyl, naphthalene, anthryl, xenyl or indenyl.Term halogen refers to chlorine, bromine, iodine
Or fluorine.
The pharmaceutical salts are organic acid, inorganic acid salt.
The inorganic acid refers to hydrochloric acid, sulfuric acid, phosphoric acid, diphosphonic acid, hydrobromic acid or nitric acid etc..
The organic acid refers to acetic acid, malic acid, maleic acid, citric acid, fumaric acid, tartaric acid, succinic acid, lactic acid, right
Toluenesulfonic acid, salicylic acid or oxalic acid etc..
The pharmaceutical salts further include pharmaceutically acceptable carrier, excipient or auxiliary material.
The second aspect of the present invention, be to provide a kind of compound containing seven membered lactams rings, its cis-trans-isomer or its
Pharmaceutical salts are preparing the purposes in anti-tumor drug or radiotherapy hypersitization medicine.
The tumour is cancer of the esophagus, gastric cancer, intestinal cancer, the carcinoma of the rectum, carcinoma of mouth, pharynx cancer, laryngocarcinoma, lung cancer, colon cancer, mammary gland
Cancer, uterine cancer, carcinoma of endometrium, oophoroma, prostate cancer, carcinoma of testis, bladder cancer, kidney, liver cancer, cancer of pancreas, osteocarcinoma, connective
Organize cancer, cutaneum carcinoma, cancer eye, the cancer of the brain, thyroid cancer, leukaemia, suddenly king's evil, lymthoma, myeloma etc..
The third aspect of the present invention is to provide a kind of radiotherapeutic sensitizer, including the chemical combination containing seven membered lactams rings
Object, its cis-trans-isomer or its pharmaceutical salts.
Due to the adoption of the above technical scheme, the present invention has the following advantages and beneficial effects:
Compound containing seven membered lactams rings of the invention has anti-tumor activity, they can be used for treating tumour, packet
Include esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, mammary gland, uterus, endometrium, ovary, prostate, testis, wing
The cancer and thyroid gland that the positions such as Guang, kidney, liver, pancreas, bone, connective tissue, skin, eye, brain and central nervous system occur
Cancer, leukaemia, suddenly king's evil, lymthoma and myeloma etc..
The radiotherapeutic response of tumour cell can be improved in compound containing seven membered lactams rings of the invention, they
It can be used for preparing radiotherapy hypersitization medicine.
The pharmacological activity of compound containing seven membered lactams rings of the invention allows to be used to prepare antitumor, anti-true
Bacterium, platelet aggregation-against and anti-drugs for nervous, therefore the invention also includes using these compounds and its pharmaceutical salts as living
The pharmaceutical composition of property ingredient.The pharmaceutical composition can be solid form or liquid form.
Compound containing seven membered lactams rings of the invention, it is any including its cis-trans-isomer and its these form
Mixture or its pharmaceutical salts are in addition to application in preparation of anti-tumor drugs, it may also be used for prepare agents: antifungal drug,
Medicament for resisting platelet aggregation, antidepressant, anxiolytic drugs, analgesic and other cardiovascular and cerebrovascular diseases and nerveous system
The therapeutic agent etc. for disease of uniting.
Detailed description of the invention
Fig. 1 is the song that the compound I-1 containing seven membered lactams rings changes the radiotherapeutic response of Panc-1 cell
Line chart.
Fig. 2 is the song that the compound I-2 containing seven membered lactams rings changes the radiotherapeutic response of Panc-1 cell
Line chart.
Fig. 3 is the song that the compound I-3 containing seven membered lactams rings changes the radiotherapeutic response of Panc-1 cell
Line chart.
Fig. 4 is the song that the compound I-1 containing seven membered lactams rings changes the radiotherapeutic response of SW1990 cell
Line chart.
Fig. 5 is the song that the compound I-2 containing seven membered lactams rings changes the radiotherapeutic response of SW1990 cell
Line chart.
Fig. 6 is the song that the compound I-3 containing seven membered lactams rings changes the radiotherapeutic response of SW1990 cell
Line chart.
Wherein: Control is blank control group.
Specific embodiment
In order to illustrate more clearly of the present invention, below with reference to preferred embodiment, the present invention is described further.Ability
Field technique personnel should be appreciated that following specifically described content is illustrative and be not restrictive, this should not be limited with this
The protection scope of invention.
Embodiment 1
The preparation of chloro- 1- cinnamyl -6,7- dihydro -1H- azatropylidene -2 (5H) -one of 3-, synthetic route are as follows:
It weighs 62mg cinnamic acid 1 to be dissolved in anhydrous methylene chloride (2mL), oxalyl chloride (0.18mL) and catalytic amount is added
DMF.It is stirred at room temperature 2 hours, decompression boils off solvent, obtains compound 2, is directly used in next step.
- 2 (5H) -one (3,68mg) of compound 3-chlorin -6,7- dihydro -1H- azatropylidene is dissolved in anhydrous tetrahydro furan (5mL)
In, it is cooled to -78 DEG C and is slowly added to n-BuLi tetrahydrofuran solution (2.5M, 0.2mL), be added dropwise after the reaction was continued 15 minutes
The anhydrous tetrahydrofuran solution for the compound 2 that one step obtains.It is slowly increased to room temperature reaction 30 minutes, is quenched, methylene chloride extraction,
Dry, decompression boils off solvent afforded crude material, and chromatography post separation obtains compound I-1, white solid, yield, and 70%.1HNMR
(600MHz,CDCl3) δ: 1.99-2.04 (m, 2H, J=6.8Hz, CH2), 2.35-2.39 (q, 2H, J=7.5Hz, CH2),
3.99-4.01 (t, 2H, J=6.3Hz, NCH2), 6.78-6.80 (t, 1H, J=7.8Hz ,=CH), 7.37-7.38 (m, 3H,
), Ar-H 7.47-7.50 (d, 1H, J=15.6Hz ,=CH), 7.57-7.59 (m, 2H, Ar-H), 7.80-7.82 (d, 1H, J=
15.6Hz ,=CH)；13C NMR(150MHz,CDCl3)δ:23.83,25.99,41.43,120.06,128.58,128.98,
129.63,130.53,134.94,137.28,145.43,167.32,167.43；HRMS:Calcd for
C15H14ClNO2275.0713Found:275.0713。
Embodiment 2
(E)-N- (4- (3- (the chloro- seven ring -1- base of 7- oxo -2,3,4,7- tetrahydro -1H- nitrogen of 6-) -3- oxo propylene -1-
Base) phenyl) acrylamide preparation, synthetic route is as follows:
It weighs 62mg compound 4 to be dissolved in anhydrous methylene chloride (2mL), oxalyl chloride (0.18mL) and catalytic amount is added
DMF.It is stirred at room temperature 2 hours, decompression boils off solvent, obtains compound 5, is directly used in next step.
- 2 (5H) -one (3,68mg) of compound 3-chlorin -6,7- dihydro -1H- azatropylidene is dissolved in anhydrous tetrahydro furan (5mL)
In, it is cooled to -78 DEG C and is slowly added to n-BuLi tetrahydrofuran solution (2.5M, 0.2mL), be added dropwise after the reaction was continued 15 minutes
The anhydrous tetrahydrofuran solution for the compound 5 that one step obtains.It is slowly increased to room temperature reaction 30 minutes, is quenched, methylene chloride extraction,
It is dry, it depressurizes and boils off solvent afforded crude material, chromatography post separation acquisition intermediate 6, white solid, yield, 55%.
Intermediate 6 (200mg) is dissolved in EtOH/H2Reduced iron is added in the in the mixed solvent of O (12mL, volume ratio=5:1)
Powder (180mg) and ammonium chloride (170mg) are warming up to 55 DEG C and react 4 hours.Methylene chloride extraction, is washed, dry, boils off solvent
Crude product, chromatography post separation obtain intermediate 7, yellow solid, yield, 69%.
Intermediate 7 (50mg) is dissolved in methylene chloride (10mL), 25 μ L of triethylamine is added, react 10 minutes at 0 DEG C, it is slow
It is slow that 40 μ L of acryloyl chloride is added, react 4 hours at 0 DEG C, methylene chloride extraction, washing, chromatography post separation obtains compound I-2, Huang
Color solid, yield, 70%.1H NMR(300MHz,CDCl3) δ: 1.97-2.06 (m, 2H, J=6.8Hz, CH2),2.34-2.41
(q, 2H, J=7.4Hz, CH2), 3.98-4.02 (t, 2H, J=6.2Hz, NCH2),4.20(s,2H,ClCH2),6.76-6.82
(t, 1H, J=7.5Hz ,=CH), 7.41-7.46 (d, 1H, J=15.5Hz ,=CH), 7.59 (s, 4H, Ar-H), 7.75-7.80
(d, 1H, J=15.5Hz ,=CH), 8.31 (s, 1H, CONH)；13C NMR(75MHz,CDCl3)δ:23.82,26.00,41.44,
42.99,119.52,119.99,120.09,129.59,131.78,137.35,144.43,163.93,167.25,157.49；
HRMS:Calcd for C17H16Cl2N2O3366.0543Found:366.0538。
Embodiment 3
(E) the chloro- N- of -2- (4- (3- (the chloro- seven ring -1- base of 7- oxo -2,3,4,7- tetrahydro -1H- nitrogen of 6-) -3- oxo third
Alkene -1- base) phenyl) acetamide preparation:
Intermediate 7 (57mg) is dissolved in methylene chloride (10mL), 18 μ L of triethylamine is added, react 10 minutes at 0 DEG C, it is slow
It is slow that 35 μ L of chloracetyl chloride is added, react 4 hours at 0 DEG C, methylene chloride extraction is washed, chromatography post separation obtains compound I-3, light
Yellow solid, yield, 68%.1H NMR(300MHz,CDCl3) δ: 1.98-2.04 (m, 2H, J=6.3Hz, CH2),2.34-
2.41 (q, 2H, J=7.0Hz, CH2), 3.97-4.02 (t, 2H, J=6.4Hz, NCH2), 5.78-5.82 (d, 1H, J=
10.5Hz ,=CH), 6.21-6.30 (dd, 1H, J1=10.0Hz, J2=10.1Hz ,=CH), 6.43-6.49 (d, 1H, J=
17.0Hz ,=CH), 6.76-6.81 (t, 1H, J=7.8Hz ,=CH), 7.39-7.44 (d, 2H, J=15.5Hz, Ar-H),
7.53-7.56 (d, 2H, J=8.6Hz, Ar-H), 7.60-7.64 (d, 2H, J=8.7Hz, Ar-H), 7.74-7.79 (d, 1H, J
=15.5Hz ,=CH)；13C NMR(75MHz,CDCl3)δ:23.82,26.04,41.45,118.99,119.97,128.61,
129.60,130.99,131.05,137.34,139.82,144.76,163.56,167.32,167.50；HRMS:Calcd for
C18H17ClN2O3344.0933Found:344.0928。
Embodiment 4
The anti-tumor activity test of the compounds of this invention
Cytostatic to tumor cell test is carried out to the compound of the present invention I-1~I-3, test method is using routine
CellTiterTMBlue method (Lv Qiujun edits " developmental pharmacology research method ", 2007:242-243).
Cell strain selection A549 (human lung carcinoma cell), Panc-1 (human pancreatic cancer cell), (human pancreas cancer is thin by SW 1990
Born of the same parents), HCT-116 (people's colon-cancer cell), PC-3 (Human Prostate Cancer Cells), by Shanghai Institute of Pharmaceutical Industry's pharmacological evaluation room freeze
It deposits and passes on.Culture solution is that RPMI1640+10%FBS+ is dual anti-.Positive control drug selects Doxorubicin.
After cell is collected in culture, cell suspension is mixed, takes 10 μ L in cell counting board, is counted under the microscope,
Calculate cell concentration；96 orifice plates (Corning, #3599) is taken, by 200 μ L of every hole, 4 × 103A cell inoculation, after inoculation
96 orifice plates are placed in 37 DEG C, cultivate for 24 hours in 5% carbon dioxide；It is moved back for 24 hours except old culture medium, every hole is added by after multiple dilution
Embodiment compound fresh culture (100,30,10,3,1,0.3 μM), control DMSO content are 1%, every 200 μ of hole culture medium
L；It is put into incubator later and is incubated for 72h, blank group uses the culture medium that contains 1%DMSO as control.
96 orifice plates are taken out after 72h, are added into every hole and are contained CellTiter BlueTMThe 200 μ L of culture medium of reagent (will
10%Cell Titer Blue is dissolved in corresponding culture medium, v/v), it is protected from light operation, is measured at microplate reader (Biotek)
Initial fluorescent intensity.96 orifice plates are incubated for 1-4h in 37 DEG C, 5% carbon dioxide, every hole terminal fluorescence is detected under microplate reader
Intensity (wavelength of fluorescence 530/35nm and 590/40nm) uses computer software Graphpad Prism analysis of fluorescence intensity data
Calculate GI50Value.Calculation formula: inhibiting rate (%)=[(Ac-As)/(Ac-Ab)] × 100%；Wherein As is experimental port (containing thin
Culture medium, the CellTiter Blue of born of the same parentsTMReagent, compound), Ac be control wells (culture medium containing cell,
CellTiterBlueTMReagent), Ab is blank well (culture medium, CellTiter Blue without cell and compoundTMExamination
Agent).
Test result is shown in Table 1, wherein sample refers to the compound for preparing in corresponding Examples 1 to 3, and (such as embodiment 1 is i.e.
Chloro- 1- cinnamyl -6,7- dihydro -1H- azatropylidene -2 (5H) -one of 3-.)
1 Compound ira vitro suppressing cell reproduction experimental result of table
The experimental results showed that, compound I-1~I-3 of the invention containing seven membered lactams rings has good anti-above
Tumor promotion all shows excellent activity to A549, HCT-116, Panc-1 and PC-3, therefore the present invention contains acyl in seven yuan
Compound I-1~the I-3 and its esters of amine ring can be used for preparing anti-tumor drug.
Embodiment 5
The radio therapy sensitization of the compounds of this invention is tested
By cell with different cell densities (200,400,600,800 and 1000/hole) plantations in 6 orifice plates, every group is set
Three wells is incubated for 24 hours.Use IC20Concentration contains compound I-1~I-3 effect 24 hours of seven membered lactams rings, then not
Ray (0,2,4,6 and 8Gy) with dosage irradiates, and radiator apparatus selects the production of U.S. Varian companyEX21.According to
After penetrating 48h, continue to be incubated for 7 days.After cell is fixed 15 minutes with methanol, with 0.5% violet staining 30 minutes.In microscope
It is lower count be more than 50 cells population of cells, cubic fitting model use one-hit multitarget model (Wang F., et al.,
Chloroquine Enhances the Radiosensitivity ofBladder Cancer Cells by
Inhibiting AutophagyandActivatingApoptosis,Cell Physiol Biochem,2018,45,54-
66.), formula: SF=1- (1-e-kD)n, wherein SF is cell survival fraction, and e is the bottom of natural logrithm, and k is the slope of curve, D
For dose of radiation suffered by cell.Radio therapy sensitization is than calculating:D0And D1Respectively non-dosing group and dosing group are averaged
Lethal dose, numerically k0And k1The slope of curve of respectively non-dosing group and dosing group.
The results are shown in attached figure 1~and 6, Fig. 1 is radiotherapy of the compound I-1 containing seven membered lactams rings to Panc-1 cell
The curve graph that sensitivity sexually revises；Fig. 2 is that the compound I-2 containing seven membered lactams rings is sensitive to the radiotherapy of Panc-1 cell
The curve graph sexually revised；Fig. 3 is that the compound I-3 containing seven membered lactams rings changes the radiotherapeutic response of Panc-1 cell
The curve graph of change；Fig. 4 is that the compound I-1 containing seven membered lactams rings changes the radiotherapeutic response of SW1990 cell
Curve graph；Fig. 5 is the curve that the compound I-2 containing seven membered lactams rings changes the radiotherapeutic response of SW1990 cell
Figure；Fig. 6 is the curve graph that the compound I-3 containing seven membered lactams rings changes the radiotherapeutic response of SW1990 cell；
Wherein: Control is blank control group.It can be seen from the figure that compound I-1~I-3 containing seven membered lactams rings be administered+
Two kinds of pancreatic cancer cell survival rates of irradiation group compare single irradiation group, and survivorship curve obviously moves down, and with exposure dose
It increases, moves down and be more obvious.Wherein enhanced sensitivity ratio (SER, when numerical value be greater than 1 expressionization of the compound I-3 in Panc-1 cell
Closing object has radio therapy sensitization effect, Fertil B et al.Mean inactivation dose:a useful concept
for intercomparison of human cell survival curves,Radiat Res,1984,99:73-84.)
It is 1.69, the SER in SW1990 cell is 1.13；SER of the compound I-2 in Panc-1 cell is 1.45, in SW1990
In be 1.30；Compound I-1 shows enhanced sensitivity in Panc-1 cell, and SER value is 1.22.Therefore, contain seven membered lactams
Compound I-1~I-3 of ring all has preferable radio therapy sensitization effect to two kinds of pancreatic cancer cells.
The basic principles, main features and advantages of the present invention have been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, various changes and improvements may be made to the invention without departing from the spirit and scope of the present invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent defines.
Claims (10)
1. a kind of compound containing seven membered lactams rings, its cis-trans-isomer or its pharmaceutical salts, it is characterised in that: structure is such as logical
Shown in formula (I):
Wherein:
R1Selected from hydrogen, halogen；
R2、R3、R4It is independently selected from following groups: hydrogen,
R5、R6It is independently selected from following groups: hydrogen, low alkyl group or R5With R6Connection forms five-membered ring or hexatomic ring, is formed
R when five-membered ring or hexatomic ring5、R6It is independently selected from hydrogen, CH, CH2, O, S or NR7；
R7Selected from hydrogen, hydroxyl, low alkyl group, naphthenic base, aryl.
2. the compound containing seven membered lactams rings, its cis-trans-isomer or its pharmaceutical salts according to claim 1, special
Sign is: in compound shown in the formula (I), R1Selected from hydrogen, halogen；
R2、R3、R4It is independently selected from following groups: hydrogen,
R5、R6It is independently selected from following groups: hydrogen, low alkyl group.
3. the compound containing seven membered lactams rings, its cis-trans-isomer or its pharmaceutical salts according to claim 2, special
Sign is: the compound containing seven membered lactams rings is selected from:
4. the compound containing seven membered lactams rings, its cis-trans-isomer or its pharmaceutical salts according to claim 1, special
Sign is: the pharmaceutical salts are organic acid, inorganic acid salt.
5. the compound containing seven membered lactams rings, its cis-trans-isomer or its pharmaceutical salts according to claim 4, special
Sign is: the inorganic acid refers to hydrochloric acid, sulfuric acid, phosphoric acid, diphosphonic acid, hydrobromic acid or nitric acid.
6. the compound containing seven membered lactams rings, its cis-trans-isomer or its pharmaceutical salts according to claim 4, special
Sign is: the organic acid refer to acetic acid, malic acid, maleic acid, citric acid, fumaric acid, tartaric acid, succinic acid, lactic acid, to first
Benzene sulfonic acid, salicylic acid or oxalic acid.
7. the compound containing seven membered lactams rings, its cis-trans-isomer or its pharmaceutical salts according to claim 4, special
Sign is: the pharmaceutical salts further include pharmaceutically acceptable carrier, excipient or auxiliary material.
8. a kind of described in any item compounds containing seven membered lactams rings of claims 1 to 3, its cis-trans-isomer or its medicine
The purposes in anti-tumor drug or radiotherapy hypersitization medicine is being prepared with salt.
9. the compound containing seven membered lactams rings, its cis-trans-isomer or its pharmaceutical salts according to claim 8 are being made
Purposes in standby anti-tumor drug or radiotherapy hypersitization medicine, it is characterised in that: the tumour is cancer of the esophagus, gastric cancer, intestinal cancer, rectum
Cancer, carcinoma of mouth, pharynx cancer, laryngocarcinoma, lung cancer, colon cancer, breast cancer, uterine cancer, carcinoma of endometrium, oophoroma, prostate cancer, testis
Cancer, bladder cancer, kidney, liver cancer, cancer of pancreas, osteocarcinoma, connective tissue cancer, cutaneum carcinoma, cancer eye, the cancer of the brain, thyroid cancer, leukaemia,
King's evil, lymthoma, myeloma suddenly.
10. a kind of radiotherapeutic sensitizer, it is characterised in that: contain seven membered lactams rings including claims 1 to 3 is described in any item
Compound, its cis-trans-isomer or its pharmaceutical salts.
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Cited By (1)
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| CN111892539A (en) * | 2020-08-03 | 2020-11-06 | 南京林业大学 | Isolongifolenone caprolactam derivative and preparation method and application thereof |
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