CN108863923A - A kind of pyridinone derivatives and its preparation method and application - Google Patents
A kind of pyridinone derivatives and its preparation method and application Download PDFInfo
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- CN108863923A CN108863923A CN201810543376.5A CN201810543376A CN108863923A CN 108863923 A CN108863923 A CN 108863923A CN 201810543376 A CN201810543376 A CN 201810543376A CN 108863923 A CN108863923 A CN 108863923A
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- pyridinone derivatives
- derivatives
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- 150000005299 pyridinones Chemical class 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 24
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 24
- VKCYHJWLYTUGCC-UHFFFAOYSA-N nonan-2-one Chemical compound CCCCCCCC(C)=O VKCYHJWLYTUGCC-UHFFFAOYSA-N 0.000 claims abstract description 18
- -1 ethoxy, hydroxypropyl Chemical group 0.000 claims abstract description 17
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 10
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 3
- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical group CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000007171 acid catalysis Methods 0.000 claims abstract description 3
- 125000002350 geranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 47
- 150000001875 compounds Chemical class 0.000 claims description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
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- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
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- 238000011925 1,2-addition Methods 0.000 claims description 2
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—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
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
The invention discloses a kind of pyridinone derivatives and preparation method thereof and its applications, and the pyridinone derivatives are mainly from R1, R2, R3Structural modification is carried out in terms of these three substituent groups, wherein R1Modification mainly pass through allyl, isopentene group, geranyl, to luorobenzyl etc.；R2Modification mainly pass through ethoxy, hydroxypropyl, amine ethyl, amine propyl etc.；R3Modification be concentrated mainly on the ethers with certain structure feature.Pyridinone derivatives of the invention significantly inhibit the pancreatic cancer cell PANC-1 under weary nutritional status, and do not influence on the cell under normal nutrition state and (prompt no cytotoxicity).The preparation method of pyridinone derivatives of the invention, synthesize bicyclic [3.3.1] nonanone of basic parent nucleus first, under toluenesulfonic acid catalysis with a series of hydramine or diamines are rearranged reacts, a kind of pyridinone derivatives to cancer of pancreas with obvious inhibiting effect are prepared, there is good practicability.
Description
Technical field
The invention belongs to chemistry and pharmaceutical technology fields, and in particular to a kind of pyridinone derivatives and preparation method thereof and
Using.
Background technique
Cancer of pancreas (Pancreatic cancer) is described as " king of cancer " by medical field, is prognosis in all malignant tumours
Worst cancer, patient make a definite diagnosis latter annual death rate and are up to 95%-98%, that is to say, that 95% or so Pancreas cancer patients are from true
It examines dead less than one-year age, 5 years very little can be lived through.Operation excision is its optimal treatment after cancer of pancreas is made a definite diagnosis
Mode, but when Pancreas cancer patients more than 80%~85% are made a definite diagnosis has been advanced stage, and for these patients, chemotherapy is can to receive
Scheme.Before 2011, although there are many tests to attempt gemcitabine and other drugs use in conjunction, advanced stage pancreas
The treatment of cancer is again without obvious progress.In recent years, the clinical application of the targeted inhibitions agent such as Kras, EGFR and COX-2 achieves
Breakthrough progress can significantly improve the prognosis of Pancreas cancer patients, but still need to due to more than somewhat expensive, side reaction etc. into one
The research of step.Currently, gemcitabine is still " goldstandard " of advanced pancreatic cancer treatment, which can block tumour cell point
Split promotion cell death；However many patients can be dead within the several months, it is usually because cancer cell, which has found one, to be hidden
The mode of drug gemcitabine effect is so that gemcitabine therapy becomes no longer valid, i.e., drug resistance leads to chemotherapy failure
One of the main reasons, therefore the clinical chemotherapy drug of the treatment cancer of pancreas of development structure and mechanism of action completely newly is needed, alleviate existing
There is the drug resistance of chemotherapeutics, extend the life of Pancreas cancer patients, improves its quality of life.
The growth of tumour and proliferation are largely dependent upon angiogenesis to realize functional supply of blood flow, due to swollen
Faster than vascular endothelial cell proliferation speed, and new vessels network disorder does not have and preferably provides for cell oncocyte
Oxygen and the function of nutrition, therefore, tumour obtains the tolerance for weary nutritional status, even if in low oxygen and nutrition supplying
Also there is very strong survival ability, pancreatic carcinoma PANC-1 is exactly one of this kind of few blood supply malignant tumour under the conditions of answering
It is typical to represent, it can be used to establish anti-pancreatic cancer screening compound model；On the other hand the environment of hypoxemia more can induce in vivo
Pancreatic tumour new vessels generate, and promote the infiltration and transfer of cancer of pancreas, and compounds on pancreatic cancer is thin under weary nutritional status
The activity of born of the same parents can more play the inhibiting effect in the cancer metastasis stage, consequently found that having good inhibitory activity under weary nutrition
And the compound of no cytotoxicity is of great significance under eutrophy.
Summary of the invention
Goal of the invention：For above-mentioned problems of the prior art, the object of the present invention is to provide a kind of pyridinones
Derivative, the pyridinone derivatives are mainly from R1, R2, R3Structural modification is carried out in terms of these three substituent groups, is made it have anti-
Tumour adjusts immune function, inhibits the important biomedical actives such as platelet aggregation.It is a further object of the present invention to provide one
The method that kind prepares above-mentioned pyridinone derivatives.Further object of the present invention is to provide a kind of above-mentioned pyridinone derivatives
Purposes.
Technical solution：In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is：
A kind of pyridinone derivatives, following structural formula any one：
R1Selected from group：Allyl, isopentene group, geranyl to luorobenzyl etc., but are not limited to these groups；
R2Selected from group：Ethoxy, hydroxypropyl, amine ethyl, amine propyl etc., but it is not limited to these substituent groups；
R3Selected from group：
N=1,2,3,4；But it is not limited to these groups；
R4、R5、R6And R7It is selected from group：Phenyl, substituted-phenyl, heterocycle etc., but it is not limited to these groups；
A method of preparing the pyridinone derivatives, by polysubstituted bicyclic [3.3.1] nonanone parent nucleus into
Rearrangement obtains target compound.Detailed process is as follows：
It is the synthesis of polysubstituted bicyclic [3.3.1] nonanone parent nucleus first, with 1, hydroresorcinol (1) is raw material and isobutanol
It is condensed dehydration under Catalyzed by p-Toluenesulfonic Acid, obtains vinylogy ester type compound 2；Compound 2 is in -78 DEG C, N2It is pulled out under protection with LDA
Fall carbonyl α-H, then with halohydrocarbons reaction, obtains compound 3；Compound 3 and lithium methide are in low temperature, N2Protection is lower to occur 1,2-
Addition reaction obtains α, beta-unsaturated ketone compound 4 after acidified；Compound 4 and the lithium dimethylcuprate now made are in low temperature, N2
Isosorbide-5-Nitrae-addition occurs for the lower reaction of protection, obtains the compound 5 of three substituted cyclohexanone structures；Compound 5 and tert-butyldimethylsilyl chloride
Silane (TBDMSC1) reaction obtains silyl enol ether 6；There is a pair of of isomers due to the difference of position of double bond on silyl enol ether,
6a/6b is to exist as a mixture, and compound 6 is reacted with malonyl chloride, and cyclization obtains parent nucleus substituted bicyclic before resetting
[3.3.1] nonanone compound 7；Compound 7 obtains targeted pyridine ketones derivant by rearrangement.Specific reaction equation is as follows：
A method of the pyridinone derivatives are prepared, reset to obtain based on bicyclic [3.3.1] nonanone parent nucleus complete
New pyridone parent nucleus.Reaction equation is as follows：
A method of it preparing the pyridinone derivatives and utilizes the activity of four hydroxyls using pyridone as parent
It is reacted by Williamson's synthetic method with a series of preparatory halides modified, obtains a series of derivatives of four etherification of hydroxyl groups
Object.Reaction equation is as follows：
A method of it preparing the pyridinone derivatives and utilizes the activity of four hydroxyls using pyridone as parent
It is reacted with a series of isocyanates, obtains a series of Esterification derivatives of four hydroxyl aminos.Reaction equation is as follows：
The pyridinone derivatives application in preparation of anti-tumor drugs.
The tumour is cancer of pancreas.
Beneficial effect：Compared with prior art, pyridinone derivatives of the invention, to the cancer of pancreas under weary nutritional status
Cell PANC-1 is significantly inhibited, and does not influence (to prompt no cell to the cell under normal nutrition state
Toxicity).The preparation method of pyridinone derivatives of the invention synthesizes bicyclic [3.3.1] nonanone of basic parent nucleus, in first first
Benzene sulfonic acid catalysis is lower to pass through rearrangement reaction with a series of hydramine or diamines, and successfully preparing a kind of cancer of pancreas has apparent inhibit
The pyridinone derivatives of effect have good practicability.
Detailed description of the invention
Fig. 1 is 2 μM of external activity data result figures of pyridinone derivatives；
Fig. 2 is mouse weight data result figure；
Fig. 3 is mouse abdomen bilateral subcutaneous transplantation tumor weight result figure.
Specific embodiment
The present invention is described further combined with specific embodiments below.
Embodiment 1
1, the preparation of compound S8, reaction equation are：
1) preparation of compound S2
By 1, hydroresorcinol (S1) synthesizes 3- isobutoxy -2- cyclonene (S2)：It is added 1 in 250mL reaction flask,
Hydroresorcinol (50mmol, 1.0eq), hydration p-methyl benzenesulfonic acid (3mmol, a 0.06eq), isobutanol (200mmol, 4.0eq)
With toluene (200mL), connects 120 DEG C of water segregator and be refluxed overnight.After the reaction was completed, decompression steams solvent and excessive isobutanol, column
Chromatography purifying, obtains yellow oily liquid 3- isobutoxy cyclonene (S2) yield 95%.
2) preparation of compound S3a/S3b/S3c/S3d
Under nitrogen protection, to the THF solution for being cooled to addition 2mol/LLDA in -78 DEG C of new steaming THF (100mL)
(30mmol, 15mL, 1.2eq) THF solution (20mL) of S2 (25mmol, 1.0eq) is added dropwise at -78 DEG C.It is simultaneously slowly extensive to react 1h
It is multiple to be cooled to -78 DEG C to 0 DEG C, isoprenyl bromide/geranyl bromide/allyl bromide, bromoallylene/to fluorobenzyl bromide (30mmol, 1.2eq) is added dropwise
And slowly restore to room temperature, reaction solution turns yellow.TLC monitoring reaction, to add saturation NH after the reaction was completed4Cl solution quenching reaction.
Ether extraction, anhydrous Na after organic phase merges2SO4Dry, column chromatographic isolation and purification obtains yellow oily liquid S3a/S3b/
S3c/S3d。
3) preparation of compound S4a/S4b/S4c/S4d
Under nitrogen protection, to the new steaming THF for the S3a/S3b/S3c/S3d (17.5mmol, 1.0eq) for being cooled to -10 DEG C
The diethyl ether solution (26.4mmol, 16.5mL, 1.5eq) of 1.6mol/L lithium methide is added dropwise in (70mL) solution.Reaction slowly restores
To room temperature, TLC detects reaction process.It is cooled to 0 DEG C after raw material point disappearance, 1mol/L dilute hydrochloric acid (50mL), room is slowly added dropwise
Temperature is lower to stir 0.5h.Water phase ether extracts and merges organic phase, anhydrous Na2SO4Dry, column chromatographic isolation and purification obtains pale yellow
Color oily liquids S4a/S4b/S4c/S4d.
4) preparation of compound S5a/S5b/S5c/S5d
Under nitrogen protection, anhydrous ether (150mL) suspension is newly steamed to the CuI (30mmol, 2.0eq) for being cooled to -10 DEG C
The middle diethyl ether solution (60mmol, 37.5mL, 4.0eq) that 1.6mol/L lithium methide is added dropwise.Reaction solution color is gradually turned yellow by ash, most
After become light brown transparency liquid.After being added dropwise, -10 DEG C of stirring 1h are kept, S4a/S4b/S4c/S4d is slowly added dropwise later
The anhydrous ether solution (100mL) of (15mmol), TLC monitor reaction process.After the reaction was completed, saturation NH is added4Cl solution is quenched
It goes out reaction, and ammonium hydroxide, which is added, keeps reaction solution transparent in navy blue.Ether extraction, merges organic phase, anhydrous Na2SO4It is dry, column layer
Analysis isolates and purifies, and obtains colourless to yellowish oily liquids S5a/S5b/S5c/S5d.
5) preparation of compound s 6 a/S6b/S6c/S6d
In 100mL reaction flask be added S5a/S5b/S5c/S5d (12.5mmol, 1.0e), newly steam triethylamine (16mmol,
It is 1.25eq) and dry acetonitrile (30mL), add tert-butyl chloro-silicane (16mmol, 1.25eq) and NaI (16mmol,
1.25eq), 2h is stirred at reflux at 90 DEG C, TLC monitoring reaction, decompression steams triethylamine and solvent after the reaction was completed, and petroleum is added
Ether (50mL) is stirred and is filtered, and petroleum ether filter cake filtrate is concentrated, column chromatographic isolation and purification, obtains by a pair of of enol silicon
Colourless oil liquid mixture S6a/S6b/S6c/S6d composed by ether isomers.
6) preparation of compound S7a/S7b/S7c/S7d
Silyl enol ether S6a/S6b/S6c/S6d (12mmol, 1.0eq) is dissolved in dry DCM (5mL), be cooled to-
10 DEG C, DCM (4mL) solution of malonyl chloride (24mmol, 2.0eq) is slowly added dropwise, after reaction stirs 12h at -10 DEG C, slowly
Mixing water (6mL) solution of potassium hydroxide (96mmol, 8.0eq) and TEBA (0.6mmol, 0.05eq) is added dropwise, and is kept for -10 DEG C
1h is reacted, is slowly restored to is stirred overnight at room temperature later.Add water and each 100mL of DCM, adjust pH=12, DCM is extracted 3 times, is merged
Organic phase, anhydrous Na2SO4Dry, evaporated under reduced pressure, column chromatographic purifying recycles raw material S5a/S5b/S5c/S5d；Water phase adjusts pH=
1, DCM extraction 3 times, merges organic phase and drying, and evaporated under reduced pressure obtains orange foam shape solid S7a/S7b/S7c/S7d (purifying
It is afterwards white to faint yellow solid), next step reaction can be carried out without purifying.
7) preparation of compound S8a/S8b/S8c/S8d
In reaction flask be added S7a/S7b/S7c/S7d (3mmol, 1.0eq), one hydration p-methyl benzenesulfonic acid (0.9mmol,
0.3eq), n-propanolamine (6mmol, 2.0eq) and toluene (150mL), load onto oil water separator (Dean-Starkapparatus)
120 DEG C of reaction 4h, after the reaction was completed, decompression steam toluene, and residue column chromatographic isolation and purification obtains white/weak yellow foam
Shape solid S8a/S8b/S8c/S8d.
2, the preparation of compound S8e/S8f/S8g/S8h/S8i, reaction equation are：
S7a (3mmol, 1.0eq), hydration p-methyl benzenesulfonic acid (0.9mmol, a 0.3eq), hydramine are added in reaction flask
(6mmol, 2.0eq) and toluene (150mL) loads onto 120 DEG C of reaction 4h of oil water separator (Dean-Starkapparatus), instead
After the completion of answering, decompression steams toluene, and residue column chromatographic isolation and purification obtains white/weak yellow foam shape solid S8e/S8f/
S8g/S8h/S8i。
3, the preparation of compound 1~60, reaction equation are as follows：
The synthesis of amino-acid ester analog derivative：In reaction flask be added S8 (3mmol, 1.0eq), isocyanates (1.2eq) and
DCM (150mL), room temperature reaction 4h are spin-dried for residue after the reaction was completed, and column chromatographic isolation and purification obtains white solid 1~8,
47~60.
The synthesis of ether derivative：In reaction flask be added S8 (3mmol, 1.0eq), corresponding halogenated hydrocarbons (6mmol,
1.2eq), potassium carbonate (2eq) and DMF (15mL), room temperature reaction 4h are spin-dried for residue after the reaction was completed, and column chromatography for separation is pure
Change, obtains white solid 9~46, specific structure is shown in Table 2.
1 compound nuclear magnetic data of table
2 compound structure of table
2 pyridinone derivatives concrete activity of embodiment
1, inhibit external pancreatic cancer cell PANC-1 experiment (table 3)
Condition of culture：DMEM in high glucose/10%FBS culture medium, 5%CO2, 37 DEG C of in-vitro simulated conditions；Cell confluency is
When 80%, PBS washing, pancreatin digestion, serum-containing media termination；Cell centrifugation is collected, goes after supernatant plus culture medium is resuspended simultaneously
It counts, with 1 × 105mL-1Density be inoculated in 96 porocyte culture plates, every 100 μ L cell liquid of hole, culture is for 24 hours；Replace weary nutrition
Culture medium, while it being separately added into the compound of control (DMSO, 0.1%) and various concentration, culture is for 24 hours；Mtt assay analyzes PANC-1
Survival rate of the cell in weary nutrition (D) and normal nutrition (R).
In vitro results prompt, pyridinone derivatives non-toxic (table 3) under the conditions of normal nutrition, and in weary nutrition (nothing
Glucose and amino acid) under the conditions of, higher inhibitory activity (table 3, Fig. 1) is shown to pancreatic cancer cell PANC-1.
3 Compound ira vitro of table inhibits pancreatic cancer cell activity data
2, anti-pancreatic cancer activity experiment (Fig. 2, Fig. 3) in pyridinone derivatives body
C57/BL6 mouse abdomen bilateral subcutaneous transplantation knurl model is established
Reagent and surgical instrument prepare：Mouse (animal quality certification number：SCXK (Soviet Union) 2015-0001) it is random according to weight
It is divided into 4 groups, respectively negative control group (Control, injecting normal saline), two various concentration intraperitoneal injection group (1 and 5mg/
Kg/d), positive drug control group (Arctigenin, 5mg/kg/d) then digests Pan-02 cell (mice pancreatic cancer cell), and
1 × 10 is made with PBS buffer solution resuspension6mL-1Cell suspension；Mouse abdomen diamond wool is shaved, it is outstanding to draw cell with syringe
Liquid is subcutaneously injected, and 100 μ L suspensions are injected in every survey；It observes and weighs daily, grown after three days with tumour, intraperitoneal injectionization
Polymer solution measures knurl product daily；Period will carry out MRI experiment after planting tumor mouse gas fiber crops, observe mouse tumor size variation；It is real
End is tested, eyeball takes blood, and liver and two sides tumor is taken to weigh.
In the subcutaneous transplantation knurl of C57/BL6 mouse abdomen two sides in experimental result, administration group mouse weight and negative control group
Mouse weight no significant difference (Fig. 2) illustrates that compound has no significant toxicity；And two sides knurl weight and negative control group have conspicuousness
Difference (Fig. 3), hence it is evident that reduce the weight of solid tumor, and there is dose dependent, show such compound to mouse pancreas cancer
There is significant inhibiting effect.
Claims (8)
1. a kind of pyridinone derivatives, which is characterized in that structural formula is：
R1Selected from group：Allyl, isopentene group, geranyl, to luorobenzyl；
R2Selected from group：Ethoxy, hydroxypropyl, amine ethyl, amine propyl；
R3Selected from group：
N=1,2,3,4；
R4、R5、R6And R7Selected from group：Phenyl, substituted-phenyl, heterocycle.
2. a kind of method for preparing pyridinone derivatives described in claim 1, which is characterized in that by polysubstituted bicyclic
[3.3.1] nonanone parent nucleus is reset to obtain target compound.
3. the method according to claim 2 for preparing pyridinone derivatives, which is characterized in that include the following steps：
1) synthesis of polysubstituted bicyclic [3.3.1] nonanone parent nucleus, with 1, hydroresorcinol (1) is raw material and isobutanol to toluene
The lower condensation dehydration of sulfonic acid catalysis, obtains vinylogy ester type compound 2；
2) compound 2 is in N2Protection and halohydrocarbons reaction, obtain compound 3；
3) compound 3 and N2Protection is lower to occur 1,2- addition reaction, and α, beta-unsaturated ketone compound 4 are obtained after acidified；
4) compound 4 and the lithium dimethylcuprate now made are in low temperature, N2Isosorbide-5-Nitrae-addition occurs for the lower reaction of protection, obtains three substitution hexamethylenes
The compound 5 of ketone structure；
5) compound 5 reacts to obtain silyl enol ether 6 with tert-butyl chloro-silicane；Since position of double bond is not on silyl enol ether
With and in the presence of a pair of of isomers, 6a/6b is to exist as a mixture；
6) compound 6 is reacted with malonyl chloride, and cyclization obtains parent nucleus substituted bicyclic [3.3.1] nonanone compound 7 before resetting；
7) compound 7 obtains targeted pyridine ketones derivant by rearrangement；
Specific reaction equation is as follows：
4. the method according to claim 3 for preparing pyridinone derivatives, which is characterized in that be based on bicyclic [3.3.1]
Nonanone parent nucleus is reset to obtain completely new pyridone parent nucleus, and reaction equation is as follows：
5. the method according to claim 3 for preparing pyridinone derivatives, which is characterized in that using pyridone as parent,
It is reacted by Williamson's synthetic method with a series of preparatory halides modified using the activity of four hydroxyls, obtains four hydroxyls
A series of derivatives of base etherificate, reaction equation are as follows：
6. the method according to claim 3 for preparing pyridinone derivatives, which is characterized in that using pyridone as parent,
It is reacted using the activity of four hydroxyls with a series of isocyanates, obtains a series of Esterification derivatives of four hydroxyl aminos；
Reaction equation is as follows：
7. pyridinone derivatives application in preparation of anti-tumor drugs described in claim 1.
8. application according to claim 7, which is characterized in that the tumour is cancer of pancreas.
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| [美]R.B.西尔弗曼主编: "《有机药物化学》", 31 January 2008, 化学工业出版社 * |
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