CN104788449B - 3-and-6-substituted 1,8-naphthyridine-4-one derivatives and preparation method and application thereof - Google Patents

3-and-6-substituted 1,8-naphthyridine-4-one derivatives and preparation method and application thereof Download PDF

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CN104788449B
CN104788449B CN201410030471.7A CN201410030471A CN104788449B CN 104788449 B CN104788449 B CN 104788449B CN 201410030471 A CN201410030471 A CN 201410030471A CN 104788449 B CN104788449 B CN 104788449B
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CN104788449A (en
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李锐
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Sichuan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention specifically relates to 3-and-6-substituted 1,8-naphthyridine-4-one derivatives and a preparation method and application thereof, belonging to the field of the chemical pharmaceutical industry. The structure of the 3-and-6-substituted 1,8-naphthyridine-4-one derivatives is shown in a formula I as described in the specification. The invention further provides the preparation method for the 3-and-6-substituted 1,8-naphthyridine-4-one derivatives and application of for the 3-and-6-substituted 1,8-naphthyridine-4-one derivatives in preparation of drugs used for treating tumors. The preparation method provided by the invention has the advantages of short synthesis route, simple reaction conditions, high yield and easy realization of derivation; and the series of derivatives provided by the invention have good antineoplastic activity and low cytotoxicity. A novel option is provided for preparation of antitumor drugs.

Description

1,8 naphthyridines -4- ketone derivatives of 3 and 6 replacements and its production and use
Technical field
The invention belongs to chemical medicine, and in particular to 1,8 naphthyridines -4- ketone derivatives of 3 and 6 replacements and its preparation Method and purposes.
Technical background
Main chemical compositions of the DNA as chromosome, store the crucial hereditary information of organism, and its integrity decides The stability of body genome.In people in life, intracellular DNA is inevitably being subjected to from external factor（Such as Ultraviolet, chemical toxicant, ionizing radiation etc.）And endogenous factor（Free radical for such as producing in vivo etc.）Impact and produce damage Wound.Eukaryotic cells are during evolution in order to tackle various external and inherent gene poison pressure, it is ensured that hereditary material energy Enough correct duplications are simultaneously accurately passed to the next generation, have developed a set of effective DNA damage acknowledgement mechanism（DNA Damage Response,DDR）To maintain stablizing for genome, including cell cycle arrest, DNA reparations and apoptosis etc..
Formed in complex network in DDR signal path, phosphatidylinositol-3-kinase sample kinase families（PIKK family） Louis-Bar syndrome mutain（ATM）Rad3 associated protein（ATR）As the summit for experiencing DNA damage One of albumen, plays vital adjustment effect to DDR paths.But in about 70% tumor cell, due to ATM or The ATM-p53 access functions that the gene mutation of TP53 is caused are damaged, and cause tumour cell cycle G1/ S checkpoints lack, and make DNA impaired tumor cell has higher duplication pressure.ATM-p53 paths are lacked and cause tumor cell to be more dependent on ATR- Chk1 paths conduct DNA corrupted informations, and then tumour cell cycle is blocked in G2/ M the phases carry out DNA reparations.Therefore materia medica Family think, Selective depression ATR-Chk1 paths can strengthen the impaired tumor cell of ATM-p53 access functions to DNA damage Medicine and the sensitivity of radiotherapy.SiRNA shows that to the inhibition test of the expression of Chk1 albumen the expression of suppression Chk1 is relieved Fluorouracil and the G of amycin mediation2/ M phase checkpoints are activated, and finally make tumor cell disintegrate and apoptosis.Vertex pharmacy is public Take charge of the equal table of vivo and vitro is used in chemotherapeutic drugs such as the ATR kinases micromolecular inhibitor VE-821 and its homologue and cisplatin for grinding Reveal obviously sensitization, and very little is increased to toxicity such as cisplatin in normal cell.AstraZeneca pharmacy is being ground In medicine AZ20 also confirm pivotal roles of the ATR in Tumour DNA injury repairing.
At present, the gamma therapy using chemicalses still as treating malignant tumor, the medicine used in which mostly are Coup injury DNA molecular affects the medicine of its normal replication, such as biological alkylating agent, platinum metals complex and topoisomerase Enzyme inhibitor etc..However, tumor cell is easy to produce drug resistance by repairing damaged dna to chemotherapeutics.ATR kinases is used as near Over year, one of newest target spot of anti-tumor chemotherapeutic enhanced sensitivity, becomes the study hotspot of research institution and pharmacy giant.ATR kinases exists Pivotal role in Tumour DNA repair signal path shows that the target spot can become raising tumor radiotherapy and chemotherapeutic treatment index Important target, with very strong Research Prospects and using value.
The content of the invention
The invention solves the problems that first technical problem be to provide it is a kind of 3 and 6 replacement 1,8 naphthyridines -4- ketone derivatives, Its structure is shown in formula I：
Wherein, R1ForSubstituted or unsubstituted heterocyclic base, C1～C8Alkyl, halogen ,-CN ,-NO2；The replacement Or unsubstituted heterocyclic base is that, containing 1～3 heteroatomic 5～10 yuan of rings, hetero atom is N, O or S；The replacement heterocyclic base Substituent group is substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The replacement of the substituted-phenyl Base is C1～C8Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；Described n=0～4；
R2For substituted or unsubstituted 5～10 yuan of aryl, substituted or unsubstituted heterocyclic base, C1～C8Alkyl, halogen ,- CN、-NO2；The substituent group of the substituted aryl is-CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C8Alkane Base；The substituted or unsubstituted heterocyclic base is that, containing 1～3 heteroatomic 5～10 yuan of rings, hetero atom is N, O or S；It is described The substituent group for replacing heterocyclic base is-CN ,-NO2、-CF3、-CHO、-NH2, halogen or C1～C8Alkyl；Described m=0～4.
As the preferred version of the present invention, in 1,8 naphthyridines -4- ketone derivatives of above-mentioned 3 and 6 replacements, R1For Described n=0～3；
R2For substituted or unsubstituted 5～10 yuan of aryl, substituted or unsubstituted heterocyclic base；The replacement of the substituted aryl Base is-CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；The substituted or unsubstituted heterocyclic base is Containing 1～3 heteroatomic 5～10 yuan of rings, hetero atom is N, O or S；The substituent group for replacing heterocyclic base is-CN ,-NO2、- CF3、-CHO、-NH2, halogen or C1～C4Alkyl；
R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted-phenyl Substituent group is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；Described m=0～3.
Preferably, R1ForDescribed n=0～3；
R2For substituted or unsubstituted phenyl, substituted or unsubstituted pyridine radicals；The substituent group of the substituted-phenyl is-CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；The substituent group of the substituted pyridinyl be-CN ,- NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；
R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted-phenyl Substituent group is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；Described m=0～3.
It is further preferred that R1ForDescribed n=0～3
R2For substituted or unsubstituted phenyl, substituted or unsubstituted pyridine radicals；The substituent group of the substituted-phenyl is-CN、-NO2、-CF3Or-CHO；The substituent group of the substituted pyridinyl is-CN ,-NO2、-CF3、-CHO、-NH2, halogen Element or C1～C4Alkyl；
R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted-phenyl Substituent group is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；Described m=0～3.
Still more preferably, R1ForDescribed n=0～3；
R2For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is-CN、- NO2、-CF3Or-CHO；
R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted-phenyl Substituent group is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；Described m=0～3.
Still more preferably, R1ForDescribed n=0～3；
R2For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl isOr-CN；
R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted-phenyl Substituent group is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；Described m=0～3.
Preferably, R1ForDescribed n=0～3；
R2For substituted or unsubstituted phenyl, substituted or unsubstituted pyridine radicals；The substituent group of the substituted-phenyl is-CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；The substituent group of the substituted pyridinyl be-CN ,- NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；
R3For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is C1～C4Alkyl, halogen ,- CN、-NO2、-CF3,-CHO or-NH2；Described m=0～3.
It is further preferred that R1ForDescribed n=0～3；
R2For substituted or unsubstituted phenyl, substituted or unsubstituted pyridine radicals；The substituent group of the substituted-phenyl is-CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；The substituent group of the substituted pyridinyl be-CN ,- NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；
R3For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is C1～C4Alkyl, halogen ,- CHO or-NH2；Described m=0～3.
Still more preferably, R1ForDescribed n=0～3；
R2For substituted or unsubstituted phenyl, substituted or unsubstituted pyridine radicals；The substituent group of the substituted-phenyl is-CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C8Alkyl；The substituent group of the substituted pyridinyl be-CN ,- NO2、-CF3、-CHO、-NH2, halogen or C1～C8Alkyl；
R3For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is C1～C4Alkyl or halogen； Described m=0～3.
Preferably, R1ForDescribed n=0～3；R2For substituted or unsubstituted phenyl or pyridine Base；The substituent group of the substituted-phenyl isOr-CN；R3For substituted or unsubstituted phenyl or pyridine radicals；The replacement The substituent group of phenyl is C1～C4Alkyl or halogen；Described m=0～3.
Optimum, R1ForDescribed n=1；R2For substituted or unsubstituted phenyl or pyridine radicals； The substituent group of the substituted-phenyl isOr-CN；R3For substituted or unsubstituted phenyl or pyridine radicals；The substituted benzene The substituent group of base is C1～C4Alkyl ,-F or-Cl；Described m=0.
As the preferred version of the present invention, work as R1ForWhen, 1,8 naphthyridines -4- ketone of above-mentioned 3 and 6 replacements derive The structure of thing is as shown in formula II：
Wherein, R2For substituted or unsubstituted 5～10 yuan of aryl, substituted or unsubstituted heterocyclic base；The substituted aryl Substituent group be-CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；The substituted or unsubstituted virtue Miscellaneous base is that, containing 1～3 heteroatomic 5～10 yuan of rings, hetero atom is N, O or S；It is described replace heterocyclic base substituent group for- CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；
R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted-phenyl Substituent group is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；
M=0～3.
Preferably, R2For substituted or unsubstituted phenyl, substituted or unsubstituted pyridine radicals；The replacement of the substituted-phenyl Base is-CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；The substituent group of the substituted pyridinyl for- CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；
R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted-phenyl Substituent group is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；
M=0～3.
It is further preferred that R2For substituted or unsubstituted phenyl, substituted or unsubstituted pyridine radicals；The substituted-phenyl Substituent group be-CN、-NO2、-CF3Or-CHO；The substituent group of the substituted pyridinyl is-CN ,-NO2、-CF3、- CHO、-NH2, halogen or C1～C4Alkyl；
R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted-phenyl Substituent group is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；
M=0～3.
Still more preferably, R2For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is-CN、-NO2、-CF3Or-CHO；
R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted-phenyl Substituent group is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；
M=0～3.
Still more preferably, R2For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl isOr-CN；
R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted-phenyl Substituent group is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；
M=0～3.
Preferably, R2For substituted or unsubstituted phenyl, substituted or unsubstituted pyridine radicals；The replacement of the substituted-phenyl Base is-CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；The substituent group of the substituted pyridinyl for- CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；
R3For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is C1～C4Alkyl, halogen ,- CN、-NO2、-CF3,-CHO or-NH2；
M=0～3.
It is further preferred that R2For substituted or unsubstituted phenyl, substituted or unsubstituted pyridine radicals；The substituted-phenyl Substituent group be-CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；The replacement of the substituted pyridinyl Base is-CN ,-NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；
R3For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is C1～C4Alkyl, halogen ,- CHO or-NH2；
M=0～3.
Still more preferably, R2For substituted or unsubstituted phenyl, substituted or unsubstituted pyridine radicals；The substituted benzene The substituent group of base is-CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C8Alkyl；The substituted pyridinyl takes Dai Jiwei-CN ,-NO2、-CF3、-CHO、-NH2, halogen or C1～C8Alkyl；
R3For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is C1～C4Alkyl or halogen；
M=0～3.
Preferably, R2For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is Or-CN；R3For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is C1～C4Alkyl or halogen；m= 0～3.
Optimum, R2For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is Or-CN；R3For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is C1～C4Alkyl ,-F or-Cl； m=0。
As the preferred version of the present invention, work as R2ForWhen, 1,8 naphthyridines -4- ketone of above-mentioned 3 and 6 replacements spread out Biological structure is as shown in formula III：
Wherein, R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted benzene The substituent group of base is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；
M=0～3.
Preferably, R3For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is C1～C4Alkane Base, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；M=0～3.
It is further preferred that R3For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is C1~ C4Alkyl, halogen ,-CHO or-NH2；M=0～3.
Still more preferably, R3For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is C1 ～C4Alkyl or halogen；M=0～3.
Optimum, R3For substituted or unsubstituted phenyl or pyridine radicals；The substituent group of the substituted-phenyl is C1～C4Alkane Base ,-F or-Cl；m=0.
The structural formula of 1,8 naphthyridines -4- ketone derivatives of above-mentioned 3 and 6 replacements is：
Present invention also offers the preparation method of 1,8 naphthyridines -4- ketone derivatives of 3 and 6 replacements described in above-mentioned 3 or 4.
Wherein, the preparation method of compound shown in formula II is comprised the following steps：
A, 2- amido -5- bromo- pyridine and diethyl ethoxymethylenemalonate are reacted into 2～3h at 120～140 DEG C, obtained To intermediate 1；The bromo- pyridine of the 2- amidos -5- is 1 1～1.2 with the mol ratio of diethyl ethoxymethylenemalonate；
B, intermediate 1 are shaken 30～40 minutes in the diphenyl ether of boiling, obtain intermediate 2 after cooling；
C, intermediate 2 obtain intermediate 7 in 30～40 minutes with hydrazine hydrate in 50～55 DEG C of reactions；The intermediate 2 and water The mol ratio for closing hydrazine is 1 3～5；
D, intermediate 7 with9～10h is reacted at 15～30 DEG C obtain intermediate 8；The intermediate 7 with's Mol ratio is 1 1.5～2；
E, by intermediate 8, thionyl chloride and pyridine 2～5h of back flow reaction, obtain intermediate 9；The intermediate 8, chlorination The mol ratio of sulfoxide and pyridine is 1 50～100 2～5；
F, intermediate 9 under the catalysis of bis-triphenylphosphipalladium palladium dichloride and natrium carbonicum calcinatum, with R3- borate is in N2Protection Under in 50～55 DEG C react 6～7 hours, obtain formula II compound；The intermediate 9 and R3The mol ratio of-borate is 1 1.1 ～1.2；
Wherein, R2For substituted or unsubstituted 5～10 yuan of aryl, substituted or unsubstituted heterocyclic base；The substituted aryl Substituent group be-CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；Described heterocyclic base is containing 1 ～3 heteroatomic 5～10 yuan of rings, hetero atom are N, O or S；The substituent group for replacing heterocyclic base is-CN ,-NO2、-CF3、- CHO、-NH2, halogen or C1～C4Alkyl；
R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted-phenyl Substituent group is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；
M=0～3.
The preparation method of compound shown in formula III is comprised the following steps：
G, by intermediate 2 and 4- mesyls phenylboric acid bis-triphenylphosphipalladium palladium dichloride and natrium carbonicum calcinatum catalysis Under, in N2Lower 60～65 DEG C of protection is reacted 8～9 hours, obtains compound 3；The intermediate 2 and 4- mesyl phenylboric acids Mol ratio is 1 1.1～1.2；
H, compound 3 are reacted 30～40 minutes at 50～55 DEG C with hydrazine hydrate, obtain intermediate 4；The compound 3 and water The mol ratio for closing hydrazine is 1 5～10；
I, intermediate 4 with9～10h is reacted at 15～30 DEG C, obtains intermediate 5；The intermediate 4 withMol ratio be 1 1.5～2；
J, by intermediate 5, thionyl chloride and pyridine 2～5h of back flow reaction, obtain formula III compound；The intermediate 5, chlorine The mol ratio for changing sulfoxide and pyridine is 1 50～100 2～5；
Wherein, R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted benzene The substituent group of base is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；M=0～3.
Above-claimed cpd of the present invention include they isotopic compound, racemic modification, optical active isomers, polycrystalline Type form or its mixture.
Present invention also offers the salt of 1,8 naphthyridines -4- ketone derivatives of above-mentioned 3 and 6 replacements.Wherein, described salt is 1,8 naphthyridines -4- ketone derivatives and the hydrochloric acid of above-mentioned 3 and 6 replacements of the present invention, hydrobromic acid, Fluohydric acid., sulphuric acid, phosphoric acid, nitric acid, Formic acid, acetic acid, propanoic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, hardship Sour in the mouth, methanesulfonic acid, ethyl sulfonic acid, isethionic acid, p-methyl benzenesulfonic acid, benzenesulfonic acid, LOMAR PWA EINECS 246-676-2, trifluoroacetic acid or aspartic acid are generated Pharmaceutically acceptable salt.The hydrochlorate or methanesulfonic acid of 1,8 naphthyridines -4- ketone derivatives of preferably above-mentioned 3 and 6 replacements Salt, most preferably hydrochlorate.
Present invention also offers 1,8 naphthyridines -4- ketone derivatives of 3 and 6 above-mentioned replacements are preparing tumor In purposes.
Present invention also offers the prodrug or hydrate of 1,8 naphthyridines -4- ketone derivatives of above-mentioned 3 and 6 replacements.Described Prodrug is the derivant of above-claimed cpd, and their own may have weaker activity or even without activity, but be administered Afterwards, in physiological conditions（For example by metabolism, solvolysiss or other mode）It is converted to corresponding biologically active form.
Present invention also offers a kind of pharmaceutical composition, is by 1,8 naphthyridines -4- ketone derivatives of 3 and 6 above-mentioned replacements Add what the pharmaceutically complementary composition of acceptable was prepared from.1,8 naphthyridines -4- ketone of 3 and 6 replacements that the present invention is provided Derivant, its structure is as shown in formula I～III.
The beneficial effects of the present invention is：The synthetic route that the present invention is provided is shorter, and reaction condition is simple, and yield is high, easily It is derivative.The compound of the present invention is mostly under ultraviolet light with compared with intense violet color fluorescence, it is easy to detect；Part of compounds has preferable Activity, with the value for further optimizing, can obtain it is active more preferably, the more preferable compound of water solublity.The compounds of this invention With preferable anti-tumor activity and relatively low cytotoxicity.
Specific embodiment
The preparation method of 1,8 naphthyridines -4- ketone derivatives of 3 and 6 replacements described in 3 or 4.
Wherein, the preparation method of compound shown in formula II is comprised the following steps：
A, 2- amido -5- bromo- pyridine and diethyl ethoxymethylenemalonate are reacted into 2～3h at 120～140 DEG C, obtained To intermediate 1；The bromo- pyridine of the 2- amidos -5- is 1 1～1.2 with the mol ratio of diethyl ethoxymethylenemalonate；
B, intermediate 1 are shaken 30～40 minutes in the diphenyl ether of boiling, obtain intermediate 2 after cooling；
C, intermediate 2 obtain intermediate 7 in 30～40 minutes with hydrazine hydrate in 50～55 DEG C of reactions；The intermediate 2 and water The mol ratio for closing hydrazine is 1 3～5；
D, intermediate 7 with9～10h is reacted at 15～30 DEG C obtain intermediate 8；The intermediate 7 with's Mol ratio is 1 1.5～2；
E, by intermediate 8, thionyl chloride and pyridine 2～5h of back flow reaction, obtain intermediate 9；The intermediate 8, chlorination The mol ratio of sulfoxide and pyridine is 1 50～100 2～5；
F, intermediate 9 under the catalysis of bis-triphenylphosphipalladium palladium dichloride and natrium carbonicum calcinatum, with R3- borate is in N2Protection Under in 50～55 DEG C react 6～7 hours, obtain formula II compound；The intermediate 9 and R3The mol ratio of-borate is 1 1.1 ～1.2.
Wherein, the step of above-mentioned preparation method in d, concrete operations are：First with benzoic acid in thionyl chloride dissolving, one is instilled Drop DMF（N,N-dimethylformamide）Flow back after making catalyst 3h, then removes thionyl chloride, is dissolved in THF（Tetrahydrofuran）；By in Mesosome 7 is dissolved in above-mentioned THF, then Deca DIEA（N, N- diisopropylethylamine）Stir, be stirred for down being slowly dropped into and contain HaveTHF solution, 5～10h of normal-temperature reaction；The intermediate 7 is 1 3～5 with the mol ratio of DIEA.
Wherein, the step of above-mentioned preparation method in f, reaction dissolvent is that volume ratio is the mixed of Isosorbide-5-Nitrae-dioxane water=5 1 Close solution.
Wherein, R2For substituted or unsubstituted 5～10 yuan of aryl, substituted or unsubstituted heterocyclic base；The substituted aryl Substituent group be-CN、-NO2、-CF3、-CHO、-NH2, halogen or C1～C4Alkyl；Described heterocyclic base is containing 1 ～3 heteroatomic 5～10 yuan of rings, hetero atom are N, O or S；The substituent group for replacing heterocyclic base is-CN ,-NO2、-CF3、- CHO、-NH2, halogen or C1～C4Alkyl；
R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted-phenyl Substituent group is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；
M=0～3.
The preparation method of compound shown in formula III is comprised the following steps：
G, by intermediate 2 and 4- mesyls phenylboric acid bis-triphenylphosphipalladium palladium dichloride and natrium carbonicum calcinatum catalysis Under, in N2Lower 60～65 DEG C of protection is reacted 8～9 hours, obtains compound 3；The intermediate 2 and 4- mesyl phenylboric acids Mol ratio is 1 1.1～1.2；
H, compound 3 are reacted 30～40 minutes at 50～55 DEG C with hydrazine hydrate, obtain intermediate 4；The compound 3 and water The mol ratio for closing hydrazine is 1 5～10；
I, intermediate 4 with9～10h is reacted at 15～30 DEG C, obtains intermediate 5；The intermediate 4 with Mol ratio be 1 1.5～2；
J, by intermediate 5, thionyl chloride and pyridine 2～5h of back flow reaction, obtain formula III compound；The intermediate 5, chlorine The mol ratio for changing sulfoxide and pyridine is 1 50～100 2～5；
Wherein, the step of above-mentioned preparation method in i, concrete operations are：First with benzoic acid in thionyl chloride dissolving, one is instilled Drop DMF（N,N-dimethylformamide）Flow back after making catalyst 3h, then removes thionyl chloride, is dissolved in THF（Tetrahydrofuran）；By in Mesosome 4 is dissolved in above-mentioned THF, then Deca DIEA（N, N- diisopropylethylamine）Stir, be stirred for down being slowly dropped into and contain HaveTHF solution, 5～10h of normal-temperature reaction；The intermediate 7 is 1 with the mol ratio of DIEA:3～5.
Wherein, R3For substituted or unsubstituted phenyl, containing 1～3 N atom 5～10 yuan of heterocyclic bases；The substituted benzene The substituent group of base is C1～C4Alkyl, halogen ,-CN ,-NO2、-CF3,-CHO or-NH2；M=0～3.
The preparation of 1 intermediate 1 of embodiment
Precise 2- amido -5- bromo- pyridine 1.73g (10mmol), diethyl ethoxymethylenemalonate 2.16g （10mmol）Stir under 130 degrees Celsius in the 250mL round-bottomed flasks, and keep open system to react about 2 hours.TLC is detected（With Volume ratio is PE（Petroleum ether）EA（Ethyl acetate）=81 mixed solvent is developing solvent）Reactant liquor is let cool after reaction completely, With dehydrated alcohol by recrystallization after solid dissolving, filter, intermediate 1 is obtained for yellow needles 2.6g, yield 75.8%.
1H NMR(400MHz,CDCl3)δ=11.12(d,J=12.5Hz,1H),9.07(d,J=12.7Hz,1H),8.39(d, J=2.2Hz, 1H), 7.75 (dd, J=8.6Hz, J=2.4Hz, 1H), 6.78 (d, J=8.6Hz, 1H), 4.50～4.12 (m, 4H), 1.36(dt,J=15.9Hz,J=7.1Hz,6H)。
The preparation of 2 intermediate 2 of embodiment
Precise 10g intermediate 1 (29.1mmol), adds the 250mL round-bottomed flasks of the diphenyl ether equipped with 30mL boilings Constantly shake 30～40 minutes under 250 degrees Celsius.Cooling reactant liquor, is poured in substantial amounts of cold petroleum ether while stirring, has big Amount white precipitate is separated out.After filtration, filter cake is washed till without diphenyl ether abnormal smells from the patient with a small amount of cold petroleum ether, obtains white after being dried solid Body 7.8g, yield 90.0%.
1H NMR(400MHz,CDCl3)δ=9.38(d,J=1.4Hz,1H),9.04(s,1H),7.97(dd,J=9.3Hz,J= 2.0Hz,1H),7.67(d,J=9.3Hz,1H),4.43(q,J=7.1Hz,2H),1.42(t,J=7.1Hz,3H)。
- 4 ketone -3- Ethyl formates of embodiment 36- (4- (mesyl) phenyl) -1,8- naphthyridines（Compound 3）Preparation
Precise 3.12g intermediate 2 (10.54mmol), 4- mesyl phenylboric acid 2.53g（12.65mmol）, double three Phenylphosphine palladium chloride 220mg（0.316mmol）With natrium carbonicum calcinatum 3.32g（31.62mmol）In 50mL flasks, volume is used 20mL dissolvings more common than mixed solution for Isosorbide-5-Nitrae-dioxane water=5 1, then deaeration in condenser, N2Protect anti-under lower 60 degrees Celsius Should about 8 hours.TLC is detected（It is DCM that developing solvent is volume ratio（Dichloromethane）The mixed solvent of EA=5 1）Will after reaction completely Reactant liquor is poured into water, and is extracted three times with DCM, merges organic faciess with a small amount of washing three times, adds anhydrous after saturated common salt washing Sodium sulfate is dried, and organic faciess vacuum distillation obtains 3.7g with volume ratio DCM EA=4 3 as eluent system column chromatography purification white Solid, yield 94.1%.233.5～234.5 DEG C of fusing point.
1H NMR(400MHz,CDCl3)δ=9.52(s,1H),9.08(s,1H),8.21(d,J=9.0Hz,1H),8.13(d, J=8.2Hz,2H),7.92(d,J=9.1Hz,1H),7.88(d,J=8.3Hz,2H),4.44(q,J=7.1Hz,2H),3.13(s, 3H),1.44(t,J=7.1Hz,3H)。
TOF-MS(ES+)C18H16N2O5S, theoretical molecular are 372.0780;Detection molecules amount is 395.0766 [M+Na]+。
The preparation of 4 intermediate 4 of embodiment
Precise 1g compounds 3 (2.68mmol) after being dissolved with 15mL methanol, are stirred at 50 degrees Celsius in 50mL flasks Mix down and be slowly added dropwise hydrazine hydrate（80%wt）20 drop left and right, half an hour or so drip off.The white suspension shape of solution, Deca during beginning After complete hydrazine hydrate, color is changed into red, 3 as a child TLC detections（It is DCM MEOH that developing solvent is volume ratio（Methanol）=20 1 it is mixed Bonding solvent）Reaction is complete.Solid is leached, is washed repeatedly to solid as yellow-white with a small amount of methanol, about 600mg.Yield 62.3%。
1H NMR(400MHz,DMSO)δ=9.77(s,1H),9.42(s,1H),9.05(s,1H),8.61(dd,J= 9.1Hz,J=1.7Hz,1H),8.14(q,J=8.4Hz,4H),8.03(d,J=9.1Hz,1H),4.71(s,2H),3.31(s, 3H)。
The preparation of 5 intermediate 5a-5h of embodiment
（1）The preparation of intermediate 5a
Precise benzoic acid 77mg（0.628mmol）In 10mL reaction tubes, dissolved with 4mL thionyl chlorides, instilled After one drop DMF makees catalyst, flow back 3h.Remaining thionyl chloride is drained after falling thionyl chloride by vacuum distillation with membrane pump or oil pump Molten 3mL THF are standby.Precise 150mg intermediate 4（0.419mmol）It is dissolved in the THF of 3mL, instills 162mgDIEA （1.257mmol）Stir.The THF solution containing acyl chlorides is slowly dropped under stirring.Stirring at normal temperature is overnight.TLC is detected（Launch Agent is the mixed solvent that volume ratio is DCM MeOH=15 1）After completion of the reaction solid insoluble in reactant liquor is leached, with a small amount of Pale solid 170mg is dried to obtain after THF washings, directly throw next step, yield 87.8% without being further purified.
（2）The preparation of intermediate 5b
Raw material is 150mg intermediate 4 and 100mg nicotinic acid, operates same 5a, yield 85.6%.
（3）The preparation of intermediate 5c
Raw material is 150mg intermediate 4 and 100mg .gamma.-pyridinecarboxylic acid, operates same 5a, yield 81.0%.
（4）The preparation of intermediate 5d
Raw material is 150mg intermediate 4 and 100mg2- picolinic acids, operates same 5a, yield 78.3%.
（5）The preparation of intermediate 5e
Raw material is 150mg intermediate 4 and 110mg m-methyl benzoic acids, operates same 5a, yield 82.6%.
（6）The preparation of intermediate 5f
Raw material is 150mg intermediate 4 and 130mg parachlorobenzoic-acids, operates same 5a, yield 80.1%.
（7）The preparation of intermediate 5g
Raw material is 150mg intermediate 4 and 110mg parafluorobenzoic acids, operates same 5a, yield 76.9%.
（8）The preparation of intermediate 5h
Raw material is 150mg intermediate 4 and 110mg p-methylbenzoic acids, operates same 5a, yield 86.4%.
The preparation of 6 intermediate 7 of embodiment
Weigh 1.5g intermediate 2 (5.08mmol), 330mg hydrazine hydrates（80%wt）The preparation with intermediate 4 is operated, is obtained Light red solid 340mg, yield 23.6%.
1H NMR(400MHz,DMSO)δ=9.73(s,1H),9.23(d,J=1.8Hz,1H),9.02(s,1H),8.32 (dd,J=9.3Hz,J=2.1Hz,1H),7.84(d,J=9.3Hz,1H),4.79(s,2H)。
The preparation of embodiment 7 intermediate 8a and 8b
（1）The preparation of intermediate 8a
Raw material is 150mg intermediate 7 and 165mg parachlorobenzoic-acids, operates same 5a, obtains brown viscous solid 370mg, slightly Product yield about 76%.Not purified direct throwing next step.
（2）The preparation of intermediate 8b
Raw material is 150mg intermediate 7 and 140mg parafluorobenzoic acids, operates same 5a, obtains brown viscous solid about 600mg, Crude yield about 90%.Not purified direct throwing next step.
The preparation of embodiment 8 intermediate 9a and 9b
（1）The preparation of intermediate 9a
Weigh 370mg intermediate 8a（0.94mmol）In 25mL flasks, 5mL thionyl chlorides are added, the lower Deca of stirring is about 160mg pyridines（About 2mmol）, back flow reaction.Taken a little in EP pipes, after drying up solvent with coarse wool tubule after 3 hours, instilled full PH value is adjusted with sodium bicarbonate solution, adds 3 to drip DCM extractions, taken organic layer point plate and do TLC detections（Developing solvent is that volume ratio is The mixed solvent of DCM MeOH=50 1）It was found that there is very bright phosphor dot.After having reacted, vacuum distillation is spin-dried for thionyl chloride first, Pour into, water layer no sapphirine under 365nm ultra-vioket radiation is extracted to DCM glimmering Light.Merge organic layer, after saturated common salt water washing with after anhydrous sodium sulfate drying by organic faciess vacuum distillation, with DCM/MeOH （Developing solvent is the mixed solvent that volume ratio is DCM MeOH=80 1）250mg glassy yellows are obtained for eluent system column chromatography purification Solid, yield 65.9%.
1H NMR(400MHz,DMSO)δ=9.27(d,J=2.2Hz,1H),9.14(s,1H),8.35(dd,J=9.3Hz,J= 2.2Hz,1H),8.13(d,J=8.6Hz,2H),7.88(d,J=9.3Hz,1H),7.73(d,J=8.6Hz,2H)。
（2）The preparation of intermediate 9b
Weigh 500mg intermediate 8b（1.77mmol）, 20g thionyl chlorides, 650mg pyridines are in 25mL flasks.Operation is same The preparation of intermediate 9a, obtains yellow solid 280mg, yield 40.8%.
1H NMR(400MHz,DMSO)δ=9.26(d,J=1.8Hz,1H),9.12(s,1H),8.34(dd,J=9.3Hz,J= 2.2Hz,1H),8.17(dd,J=8.8Hz,J=5.4Hz,2H),7.87(d,J=9.3Hz,1H),7.50(t,J=8.9Hz,2H)。
Embodiment 96- (4- (mesyl) phenyl) -3-（5- phenyl -1,3,4- dioxazoles）- 4 ketone of -1,8- naphthyridines（Chemical combination Thing 6a）Preparation
Weigh 150mg intermediate 5a（0.32mmol）, in 10mL reaction tubes.5mL thionyl chlorides are added, stirring is lower to drip Plus about 50mg pyridines（About 0.64mmol）, back flow reaction.TLC detections after 3 hours（It is DCM MeOH=40 that developing solvent is volume ratio 1 mixed solvent）.React rear vacuum distillation and removed thionyl chloride, pour adjustment pH value in saturated sodium bicarbonate solution into left to 7 The right side, is extracted to water layer no bright blue fluorescence under 365nm ultra-vioket radiation with DCM.Merge organic layer, after saturated common salt water washing With after anhydrous sodium sulfate drying by organic faciess vacuum distillation, be eluting body with volume ratio as the mixed solvent of DCM MeOH=50 1 Bitt chromatography purification obtains 75mg yellow solids, yield 52.8%.301.1-302.0 DEG C of fusing point.
1H NMR(400MHz,DMSO)δ=9.49(s,1H),9.16(s,1H),8.65(d,J=9.0Hz,1H),8.19(d, J=8.1Hz,2H),8.13(d,J=7.6Hz,4H),8.07(d,J=9.1Hz,1H),7.67(s,3H),3.32(s,3H)。
TOF-MS(ES+)C23H16N4O4S, theoretical molecular are 444.0892;Detection molecules amount is 445.0891 [M+H]+。
Embodiment 106- (4- (mesyl) phenyl) -3-（5-（3- pyridine radicals）- 1,3,4- dioxazoles）- 1,8- naphthyridines -4 Ketone（Compound 6b）Preparation
Weigh 150mg intermediate 5b（0.32mmol）, in 10mL reaction tubes.5mL thionyl chlorides are added, stirring is lower to drip Plus about 50mg pyridines（About 0.64mmol）, back flow reaction.The preparation of remaining operation reference compound 6a.Obtain 70mg yellow solid Body, yield 49.1%.297.7-299.2 DEG C of fusing point.
1H NMR(400MHz,DMSO)δ=9.49(s,1H),9.30(s,1H),9.19(s,1H),8.84(s,1H),8.65 (d,J=8.5Hz,1H),8.49(d,J=6.8Hz,1H),8.16(d,J=14.9Hz,4H),8.07(d,J=8.1Hz,1H),7.70 (s,1H).3.32(s,3H)。
TOF-MS(ES+)C23H15N5O4S, theoretical molecular are 445.0845；Detection molecules amount is 468.0801 [M+Na]+。
Embodiment 116- (4- (mesyl) phenyl) -3-（5-（4- pyridine radicals）- 1,3,4- dioxazoles）- 1,8- naphthyridines -4 Ketone（Compound 6c）Preparation
Weigh 150mg intermediate 5c（0.32mmol）, in 10mL reaction tubes.5mL thionyl chlorides are added, stirring is lower to drip Plus about 50mg pyridines（About 0.64mmol）, back flow reaction.The preparation of remaining operation reference compound 6a.Obtain 86mg yellow solid Body, yield 60.3%.320.9-321.6 DEG C of fusing point.
1H NMR(400MHz,DMSO)δ=9.51(s,1H),9.20(s,1H),8.89(d,J=5.3Hz,2H),8.67(d, J=9.5Hz,1H),8.19(d,J=8.4Hz,2H),8.14(d,J=8.3Hz,2H),8.09(d,J=9.1Hz,1H),8.05(d,J =5.4Hz,2H),3.32(s,3H)。
TOF-MS(ES+)C23H15N5O4S, theoretical molecular are 445.0845；Detection molecules amount is 68.0789 [M+Na]+。
Embodiment 126- (4- (mesyl) phenyl) -3-（2-（3- pyridine radicals）- 1,3,4- dioxazoles）- 1,8- naphthyridines -4 Ketone（Compound 6d）Preparation
Weigh 150mg intermediate 5e（0.32mmol）, in 10mL reaction tubes.5mL thionyl chlorides are added, stirring is lower to drip Plus about 50mg pyridines（About 0.64mmol）, back flow reaction.The preparation of remaining operation reference compound 6a.Obtain 60mg yellow solid Body, yield 42.1%.291.2-292.3 DEG C of fusing point.
1H NMR(400MHz,DMSO)δ=9.48(d,J=2.0Hz,1H),9.11(s,1H),8.83(d,J=4.8Hz, 1H),8.67(d,J=2.1Hz,1H),8.64(d,J=2.2Hz,1H),8.27(d,J=7.8Hz,1H),8.18(d,J=8.5Hz, 4H),8.09(dd,J=9.5Hz,J=5.3Hz,2H),7.67(dd,J=7.5Hz,J=5.0Hz,1H).3.32(s,3H)。
TOF-MS(ES+)C23H15N5O4S, theoretical molecular are 445.0845；Detection molecules amount is 468.0790 [M+Na]+。
Embodiment 136- (4- (mesyl) phenyl) -3-（5-（3- aminomethyl phenyls）- 1,3,4- dioxazoles）- 1,8- naphthalenes - 4 ketone of pyridine（Compound 6e）Preparation
Weigh 110mg intermediate 5e（0.23mmol）, in 10mL reaction tubes.5mL thionyl chlorides are added, stirring is lower to drip Plus about 36mg pyridines（About 0.46mmol）, back flow reaction.The preparation of remaining operation reference compound 6a.Obtain 50mg yellow solid Body, yield 46.8%.311.2-312.9 DEG C of fusing point.
1H NMR(400MHz,DMSO)δ=9.49(d,J=1.9Hz,1H),9.15(s,1H),8.64(dd,J=9.1Hz,J= 2.1Hz,1H),8.19(d,J=8.5Hz,2H),8.13(d,J=8.4Hz,2H),8.06(d,J=9.1Hz,1H),7.94(s, 1H),7.92(d,J=7.8Hz,1H),7.54(t,J=7.6Hz,1H),7.48(d,J=7.5Hz,1H),3.32(s,3H),2.45 (s,3H)。
TOF-MS(ES+)C24H18N4O4S, theoretical molecular are 458.1049；Detection molecules amount is 459.1048 [M+H]+。
Embodiment 146- (4- (mesyl) phenyl) -3-（5-（4- chlorphenyls）- 1,3,4- dioxazoles）- 1,8- naphthyridines -4 Ketone（Compound 6f）Preparation
Weigh 230mg intermediate 5f（0.46mmol）, in 10mL reaction tubes.5mL thionyl chlorides are added, stirring is lower to drip Plus about 72mg pyridines（About 0.92mmol）, back flow reaction.The preparation of remaining operation reference compound 6a.Obtain 120mg yellow solid Body, yield 54.5%.320.0-320.9 DEG C of fusing point.
1H NMR(400MHz,DMSO)δ=9.49(s,1H),9.16(s,1H),8.65(dd,J=9.1Hz,J=1.9Hz, 1H),8.18(d,J=8.3Hz,2H),8.13(d,J=7.6Hz,4H),8.07(d,J=9.1Hz,1H),7.74(d,J=8.5Hz, 2H),3.31(s,3H)。
TOF-MS(ES+)C23H15ClN4O4S, theoretical molecular are 478.0503；Detection molecules amount is 501.0789 [M+ Na]+。
Embodiment 156- (4- (mesyl) phenyl) -3-（5-（4- fluorophenyls）- 1,3,4- dioxazoles）- 1,8- naphthyridines -4 Ketone（Compound 6g）Preparation
Weigh 208mg intermediate 5g（0.43mmol）, in 10mL reaction tubes.5mL thionyl chlorides are added, stirring is lower to drip Plus about 68mg pyridines（About 0.86mmol）, back flow reaction.The preparation of remaining operation reference compound 6a.Obtain 100mg yellow solid Body, yield 50.3%.307.3-308.2 DEG C of fusing point.
1H NMR(400MHz,DMSO)δ=9.49(d,J=2.0Hz,1H),9.16(s,1H),8.65(dd,J=9.1Hz,J= 2.2Hz,1H),8.21–8.19(m,1H),8.18(d,J=2.2Hz,2H),8.13(d,J=8.5Hz,2H),8.07(d,J= 9.1Hz,1H),7.51(t,J=8.9Hz,2H),3.32(s,3H)。
TOF-MS(ES+)C23H15FN4O4S, theoretical molecular are 462.0798；Detection molecules amount is 485.0783 [M+Na ]+。
Embodiment 166- (4- (mesyl) phenyl) -3-（5-（4- aminomethyl phenyls）- 1,3,4- dioxazoles）- 1,8- naphthalenes - 4 ketone of pyridine（Compound 6h）Preparation
Weigh 213mg intermediate 5h（0.48mmol）, in 10mL reaction tubes.5mL thionyl chlorides are added, stirring is lower to drip Plus about 76mg pyridines（About 0.96mmol）, back flow reaction.The preparation of remaining operation reference compound 6a.Obtain 130mg yellow solid Body, yield 59.1%.300.0-301.2 DEG C of fusing point.
1H NMR(400MHz,DMSO)δ=9.48(d,J=1.7Hz,1H),9.13(s,1H),8.64(dd,J=9.1Hz,J= 2.0Hz,1H),8.18(d,J=8.4Hz,2H),8.13(d,J=8.4Hz,2H),8.05(d,J=9.1Hz,1H),8.00(d,J= 8.0Hz,2H),7.45(d,J=8.0Hz,2H),3.32(s,3H),2.42(s,3H)。
TOF-MS(ES+)C24H18N4O4S, theoretical molecular are 458.1049；Detection molecules amount is 481.0988 [M+Na]+。
Embodiment 173-（5-（4- chlorphenyls）- 1,3,4- dioxazole bases）- 6- (3- pyridine radicals) -4 ketone of -1,8- naphthyridines（Change Compound 10a）Preparation
Precise 30mg intermediate 9a (0.074mmol), pyridine -3- boric acid 10mg（0.089mmol）, bi triphenyl phosphine Palladium chloride 3mg（0.004mmol）With natrium carbonicum calcinatum 23mg（0.223mmol）In 10mL reaction tubes, with Isosorbide-5-Nitrae-dioxy The common 5mL of mixed solvent of clustered water=5 1 dissolves, then deaeration in condenser, N2Protect and under lower 50 degrees Celsius, react about 6 hours.TLC Detection（The volume ratio of developing solvent is DCM MeOH=40 1）Reactant liquor is poured into water after reaction completely, is extracted three times with DCM, Merge organic faciess with a small amount of washing three times, after saturated common salt washing, add anhydrous sodium sulfate drying, organic faciess vacuum distillation, with body Product obtains 24mg yellow powders, yield 80.4% than the mixed solvent for DCM MeOH=40 1 for eluent system column chromatography purification. 305.5～306.5 DEG C of fusing point.
1H NMR(400MHz,DMSO)δ=9.47(s,1H),9.16(s,1H),9.10(s,1H),8.73(d,J=4.8Hz, 1H),8.65(d,J=8.9Hz,1H),8.33(d,J=8.0Hz,1H),8.13(d,J=8.5Hz,2H),8.06(d,J=9.4Hz, 1H), 7.74 (d, J=8.5Hz, 2H), 7.67～7.56 (m, 2H).
TOF-MS(ES+)C21H12ClN5O2, theoretical molecular is 401.0680；Detection molecules amount is 424.0650 [M+Na ]+。
Embodiment 183-（5-（4- chlorphenyls）- 1,3,4- dioxazole bases）- 6- (4- cyano-phenyls) -4 ketone of -1,8- naphthyridines （Compound 10b）Preparation
Precise 50mg intermediate 9a (0.124mmol), 4- cyanophenylboronic acid ester 33mg（0.148mmol）, double triphens Base phosphine dichloride palladium 3mg（0.004mmol）With natrium carbonicum calcinatum 23mg（0.223mmol）. in 10mL reaction tubes.Operation is same The preparation of compound 10a, obtains 36mg yellow powders, yield 68.3%.292.5～293.5 DEG C of fusing point.
1H NMR (400MHz, DMSO) δ=9.48 (s, 1H), 9.16 (s, 1H), 8.64 (d, J=8.9Hz, 1H), 8.16～ 8.10 (m, 2H), 8.08 (s, 1H), 8.07～8.04 (m, 1H), 7.74 (d, J=8.4Hz, 2H).
TOF-MS(ES+)C23H12ClN5O2, theoretical molecular is 425.0680；Detection molecules amount is 448.1680 [M+Na ]+。
Embodiment 193-（5-（4- chlorphenyls）- 1,3,4- dioxazole bases）- 4 ketone of -6- phenyl -1,8- naphthyridines（Compound 10c）Preparation
Precise 50mg intermediate 9a (0.124mmol), borate ester 18mg（0.148mmol）, bi triphenyl phosphine two Palladous chloride. 3mg（0.004mmol）With natrium carbonicum calcinatum 23mg（0.223mmol）.The preparation with compound 10a is operated, is obtained 40mg yellow powders, yield 80.6%.238.9～239.2 DEG C of fusing point.
1H NMR(400MHz,DMSO)δ=9.39(d,J=1.9Hz,1H),9.13(s,1H),8.60(dd,J=9.1Hz,J= 2.1Hz,1H),8.12(d,J=8.5Hz,2H),8.02(d,J=9.1Hz,1H),7.88(t,J=8.0Hz,2H),7.73(d,J= 8.5Hz,2H),7.61(t,J=7.4Hz,2H),7.53(t,J=7.3Hz,1H)。
TOF-MS(ES+)C22H13ClN4O2, theoretical molecular is 400.0727；Detection molecules amount is 401.0726 [M+H]+。
Embodiment 203-（5-（4- fluorophenyls）- 1,3,4- dioxazole bases）- 6- (3- pyridine radicals) -4 ketone of -1,8- naphthyridines（Change Compound 10d）Preparation
Precise 50mg intermediate 9b (0.13mmol), pyridine -3- boric acid 19mg（0.155mmol）, bi triphenyl phosphine Palladium chloride 5mg（0.006mmol）With natrium carbonicum calcinatum 70mg（0.39mmol）.The preparation with compound 10a is operated, is obtained 41mg yellow powders, yield 81.9%.306.2～307.1 DEG C of fusing point.
1H NMR(400MHz,DMSO)δ=9.47(s,1H),9.15(s,1H),9.10(s,1H),8.73(s,1H),8.65 (d,J=8.9Hz,1H),8.33(d,J=7.3Hz,1H),8.19(s,1H),8.06(d,J=9.1Hz,1H),7.62(s,1H), 7.51(t,J=8.6Hz,2H)。
TOF-MS(ES+)C21H12FN5O2, theoretical molecular is 385.0975；Detection molecules amount is 386.0974 [M+H]+。
Embodiment 213-（5-（4- fluorophenyls）- 1,3,4- dioxazole bases）- 6- (4- pyridine radicals) -4 ketone of -1,8- naphthyridines（Change Compound 10e）Preparation
Precise 50mg intermediate 9b (0.13mmol), pyridine -4- boric acid 19mg（0.155mmol）, bi triphenyl phosphine Palladium chloride 5mg（0.006mmol）With natrium carbonicum calcinatum 70mg（0.39mmol）.The preparation with compound 10a is operated, is obtained 38mg yellow powders, yield 75.9%.260.1～262.1 DEG C of fusing point.
1H NMR(400MHz,DMSO)δ=9.53(d,J=1.8Hz,1H),9.15(s,1H),8.78(d,J=5.1Hz, 2H),8.65(dd,J=9.1Hz,2.0,1H),8.18(dd,J=8.7Hz,J=5.4Hz,2H),8.06(d,J=9.1Hz,1H), 7.94(d,J=5.8Hz,2H),7.50(t,J=8.8Hz,2H)。
TOF-MS(ES+)C21H12FN5O2, theoretical molecular is 385.0975；Detection molecules amount is 386.0974 [M+H]+。
Embodiment 223-（5-（4- fluorophenyls）- 1,3,4- dioxazole bases）- 6- (4- cyano-phenyls) -4 ketone of -1,8- naphthyridines （Compound 10f）Preparation
Precise 50mg intermediate 9b (0.131mmol), 4- cyanophenylboronic acid ester 24mg（0.155mmol）, double triphens Base phosphine dichloride palladium 5mg（0.006mmol）With natrium carbonicum calcinatum 70mg（0.39mmol）.The preparation with compound 10a is operated, is obtained To 46mg yellow powders, yield 85.9%.339.0～340.5 DEG C of fusing point.
1H NMR(400MHz,DMSO)δ=9.48(s,1H),9.16(s,1H),9.03(s,1H),8.63(d,J=8.9Hz, 1H), 8.22～8.15 (m, 2H), 8.12 (d, J=8.4Hz, 2H), 8.08 (s, 1H), 8.05 (d, J=8.9Hz, 1H).
TOF-MS(ES+)C21H12FN5O2, theoretical molecular is 409.0975；Detection molecules amount is 432.0959 [M+Na]+。
23 positive drug 2- amidos -5 of embodiment（4-（Mesyl）Phenyl）The preparation of-N- phenyl nicotiamide
Due to document report selectivity ATR inhibitor VE-821（3- amido -6-（4-（Mesyl）Phenyl）- N- phenyl Pyrazine -2- amide）It is expensive, and synthesis needed raw material price is also very high, therefore in this experiment using in patent documentation report In road therewith activity quite, but synthesize the cheap more 2- amidos -5 of needed raw material（4-（Mesyl）Phenyl）- N- phenyl cigarettes Amide as positive control medicine, numbering ATR-1 in this experiment.
VE-821 only differs 1 nitrogen-atoms in structure with ATR-1, in experiment is docked with ATR kinases, the two chemical combination Thing binding pattern almost no difference.In document report, VE-821 is 0.026 μM to ATR inhibitory activity, in patent documentation In, ATR-1 is to the inhibitory activity of ATR kinases in 10-100nm is interval, it may have similar higher inhibitory activity.
Synthesis ATR-1 needs two steps, and the first step is prepared by condensation reaction middle with 2- amido -5- bromo-nicotinic acids as raw material The bromo- N- phenyl nicotiamide of body 2- amido -5-（Intermediate 11）, then target product is obtained with the coupling of 4- mesyls phenylboric acid.Close It is as follows into route：
（1）The preparation of intermediate 11
Precise 2- amido -5- bromo-nicotinic acid 434mg（2mmol）And EDCI576mg（3mmol）In 25mL round-bottomed flasks In, the DMF of 10mL is added, stirring is lower to instill the aniline 186mg being scattered in the DMF of 5mL（2mmol）, control drop speed make its 10 minutes or so completion of dropping.Continue to be stirred overnight under room temperature, reactant liquor is poured in water after TLC detection reactions completely, with second Acetoacetic ester is extracted three times, is merged organic faciess with a small amount of washing three times, is added anhydrous sodium sulfate drying after saturated common salt washing.It is organic Phase vacuum distillation, obtains 300mg white solids, yield 51.5% by eluent system column chromatography purification of ethyl acetate/petroleum ether.
1H NMR(400MHz,DMSO)δ=10.25(s,1H),8.24(d,J=2.4Hz,1H),8.21(d,J=2.4Hz, 1H),7.69(d,J=7.6Hz,2H),7.36(dd,J=10.8Hz,J=5.1Hz,2H),7.16(s,1H),7.12(t,J= 7.4Hz,1H)。
（2）The preparation of ATR-1
The bromo- N- phenyl nicotiamide of precise 2- amido -5-（Intermediate 11）60mg (0.2mmol), 4- mesyl benzene Boric acid 48mg（0.24mmol）, bis-triphenylphosphipalladium palladium dichloride 7mg（About 0.01mmol）With natrium carbonicum calcinatum 63mg（0.6mmol） In 10mL reaction tubes, with Isosorbide-5-Nitrae-dioxane/water=5:Deaeration in condenser after 1 common 6mL dissolvings, N2Protect under lower 60 degrees Celsius Reaction about 8 hours.Reactant liquor is poured into water after TLC detection reactions completely, is extracted three times with DCM, merge organic faciess with a small amount of Washing three times, adds anhydrous sodium sulfate drying after saturated common salt washing, and organic faciess vacuum distillation, with DCM/EA as eluent system post Chromatography purification obtains 60mg white solids, yield 81.7%, 296.1～297.8 DEG C of fusing point.
1H NMR(400MHz,DMSO)δ=10.33(s,1H),8.61(d,J=2.0Hz,1H),8.43(d,J=2.0Hz, 1H),8.00(q,J=8.5Hz,4H),7.70(d,J=7.8Hz,2H),7.38(t,J=7.8Hz,2H),7.29(s,2H),7.13 (t,J=7.4Hz,1H),3.25(s,3H)。
TOF-MS(ES+)C19H17N3O3S, theoretical molecular are 367.0991；Detection molecules amount is 368.0991 [M+H]+。
Pharmacodynamic experiment part
1st, inhibitory activity of the mtt assay detection compound combination with cisplatin to HCT116 cells
1.1 experiment materials and method
DMEM（H）, hyclone, pancreatin etc. be purchased from Gibco BRL companies (Invitrogen Corporation, USA), Thiazole bromide blue tetrazolium (MTT), dimethyl sulfoxide (DMSO) are purchased from sigma companies.CO2Incubator (Thermo companies, the U.S.), Put phase contrast microscope CK31 (Olympus companies), the full-automatic microplate reader of BioTek ELx800 (BioTek companies, the U.S.).
Tested tumor cell：Human colon cancer cell strain HCT116 and human liver cell strain LO2 are purchased from U.S. ATCC（American Type Culture Collection）Company, is preserved by this laboratory.
Test medicine：Positive control medicine ATR-1, compound 6a-6h, 10a-10e are voluntarily synthesized by laboratory, external real 20mg/mL storing liquids are configured to DMSO when testing, 4 DEG C of refrigerators are placed in and are kept in dark place standby, facing the used time is diluted with complete culture solution To desired concn.Cisplatin is purchased from sigma companies.
Take the logarithm HCT116 the and LO2 cells of phase, use complete medium DMEM（H）It is 1 by cell suspension concentration dilution ～2 × 104/ mL, is inoculated in 96 orifice plates with the density in 4000～6000/ holes, adds 100 μ L per hole, is continued in 37 DEG C, 5%CO2's Under the conditions of cultivate 24h after, with the compound of variable concentrations, (final concentration is respectively 20 μM, 10 μM, 5 μM, 2.5 μM, 1.25 μ respectively M it is) alone, or with the same cisplatin of 20 μM of concentration（5μM、2.5μM、1.25μM、0.625μM、0.312μM）Combination processes cell, while If solvent control group, positive group, medicine concentration is 0.1%DMSO dissolvings (0.1% DMSO cell proliferations are without impact).Each Concentration sets 3 multiple holes, after culture 48h, the addition 20 μ L solution of MTT containing 5mg/mL per hole, and 37 DEG C, 5%CO2Incubation 2-3h.Abandon Clearly, add 150 μ L DMSO per hole, put shaking table and shake 15min, the OD values surveyed at 570nm in microplate reader.Relative cell proliferation presses down Rate (%) processed=(solvent control group A570- experimental group A570)/solvent control group A570×100%.Each compound on intracellular is bred above Inhibitory action, is represented using cell proliferation inhibition rate (%), using IC50Software for calculation obtains half-inhibition concentration (IC50, it is single Position is μm ol/L).
1.2 experimental result
By inhibitory activity or joint of mtt assay when alone to compound 3,6a-6h, 10a-10f to HCT116 cells Killing activity of the cisplatin to HCT116 cells, with LC50Represent.The results are shown in Table 1.The LC of cisplatin is calculated during drug combination50Value, it is single With calculating compound IC during medicine50Value."-" in table 1 represents activity of the activity after combination less than cisplatin independent medication； "～" expression is approximately equal to；The IC50 values and the IC50 values of drug combination of " multiple (cisplatin/combination) " expression cisplatin independent medication Ratio.
The biological activity of table 1 compound 6a-6h, 10a-10f in HCT116 cells
Compound 6a, 6f, 6h inhibitory activity when alone is more general, respectively 19.5 μM, 24.0 μM, 25.7 μM, Less than ATR-1.But find that the activity of cisplatin can be increased to 0.38 μM, 0.47 μM, 0.25 μM by respectively during combination, increase Quick multiple is for about 7 times, 5.5 times and about 10 times respectively.Wherein compound 6h sensitizing activities have exceeded positive control medicine ATR-1. In structure, series compound 3,6a-6h has to methanesulfonylphenYl replacement in the 6- positions of parent nucleus, and wherein 3- positions replace Compound 3 for ester group is not significantly increased to the toxicity of HCT16 cells in combination, also no inhibitory activity when alone.And 3- positions show certain sensitizing activity when replacing with 1,3,4- diazole this 5-membered aromatic heterocycle.1,3,4- diazole rings The different replacements in upper 5- positions are also more obvious to activity influence, when wherein being replaced with phenyl ring（6a）It is active preferable, and taken with pyridine ring Dai Hou（6b-6d）Although alone activity has certain rising, combination sensitizing activity declines more substantially, does not almost show Sensitizing activity.
2nd, toxotest of the compound combination with cisplatin to normal cell strain LO2
It is identical with HCT116 cellular modalities are processed, by mtt assay to compound 3,6a-6h, 10a-10f combination with cisplatin or list With the toxicity to LO2 cells, equally with LC50Represent, the results are shown in Table 2.The LC of cisplatin is calculated during drug combination50Value.In table 2, "-" represents activity of the activity after combination less than cisplatin independent medication；"～" expression is approximately equal to；" multiple (cisplatin/combination) " Represent the ratio of the IC50 values of cisplatin independent medication and the IC50 values of drug combination.
The toxicity of table 2 compound 6a-6h, 10a-10f to LO2 cells
In normal cell LO2 toxotests, the preferable compound 6a and 6f of antitumor sensitizing activity is relative to positive drug Increase degree for thing to the toxicity of cisplatin relatively low, only about 2 times.And the best compound 6h of activity does not almost increase cisplatin Toxicity, not only toxicity itself is relatively low and higher to the effect of enhanced sensitivity selectivity of tumor cell to show the compound, to ATR The selective inhibitory activity of kinases is likely to higher.
The synthetic route that the present invention is provided is shorter, and simply, yield is high for reaction condition, easily derivative, and the one of present invention offer Series compound has preferable anti-tumor activity and relatively low cytotoxicity.

Claims (6)

1,8 naphthyridines -4- ketone derivatives of 1.3 and 6 replacements, its structure is as shown in formula III：
Wherein, R3For substituted or unsubstituted phenyl；The substituent group of the substituted-phenyl is C1～C4Alkyl or halogen.
2. it is according to claim 13 and 6 replacement 1,8 naphthyridines -4- ketone derivatives, it is characterised in that：R3For replace or Unsubstituted phenyl；The substituent group of the substituted-phenyl is C1～C4Alkyl ,-F or-Cl.
3. it is according to claim 1 and 23 and 6 replacement 1,8 naphthyridines -4- ketone derivatives, it is characterised in that：Its structure Formula is
4. described in any one of claims 1 to 33 and 6 replacement 1,8 naphthyridines -4- ketone derivatives preparation method, including following Step：
G, by intermediate 2 with 4- mesyls phenylboric acid under the catalysis of bis-triphenylphosphipalladium palladium dichloride and natrium carbonicum calcinatum, in N2 Lower 60～65 DEG C of protection is reacted 8～9 hours, obtains compound 3；The mol ratio of the intermediate 2 and 4- mesyl phenylboric acids For 1 1.1～1.2；
H, compound 3 are reacted 30～40 minutes at 50～55 DEG C with hydrazine hydrate, obtain intermediate 4；The compound 3 and hydrazine hydrate Mol ratio be 1 5～10；
I, intermediate 4 with9～10h is reacted at 15～30 DEG C, obtains intermediate 5；The intermediate 4 withRub You are than being 1 1.5～2；
J, by intermediate 5, thionyl chloride and pyridine 2～5h of back flow reaction, obtain formula III compound；The intermediate 5, protochloride The mol ratio of sulfone and pyridine is 1 50～100 2～5；
Wherein, R3For substituted or unsubstituted phenyl；The substituent group of the substituted-phenyl is C1～C4Alkyl or halogen.
5. 1,8 naphthyridines -4- ketone derivatives of 3 and 6 replacements described in any one of claims 1 to 3 are preparing medicine for treating tumor Purposes in thing.
6. pharmaceutical composition, is that 3 and 61,8 naphthyridines -4- ketone derivatives for replacing by described in any one of claims 1 to 3 add Plus pharmaceutically acceptable complementary composition is prepared from.
CN201410030471.7A 2014-01-22 2014-01-22 3-and-6-substituted 1,8-naphthyridine-4-one derivatives and preparation method and application thereof Expired - Fee Related CN104788449B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1259947A (en) * 1997-03-07 2000-07-12 北卡罗来纳-查佩尔山大学 2-aryl-naphthyridin-4-ones as antitumor agent
CN1733764A (en) * 2005-08-18 2006-02-15 中国药科大学 3-substituted nalidixic acid analog compound and its preparation method and uses in pharmacy
CN101990539A (en) * 2008-02-01 2011-03-23 Irm责任有限公司 Compounds and compositions as kinase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1259947A (en) * 1997-03-07 2000-07-12 北卡罗来纳-查佩尔山大学 2-aryl-naphthyridin-4-ones as antitumor agent
CN1733764A (en) * 2005-08-18 2006-02-15 中国药科大学 3-substituted nalidixic acid analog compound and its preparation method and uses in pharmacy
CN101990539A (en) * 2008-02-01 2011-03-23 Irm责任有限公司 Compounds and compositions as kinase inhibitors

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