CN108484489A - A kind of pyridine compounds and their of the substituent group containing adamantane and its purposes in the preparation of antitumor drugs - Google Patents
A kind of pyridine compounds and their of the substituent group containing adamantane and its purposes in the preparation of antitumor drugs Download PDFInfo
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- CN108484489A CN108484489A CN201810509273.7A CN201810509273A CN108484489A CN 108484489 A CN108484489 A CN 108484489A CN 201810509273 A CN201810509273 A CN 201810509273A CN 108484489 A CN108484489 A CN 108484489A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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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
Abstract
The pyridine compounds and their formula containing adamantane that the invention discloses a kind of（Ⅰ）And its purposes in the preparation of antitumor drugs,, wherein：R1、R2、R3It is independently selected from H, F or OCH3.By the pharmacological results it is found that the compounds of this invention has MNK1 kinase inhibitory activities, wherein ICs of JMNK H001~JMNK H010 to MNK1 kinase inhibiting activities50Between the nM of 64nM~114, and the compounds of this invention has preferable external inhibitory activity to human pancreatic cancer cell MiaPaCa2.Illustrate that the compounds of this invention can be used for anticancer drug and be studied.
Description
Technical field
The invention belongs to chemical medicines, are related to a kind of pyridine compounds and their formula of the substituent group containing adamantane（Ⅰ）And its
Purposes in the preparation of antitumor drugs.
Background technology
Cancer is a kind of malignant disease that the death rate is high, and treatment difficulty is high, and the death rate is brought heavy to patient and family
Burden.In recent years, China's cancer incidence obviously increases, and prevention and control of cancer is made to be faced with severe situation.In recent years, China
Cancer incidence is in trend is gradually increasing, by the extensive concern of personages of various circles of society.It shows according to research reports, in 20 generation
It records the seventies, China's cancer increases to 22.32% by 10.13%, and dead increment rate is 82.11%.Cancer comes city death
First, second is arranged as in rural area.Especially aging increasingly aggravates now, smoking, dietary structure variation, microorganism sense
Dye, fat, activity is reduced, the factors such as bad of working and resting are the main reason for causing cancer to occur.The especially overweight rate in China and fertilizer
Fat rate is significantly more than 50%.At present come China's cancer top ten be：Lung cancer, gastric cancer, colorectal cancer, liver cancer, the cancer of the esophagus, female
Property breast cancer, cancer of pancreas, lymph cancer, carcinoma of urinary bladder and thyroid cancer.Lung cancer is city male's common disease, and breast cancer is city female
Property common cancer；Gastric cancer is that rural area men and women morbidity is the first, and lung cancer mortality occupies highest order.The exploitation of cancer drug is for a long time
The hot spot always researched and developed, chemical classes drug and biological species drug fall over each other to contend, but new effective treating malignant tumor medicine
Object is still in urgent need.
MNK full name are that mitogen-activated protein kinases act on kinases（MAP kinase-interacting
kinase or MAP kinase signal-integrating kinase）, it is a kind of serine/threonine protein kitase,
It is used as extracellular regulated protein kinase within 1997（ERK）Substrate or binding factor are found for the first time.The translation process of protein
By the stringent regulation and control of cell-signaling pathways, the correlation factor in these accesses is all good target in treatment of cancer, activation
The subsequent phosphorylation stream substrates e IF4E of MNK.In addition, growth factor activates PI3K/Akt/mTOR accesses, mTOR can be with
Phosphorylation 4E binding proteins p-4E-BP1 then discharges the e IF4E of combination, promotes the assembling of e IF4F compounds, is turned over various
The translation process of initiation protein under the action of translation factor.The translation process advanced activation of protein in tumour cell is related
Therefore enzyme height expression in signal path inhibits the activity of MNK that can inhibit the protein translation process of tumour cell.
MNK plays critical function in the occurrence and development of tumour, but its missing influences less normal cell, it means that exploitation
MNK inhibitor can selectively be directed to tumour cell.
Invention content
The invention discloses a kind of pyridine compounds and their formulas of substituent group containing adamantane（Ⅰ）, structure is：
, wherein：R1、R2、R3It is independently selected from H, F or OCH3.The present invention is also
It is related to the pyridine compounds and their formula containing adamantane（Ⅰ）Pharmaceutically acceptable salt or solvate.
Further, the pyridine compounds and their formula containing adamantane described in some preferred schemes（Ⅰ）For：
。
Another object of the present invention discloses the pyridine compounds and their formula containing adamantane（Ⅰ）Synthetic route be：
。
Specifically synthetic method is：
1) under suitable temperature, compound 1 occurs Buchwald substitution reaction with compound 2 and generates (1r, 3r, 5r, 7r) -2-
(4- chloro-2-methyls phenoxy group) -2- methyl adamantanes (compound 3)；2) in the presence of inorganic base and catalyst, compound 3 with
Suzuki cross-coupling reactions occur for boric acid, generate 2- chloro- 5- (3- methyl -4- (((1R, 3R, 5R, 7R) -2- methyl adamantanes -
2- yls) oxygroup) phenyl) pyridine (compound 4)；3) in the presence of inorganic base and catalyst, compound 4 further occurs with boric acid
Suzuki cross-coupling reactions generate corresponding pyridine derivatives.
Further, the reaction temperature in the step 1) is 0-30 DEG C, and temperature is 0-10 DEG C during charging, preferably 0-
5℃。
Further, the alkali in the step 2) and step 3) can be sodium carbonate, potassium carbonate, potassium acetate etc., preferably carbon
Sour sodium.
Another object of the present invention discloses the pyridine compounds and their formula containing adamantane（Ⅰ）And its it is pharmaceutically acceptable
Salt and/or solvate as mitogen-activated protein kinases act on kinases（MNK）The application of inhibitor.
Another object of the present invention discloses the pyridine compounds and their formula containing adamantane（Ⅰ）And its it is pharmaceutically acceptable
The application as antitumor drug of salt and/or solvate.
Pharmacological activity experimental section of the present invention is thin to MNK1 kinase inhibitory activities and to human pancreas cancer to the compounds of this invention
The external inhibitory activity of born of the same parents system MiaPaCa2 is evaluated, it is found that the compounds of this invention has good MNK1 kinase inhibiting activities,
ICs of the wherein JMNK-H001~JMNK-H010 to MNK1 kinase inhibiting activities50Between the nM of 64nM~114, and it is right
MiaPaCa2 has good external inhibitory activity.
The compounds of this invention can significantly inhibit human map kinase interaction kinases（MNK or MKNK）.MNK be one group by
Two genes（Gene symbol：MKNK1 and MKNK2）Four kinds of protein of coding（Bu Sade M.（Buxade M.）Et al., biology
Science frontier（Frontiers in Bioscience）5359-5373,2008）.MNK is the protein-silk ammonia generally expressed
Acid/threonine kinase.MNK1b and MNK2b variants, which lack, to combine knot positioned at the map kinase of the ends C- of MNK1a and MNK2a
Structure domain.The catalyst structure domain of MNK1a/b and MNK2a/b is highly conserved typical kinase domain, it shows three kinds and does not seek
Normal characteristic.Typical DFG- of the MNK kinases there is DFD- tripeptides in ATP-binding domain rather than found in every other kinases
Tripeptides is characterized（Credit section R.（Jauch R.）Et al., structure（Strcture）13,1559-1568,2005 and credit section R. et al.,
European Molecular Bioglogy Organization's magazine（EMBO J.）, 25,4020-4032,2006）.In addition, compared with other protein kinases,
There are two short Insert Fragments for MNK tools.Upstream kinases ERK can be combined and be activated both MNK1a and MNK2a.In contrast,
P38MAP kinases only activates MNK1a.MNK1b under all conditions all have secondary activity, and MNK2b have independently of
The Basal activity of p38MAP or ERK kinases（Karr alunite Lip river M.（Cargnello M.）With Shandong P.P.（Roux P.P.）, microorganism
It learns and molecular biology is commented on（Microbiol.Mol.Biol.Rev.）, 75,50-83,2011）.
MNK has been proved to phosphorylatable several protein substrates.Among the target of MNK phosphorylations, most characterize extensively
Be eukaryotic initiation factor eIF4E.Furthermore, it has been reported that the following protein of MNK phosphorylations：Heterogeneous ribonucleoprotein A1
（hnRNPA1）, Sprouty 2, poly pyrimidine sequence binding protein correlation splicing factor（PSF）And cPLA2 A2
（cPLA2）（Qiao Xi S.（Joshi S.）With pula Ta Niyasi L.C.（Platanias L.C.）, world's journal of biological chemistry
（World J.Biol.Chem.）, 5.321-333,2014）.
Eukaryotic translation initiation factor eIF4E is the oncogene being over-expressed in many cancers（Ma Manei Y.（Mamane
Y.）Et al., oncogene（Oncogene）, 23,3172-3179,2004；Moral Bennet A.（De Benedetti A.）And lattice
Pressgang J.R.（Graff J.R.）, oncogene, 23,3189-3199,2004 and Bu Yueensidi M.A（Bjornsti M.A）
Pause P.J. suddenly（Houghton P.J.）, cancer cell（Cancer Cell）, 5,519-523,2004）.It is by MNK in serine
Exclusively phosphorylation on 209, as proved by being completely absent phosphorylation in MNK1/2 knock out mice（Upper field T
（Ueda T）Et al. molecule and cell biology（Mol.Cell Biol.）, 24,6539-6549,2004）.EIF4E and eIF4G
Form eIF4F compounds together with eIF4A, which contributes to the translation of cell mRNA（Plain En Baige N.（Sonenberg
N.）With conspicuous grace Bush, A.G.（Hinnebusch,A.G.）, molecular cell（Mol.Cell）, 28,721-729,2007）.eIF4F
The eIF4E subunits of compound are bound to the 7- methylguanosine caps found at the 5 ' ends of mRNA, to which mRNA is delivered to ribose
Body（Pu Sitewa T.V.（Pestova T.V.）Et al., National Academy of Sciences proceeding（Proc.Natl,Acad.Sci.USA）,
98,7029-7036,2001）.MRNA subsets depend particularly on increased eIF4E activity and are translated.These mRNA have it is long and
5 ' complicated non-translational regions；Many of which compiles the protein to play a significant role in tumour generation and tumor proliferation
Code, such as c-myc, Cyclin D_1 gene, VEGF, Bcl-2, survivin etc.（Crewe rice Lars A.E.（Koromilas A.E.）
Et al., European Molecular Bioglogy Organization's magazine（EMBO J.）, 11,4153-4158,1992 and her N. of sea（Hay N.）And element
Grace Burger N.（Sonenberg N.）, gene with development（Genes Dev.）, 18,1926-1945,2004）.It is swollen in many entities
Detected in tumor the overexpression of eIF4E, including tumor of breast, tumor of prostate, tumor of bladder, H/N tumors and cervix neoplasms with
And leukaemia（Zimmer that S.G.（Zimmer S.G.）Et al., anticancer research（Anticancer Res.）, 20,1343-1351,
The 2000 and graceful p.B of bit（Bitterman p.B）With this triumphant V.A. of Pu Lu Novi（Polunovsky V.A.）, biochemistry
With biophysics journal（Biochim.Biophys.Acta）, 2014）.The activity of eIF4E and expression are by oncogene and growth
The factor shows that eIF4E is located at the point of many conversion signal pathways convergence in multiple horizontal stringent regulation and control（Labor Ford B.
（Raught B.）With Gingras A.C.（Gingras A.C.）, biochemistry and cell biology international magazine（The
Int.J.Biochem.&Cell Biol.）, 31,43-57,1999）.This is by the fact that be illustrated, i.e. the mistake of eIF4E
Expression leads to the neoplastic transformation of cell line（Plain En Baige N.（Sonenberg N.）With conspicuous grace Bush A.G.（Hinnebusch
A.G.）, cell（Cell）, 136,731-745,2009）.By the activity of reduction eIF4E, or by being reduced with antisense RNA
It is horizontal（Big vast D.D.（Hong D.D.）Et al., Clinical Cancer Research（Clin.Cancer Res.）, 17,6582-6591,
2011）Or by being overexpressed inhibition 4E binding proteins, the growth of many tumor cell lines can be inhibited（A Lan T.
（Alain T.）Et al. cancer research（Cancer Res.）, 72,6468-6476,2012）.
Pharmaceutically acceptable salt of the present invention refers to the organic salt and inorganic salts of the compounds of this invention.Pharmaceutically may be used
The salt that the nontoxic acid received is formed includes, but is not limited to, inorganic acid salt, such as hydrochloride, hydrobromate, phosphate, sulfuric acid
Salt, perchlorate；Acylate, such as acetate, oxalates, maleate, tartrate, citrate, succinate, the third two
Hydrochlorate；Or these salt are obtained by other methods described in the books or literature such as ion-exchange.Other can pharmaceutically connect
The salt received includes adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate,
Borate, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, second
Sulfonate, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate,
Caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, apple
Hydrochlorate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfuric acid
Salt, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, 11
Hydrochlorate, valerate, etc..By including alkali metal, alkaline-earth metal, ammonium and N+ (C1-4 alkane with alkali appropriate salt obtained by the reaction
Base) 4 salt.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Can with the alkali metal of forming salt or
Alkaline-earth metal includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises appropriate, nontoxic ammonium, season
The amine cation that ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitre
Acidulants, C1-8 azochlorosulfonate acid compounds and aromatic sulphonic acid compound.
Solvate of the present invention refers to that one or more solvent molecules are formed by with the compound of the present invention and form
Close object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate,
Acetic acid and ethylaminoethanol.
Specific implementation mode
Embodiment 1：2- (1- cyclohexylvinyls) -5- (3- methyl -4- (((1R, 3R, 5R, 7R) -2- methyl adamantanes -
2- yls) oxygroup) phenyl) and pyridine synthesis
1.1, the synthesis of (1r, 3r, 5r, 7r) -2- (4- chloro-2-methyls phenoxy group) -2- methyl adamantanes
At 0-5 DEG C, to (1R, 3R, 5R, the 7R) -2- methyl Buddha's warrior attendant -2- alcohol (compound 1) being dissolved in DMF (6.7mL)
The NaH (34.8mg, 0.87mmol) of mass fraction 60% is added in the solution of (111.4mg, 0.67mmol), it then will be above-mentioned molten
Liquid is stirred at room temperature 30 minutes, and the chloro- 2- methylbenzenes (compound 2) (107.9mg, 0.67mmol) of Isosorbide-5-Nitrae-two are added and will react
Object stirs 1 hour.Obtained crude product is diluted with EtOAc.It is transferred in separatory funnel, is layered and isolates organic layer, it will
Organic layer water (30mL), salt water washing, through Na2SO4It is dry, it filters and is concentrated under reduced pressure, obtain (1r, 3r, 5r, 7r) -2- (4-
Chloro-2-methyl phenoxy group) -2- methyl adamantanes (compound 3), 146.1mg, yield 75%.Crude product is not necessarily to be further purified,
It is directly used in next step synthesis step.1H-NMR (400 MHz, CDCl3) δ: 0.79-0.83(m, 4H), 1.07(t,
1H), 1.36(s, 3H), 1.72(t, 1H), 1.91(m, 2H), 1.97-2.07(m, 4H), 2.15(s, 3H),
2.21(t, 2H), 6.82(d, 1H), 7.29(d, 1H), 7.34(s, 1H). 13C-NMR (125 MHz, CDCl3)
δ: 16.02, 19.97, 31.45, 34.71, 35.26, 37.62, 80.50, 116.76, 127.30, 127.66,
130.07, 133.31, 153.28. LC-MS(ESI, pos, ion) m/z: 291[M+H]。
1.2, the chloro- 5- of 2- (3- methyl -4- (((1R, 3R, 5R, 7R) -2- methyl adamantane -2- bases) oxygroup) phenyl) pyridine
Synthesis
By (6- chloropyridine -3- bases) boric acid (78.68mg, 0.50mmol), compound 3 (146.1mg, 0.50mmol), Na2CO3
(159.0mg, 1.50mmol), DME (0.81mL) and H2O (0.20mL) is added in 5mL microwave vials.Bottle N2Degassing 15
Minute, PdCl is then added2(dppf)CH2Cl2(44.1mg, 0.06mmol) adduct.By microwave irradiation by reaction mixture
It is heated 60 minutes at 120 DEG C.Obtained mixture is diluted with ethyl acetate and is filtered by diatomite, is then concentrated in vacuo.It is logical
Purified by flash chromatography is crossed, uses 0-100% ethyl acetate/heptanes as eluant, eluent, obtains yellow powder 2- chloro- 5- (3- first
Base -4- (((1R, 3R, 5R, 7R) -2- methyl adamantane -2- bases) oxygroup) phenyl) pyridine (compound 4), 137.97mg, yield
75%。1H-NMR (400 MHz, CDCl3) δ: 0.79-0.83(m, 4H), 1.07(t, 1H), 1.36(s, 3H),
1.72(t, 1H), 1.96(m, 2H), 2.01-2.07(m, 4H), 2.15(s, 3H), 2.21(t, 2H), 7.07(d,
1H), 7.49(d, 1H), 7.61(d, 1H), 7.78(s, 1H), 8.16(d, 1H), 8.99(s, 1H). 13C-NMR
(125 MHz, CDCl3) δ: 16.02, 19.97, 31.45, 34.71, 35.26, 37.62, 80.50, 112.21,
123.03, 126.59, 129.90, 130.11, 133.47, 134.18, 134.21, 147.40, 150.98,
154.81. LC-MS(ESI, pos, ion) m/z: 368[M+H].
1.3,2- (1- cyclohexylvinyls) -5- (3- methyl -4- (((1R, 3R, 5R, 7R) -2- methyl adamantane -2- bases) oxygen
Base) phenyl) pyridine synthesis
By (1- cyclohexylvinyls) boric acid (0.375mmol), compound 4 (137.97mg, 0.375mmol), Na2CO3
(119.8mg, 1.13mmol), DME (0.61mL) and H2O (0.15mL) is added in 5mL microwave vials.Bottle N2Degassing 11
Minute, PdCl is then added2(dppf)CH2Cl2(33.1mg, 0.045mmol) adduct.Reaction is mixed by microwave irradiation
Object heats 50 minutes at 120 DEG C.Obtained mixture is diluted with ethyl acetate and is filtered by diatomite, is then concentrated in vacuo.
By purified by flash chromatography, uses 0-100% ethyl acetate/heptanes as eluant, eluent, obtain glassy yellow powdered 2- (1- hexamethylenes
Base vinyl) -5- (3- methyl -4- (((1R, 3R, 5R, 7R) -2- methyl adamantane -2- bases) oxygroup) phenyl) pyridine,
124.2mg yield 75%.1H-NMR (400 MHz, CDCl3) δ: 0.79-0.83(m, 4H), 1.07(t, 1H), 1.12
(m, 1H), 1.20(m, 2H), 1.36(s, 3H), 1.60(m, 1H), 1.72(t, 1H), 1.81(m, 2H),
1.94(m, 2H), 1.99-2.07(m, 4H), 2.15(s, 3H), 2.21(t, 2H), 2.26(m, 1H), 2.75(m,
2H), 4.16(m, 2H), 4.90(s, 1H), 5.41(s, 1H), 7.07(d, 1H), 7.61(d, 1H), 7.67(d,
1H), 7.78(s, 1H), 7.94(d, 1H), 8.93(s, 1H). 13C-NMR (125 MHz, CDCl3) δ: 16.02,
19.97, 25.15, 25.92, 31.45, 31.77, 34.71, 35.26, 37.62, 44.17, 80.50, 112.21,
116.29, 121.51, 126.59, 129.90, 130.11, 132.63, 134.18, 136.05, 140.53,
150.62, 154.81, 161.64. LC-MS(ESI, pos, ion) m/z: 442[M+H]。
Embodiment 2：2- (1- (3- fluorine cyclohexyl) vinyl) -5- (3- methyl -4- (((1R, 3R, 5R, 7R) -2- methyl gold
Rigid alkane -2- bases) oxygroup) phenyl) and pyridine synthesis
By (1- (3- fluorine cyclohexyl) vinyl) boric acid (0.375mmol), compound 4 (137.97mg, 0.375mmol),
Na2CO3(119.8mg, 1.13mmol), DME (0.61mL) and H2O (0.15mL) is added in 5mL microwave vials.Bottle N2
Degassing 11 minutes, is then added PdCl2(dppf)CH2Cl2(33.1mg, 0.045mmol) adduct.It will be anti-by microwave irradiation
Mixture is answered to be heated 50 minutes at 120 DEG C.Obtained mixture is diluted with ethyl acetate and is filtered by diatomite, then vacuum
Concentration.By purified by flash chromatography, uses 0-100% ethyl acetate/heptanes as eluant, eluent, obtain the powdered 2- (1- of glassy yellow
(3- fluorine cyclohexyl) vinyl) -5- (3- methyl -4- (((1R, 3R, 5R, 7R) -2- methyl adamantane -2- bases) oxygroup) phenyl)
Pyridine, 134.3mg, yield 78%.LC-MS(ESI, pos, ion) m/z: 460[M+H].
Embodiment 3：2- (1- (3- methoxycyclohexyls) vinyl) -5- (3- methyl -4- (((1R, 3R, 5R, 7R) -2- first
Base adamantane -2- bases) oxygroup) phenyl) and pyridine synthesis
By (3- methoxycyclohexyls) vinyl) boric acid (0.375mmol), compound 4 (137.97mg, 0.375mmol),
Na2CO3(119.8mg, 1.13mmol), DME (0.61mL) and H2O (0.15mL) is added in 5mL microwave vials.Bottle N2
Degassing 11 minutes, is then added PdCl2(dppf)CH2Cl2(33.1mg, 0.045mmol) adduct.It will be anti-by microwave irradiation
Mixture is answered to be heated 50 minutes at 120 DEG C.Obtained mixture is diluted with ethyl acetate and is filtered by diatomite, then vacuum
Concentration.By purified by flash chromatography, uses 0-100% ethyl acetate/heptanes as eluant, eluent, obtain the powdered 2- (1- of glassy yellow
(3- methoxycyclohexyls) vinyl) -5- (3- methyl -4- (((1R, 3R, 5R, 7R) -2- methyl adamantane -2- bases) oxygroup) benzene
Base) pyridine, 134.2mg, yield 76%.LC-MS(ESI, pos, ion) m/z: 472[M+H].
Embodiment 4：2- (1- (the fluoro- 4- methoxycyclohexyls of 3-) vinyl) -5- (3- methyl -4- (((1R, 3R, 5R,
7R) -2- methyl adamantanes -2- bases) oxygroup) phenyl) and pyridine synthesis
By (the fluoro- 4- methoxycyclohexyls of 3-) vinyl) boric acid (0.375mmol), compound 4 (137.97mg,
0.375mmol), Na2CO3(119.8mg, 1.13mmol), DME (0.61mL) and H2O (0.15mL) is added to 5mL microwave vials
In.Bottle N2Degassing 11 minutes, is then added PdCl2(dppf)CH2Cl2(33.1mg, 0.045mmol) adduct.By micro-
Wave irradiation heats reaction mixture 50 minutes at 120 DEG C.Obtained mixture is diluted with ethyl acetate and passes through diatomite mistake
Filter, is then concentrated in vacuo.By purified by flash chromatography, uses 0-100% ethyl acetate/heptanes as eluant, eluent, obtain glassy yellow
Powdered 2- (1- (the fluoro- 4- methoxycyclohexyls of 3-) vinyl) -5- (3- methyl -4- (((1R, 3R, 5R, 7R) -2- methyl gold
Rigid alkane -2- bases) oxygroup) phenyl) pyridine, 148.5mg, yield 81%.LC-MS(ESI, pos, ion) m/z: 490[M+H].
The pharmacological activity of the compounds of this invention is tested：
One, to MNK1 kinase inhibitory activities
The present invention uses the activity of Z-Lyte kinase assays systematic survey MNK1 kinases, the kinase activity of more specifical MNK1 to adopt
With 7 peptides of Z-Lyte kinase assays kits Ser/Thr（Life Technologies PV3180）It is quantified.Specific method
Referring to the kit specification of supplier, method is briefly described below：
Recombinate GST-MNK1 fusion proteins（GST-MNK1 life technologies PV6023）To be produced in the insect cell of baculovirus infection
It gives birth to and purifies.In 384 hole round bottom black microtiter plates（It is healthy and free from worry（Corning）3676）Middle progress MNK1 enzymatic determinations.By kinases
Reaction carries out 3 hours at 31 DEG C.Selection enzyme amount as indicated by the supplier by kit, so that about 30% peptide substrate
It is phosphorylated in the control wells only comprising buffer solution.By by compound with 10000,5000,2000,1000,500,200,
100, the concentration of 50nM is added to the MNK1 inhibitory activity that these compounds are tested in kinase reaction.In addition 20,10,5,2,
The compound inhibited with strong MNK1 is tested under 1 and 0.5nM.It is dense that each compound is at least tested in duplicate
Degree.As calculated percentage phosphorylation of the peptide substrate under each compound concentration described in measurement handbook.In Biotek
Fluorescence signal is recorded in 3 microplate reader of Cytation.With 6 softwares of Grafit（Erythacus software companys）Calculate IC50（If
By the concentration of substrate phosphorylation reduction 50% compared with the hole of only buffer solution）.
Two, to human pancreatic cancer cell inhibiting effect
By by human pancreatic cancer cell MiaPaCa2（ATCC CRL-1420）Compound on intracellular is tested to compound exposure
The inhibition of growth.In 384 hole clear bottom white microtiter plates（Greiner #781098）In be measured.Each hole is used
The Dulbecco modified Eagle medium of 20 μ l（Dulbecco’s modified Eagle’s medium）（Sigma
D6796）In 103A cell inoculation, the culture medium are supplemented with 10% fetal calf serum（Sigma F7524）, 2.5% horse serum
（Sigma H0146）, 1% Pen .- Strep Sigma P0781）, 1%MEM nonessential amino acid solutions 100x（Sigma
M71459）And 1%200mM L-Glutamines（Sigma G7513）Culture medium.In 5%CO at 37 DEG C2After middle overnight incubation,
Compound is added by following concentration：100,50,20,10,5,2,1,0.5,0.2 and 0.1 μM.Eachization is tested in quadruplicate
Close object concentration.Then it will be incubated and continue 72 hours.After 72 hours, as indicated by supplier, passed through addition
CellTiterGlo reagents（Pu Luomaige（Promega）G9242）Assess the growth of cell.In SpectraMax M2 microplate reader
Upper record luminous signal.It, will be comprising there is no compounds after subtracting the signal obtained in the hole of only culture medium
In the case of the signal that obtains in the hole of cell cultivated be set as 100% growth.By subtract the only value of culture medium and divided by
100% growth value calculates the growths of the % in each hole.With GraFit6 softwares（Erythacus softwares）Calculate the IC of cell growth50
（Cell growth is reduced to the concentration of 50% compound）.
Three, experimental result
By the pharmacological results it is found that the compounds of this invention has MNK1 kinase inhibitory activities, wherein JMNK-H001~JMNK-
ICs of the H010 to MNK1 kinase inhibiting activities50Between the nM of 64nM~114, and the compounds of this invention is to human pancreatic cancer cell
Being MiaPaCa2 has preferable external inhibitory activity.Illustrate that the compounds of this invention can be used for anticancer drug and be studied.
Claims (6)
1. a kind of pyridine compounds and their formula containing adamantane（Ⅰ）, structure is
, wherein：R1、R2、R3It is independently selected from H, F or OCH3。
2. the pyridine compounds and their formula containing adamantane as described in claim 1（Ⅰ）Pharmaceutically acceptable salt or solvation
Object.
3. the pyridine compounds and their formula containing adamantane as described in claim 1（Ⅰ）, characterized in that it is selected from following compound：
。
4. the pyridine compounds and their formula containing adamantane as described in claim 1（Ⅰ）Synthetic route be：
。
5. the pyridine compounds and their formula containing adamantane as claimed in claim 1 or 2（Ⅰ）Albumen as mitogen activation
The application of zymogenesis kinase inhibitor.
6. the pyridine compounds and their formula containing adamantane as claimed in claim 1 or 2（Ⅰ）Application as antitumor drug.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483284A (en) * | 2019-08-26 | 2019-11-22 | 浙江工业大学 | A kind of 1- adamantanecarboxylic acid -2- (substituted benzoyl acyloxy) ethyl ester compound and its synthetic method and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107428692A (en) * | 2015-02-11 | 2017-12-01 | 巴斯利尔药物国际股份公司 | Substituted single azepine naphthalene derivatives and polyazanaphthlene derivative and application thereof |
| CN107903274A (en) * | 2017-12-28 | 2018-04-13 | 窦玉玲 | A kind of aminated compounds and its application in antitumor drug |
-
2018
- 2018-05-25 CN CN201810509273.7A patent/CN108484489A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107428692A (en) * | 2015-02-11 | 2017-12-01 | 巴斯利尔药物国际股份公司 | Substituted single azepine naphthalene derivatives and polyazanaphthlene derivative and application thereof |
| CN107903274A (en) * | 2017-12-28 | 2018-04-13 | 窦玉玲 | A kind of aminated compounds and its application in antitumor drug |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483284A (en) * | 2019-08-26 | 2019-11-22 | 浙江工业大学 | A kind of 1- adamantanecarboxylic acid -2- (substituted benzoyl acyloxy) ethyl ester compound and its synthetic method and application |
| CN110483284B (en) * | 2019-08-26 | 2022-05-13 | 浙江工业大学 | 1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound and synthetic method and application thereof |
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