CN107915671A - The derivative and preparation method and purposes of a kind of Fascaplysin - Google Patents
The derivative and preparation method and purposes of a kind of Fascaplysin Download PDFInfo
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- CN107915671A CN107915671A CN201711241294.7A CN201711241294A CN107915671A CN 107915671 A CN107915671 A CN 107915671A CN 201711241294 A CN201711241294 A CN 201711241294A CN 107915671 A CN107915671 A CN 107915671A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
Abstract
The present invention discloses a kind of derivative of Fascaplysin, and its preparation and the application in medicine.The derivative general formula such as formula (I) of Fascaplysin of the present invention shows, compound of the invention can prepare prevention or
Description
Technical field
The present invention relates to a kind of compound and its purposes of preparation and this compound, exactly the present invention relates to one kind
The derivative of Fascaplysin, and its preparation and the application in medicine.
Background technology
Fascaplysin is a kind of red pigments, in 1988 first by Roll et al. from Fijian marine sponge
Isolated in Fascaplysinopsis sp, and first five rings ring system 12H- pyrido [1,2-a naturally deposited：3,4-b]
Two indoles members.Fascaplysin shows extensive bioactivity, including antibacterium, antimycotic, antiviral, HIV-1-RT,
P56 tyrosine kinase, anti-malarial is also effective to many cancerous cell lines, and CDK4 inhibitory action.Fascaplysin can press down
Make the growth of several microorganisms, including staphylococcus aureus, Escherichia coli, Candida albicans and saccharomyces cerevisiae.
Fascaplysin shows the suppression of the propagation to mouse leukemia cell L-1210, and ED50 values are 0.2 μM/mL, and in mouse
Selectivity is shown in cytotoxicity measure.Fascaplysin shows the antiproliferative work to HeLa Cells
With, it is apoptosis-induced by exogenous apoptotic pathway and mitochondria pathway, but cell-cycle arrest cannot be carried out in the G1 phases.
Fascaplysin is blocked by vascular endothelial growth factor (VEGF) and is carried out cell-cycle arrest to Human umbilical vein endothelial cells
And apoptosis, it is shown anti-angiogenesis activity.Nearest Yan et al. reports fascaplysin and suppresses the implantation of S180 cells
The growth of tumour, may pass through apoptosis, anti-angiogenesis or cell cycle arrest mechanism.Fascaplysin also shows that spy
Different in nature CDK4 inhibitory activity, its IC50 value are 0.35 μM, and also growth of the blocking cancer cell in the G0/G1 phases of cell cycle.
However, it has also been observed that fascaplysin is to the active poor of other CDKs, the IC50 of CDK1/Cyclin B>100 μM,
The IC50 of CDK2/Cyclin A and CDK-2/Cyclin E>50 μM, the IC50 values of CDK5/p35 are 20 μM.It is interesting that
CDK4/Cyclin D2 and CDK4/Cyclin D3 exist>It is not suppressed during 100 μM of concentration, and CDK6/Cyclin D2 are suppressed,
Its IC50 is 35 μM.This can reflect that cyclin is combined in a different manner with its CDKs.Fasacaplysin due to
Its plane five ring structures, also shows DNA insertion activity.Research find fascaplysin binding pattern and affinity costant with
The binding pattern and affinity costant of other typical DNA intercalators are suitable.This be fitted together to makes fascaplysin have higher cell
Toxicity, toxic side effect is big, seriously limits its clinical practice.
The content of the invention
On the basis of the present invention have studied a large amount of domestic and foreign literatures, lived with the CDK4 little molecules in inhibiting with specific selectivity
The natural products Fascaplysin (plane five rings quaternary ammonium salt) of property is lead compound, soft using Computer-Aided Drug Design
Part devises the derivative of Fascaplysin a series of, to reduce its DNA insertion abilities, and retains the medicine of CDK4 inhibitor
Effect acts on, and pharmacological evaluation proves that compound of the invention has preferable antitumor activity.
The compound formula such as formula (I) of the present invention is shown：
Wherein, substituent R1For chlorine, methyl, methoxyl group, nitro.
Formula (I) of the present invention shows compounds process for production thereof referring to formula (II), i.e.,：In reaction vessel
Sequentially add 1,2 dichloroethanes (20ml), triphosgene (2mmol), under ice bath stirring by corresponding amine (4mmol),
Triethylamine (16mmol), which is dissolved in 1,2 dichloroethanes, is added dropwise in round-bottomed flask (t=30min), after 85 DEG C of reflux stir
4h is mixed, reaction solution can be obtained by inter-mediate isocyanate by vacuum distillation.Intermediate adds 1,2 dichloroethanes (20ml),
Tryptamines (4mmol) is added portionwise under stirring, then adds triethylamine (5mmol), 24h is stirred at room temperature, contact plate monitoring, treats product point
Color is no longer deepened, and accessory substance has light point to occur, and reaction stops, vacuum distillation, successively with saturated sodium-chloride water solution, 5%
Sodium bicarbonate aqueous solution washs, anhydrous magnesium sulfate drying, chromatographic column (petroleum ether:Dichloromethane：Ethyl acetate=4:2:1) purify
Obtain target compound.
Formula (I) shows that compound can suppress preparing prevention or treatment with cell cycle protein dependent kinase CDK4
Application in the medicine of the related disease of agent.
Formula (I) shows compound in can prepare prevention or the application in treating the medicine of following disease, described
Disease is:Melanoma, liver cancer, stomach cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, colorectal cancer, cancer of pancreas, ovum
Nest cancer, breast cancer, the cancer of the esophagus, gastrointestinal cancer.
Above-claimed cpd shows compound and its pharmaceutically acceptable salt including formula (I), such as formed with following acid
Acid-addition salts：Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, naphthalene sulfonic acids, p-methyl benzenesulfonic acid, lactic acid, pyruvic acid, citric acid, wine
Stone acid, acetic acid, maleic acid, benzene sulfonic acid, butanedioic acid, fumaric acid, salicylic acid, phenylacetic acid or tussol；Additionally include inorganic
The acid salt of alkali, such as：Contain alkali metal cations, alkaline earth metal cation, ammonium cation salt.
The compound of the present invention is primarily directed to using CDK4 as target spot, and the one of natural products fascaplysin structure of modification
Series compound, retains the drug action of CDK4 inhibitor, and compound yield is high, relatively stablizes in atmosphere, water-soluble ratio
Preferably, easy to operate, its preparation method is opposite to be with prior art advantage：Raw material is easy to get, cheap, and syntheti c route is short, system
Preparation Method is simple, and production cost is low.
Brief description of the drawings
Fig. 1 Fascaplysin and CDK4/Cyclin D1 molecular docking schematic diagrames.
Fig. 2 I -9 and CDK4/Cyclin D1 molecular docking schematic diagrames.
Embodiment
First, the preparation of the compound of formula (I) is referring to following formula, i.e.,：
Reagents and conditions:(a)BTC,TEA,ClCH2CH2Cl,85℃4h；(b)TEA,
ClCH2CH2Cl,rt24h；
1,2 dichloroethanes (20ml), triphosgene (2mmol) are sequentially added in round-bottomed flask, ice bath stirring is lower will be corresponding
Amine (4mmol), triethylamine (16mmol) be dissolved in 1,2 dichloroethanes and (t=30min) be added dropwise in round-bottomed flask, finish
It is refluxed 4h for 85 DEG C afterwards, reaction solution can be obtained by inter-mediate isocyanate by vacuum distillation.Intermediate adds 1,2 dichloros
Ethane (20ml), is added portionwise tryptamines (4mmol) under stirring, then add triethylamine (5mmol), and 24h, contact plate prison is stirred at room temperature
Survey, treat that product point color is no longer deepened, accessory substance has light point to occur, and reaction stops, and vacuum distillation, uses saturated sodium-chloride successively
Aqueous solution, the washing of 5% sodium bicarbonate aqueous solution, anhydrous magnesium sulfate drying, chromatographic column (petroleum ether:Dichloromethane：Ethyl acetate=
4:2:1) purification obtains target compound.
The embodiment of the present invention preferably prepares following structural compounds：
N- [2- (1H- indoles -3-) ethyl]-N '-phenylurea (I -1)
N- [2- (1H- indoles -3-) ethyl]-N '-(2- aminomethyl phenyls) urea (I -2)
N- [2- (1H- indoles -3-) ethyl]-N '-(3- aminomethyl phenyls) urea (I -3)
N- [2- (1H- indoles -3-) ethyl]-N '-(2- chlorphenyls) urea (I -4)
N- [2- (1H- indoles -3-) ethyl]-N '-(3- chlorphenyls) urea (I -5)
N- [2- (1H- indoles -3-) ethyl]-N '-(4- chlorphenyls) urea (I -6)：
N- [2- (1H- indoles -3-) ethyl]-N '-(2- methoxyphenyls) urea (I -7)
N- [2- (1H- indoles -3-) ethyl]-N '-(3- nitrobenzophenones) urea (I -8)
N- [2- (1H- indoles -3-) ethyl]-N '-(4- nitrobenzophenones) urea (I -9)
Above-claimed cpd is characterized as below：
N- [2- (1H- indoles -3-) ethyl]-N '-phenylurea (I -1)
Beige solid；Yield：24.11%；mp:190-191℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ
10.85 (s, 1H, NH), 8.48 (s, 1H, NH), 7.57 (d, J=7.8Hz, 1H, Ar-H), 7.36 (dd, J=13.6,8.1Hz,
3H, Ar-H), 7.20 (dd, J=13.3,5.3Hz, 3H, Ar-H), 7.07 (t, J=7.5Hz, 1H, Ar-H), 6.98 (t, J=
7.4Hz, 1H, Ar-H), 6.87 (t, J=7.2Hz, 1H, Ar-H), 6.12 (s, 1H, Ar-H), 3.44-3.38 (m, 2H, CH2-
), NH 2.85 (t, J=7.1Hz, 2H, CH2).13C NMR(100MHz,DMSO-d6,TMS,ppm):δ155.66,141.11,
136.73,129.16,129.16,127.76,123.28,121.47,121.43,118.90,118.75,118.09,118.09,
112.28,111.89,42.59,26.40.MS(ESI+)m/z:280.1451[M+H]+.。
N- [2- (1H- indoles -3-) ethyl]-N '-(2- aminomethyl phenyls) urea (I -2)
White solid；Yield：45.30%；mp:149-151℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ
10.85 (s, 1H, NH), 7.82 (d, J=8.1Hz, 1H, Ar-H), 7.64 (s, 1H, NH), 7.57 (d, J=7.8Hz, 1H, Ar-
), H 7.35 (d, J=8.1Hz, 1H, Ar-H), 7.18 (s, 1H, Ar-H), 7.12-7.04 (m, 3H, Ar-H), 6.98 (t, J=
7.3Hz, 1H, Ar-H), 6.86 (t, J=7.3Hz, 1H, Ar-H), 6.57 (s, 1H, Ar-H), 3.44-3.38 (m, 2H, CH2-
), NH 2.86 (t, J=7.0Hz, 2H, CH2),2.15(s,3H,CH3).13C NMR(100MHz,DMSO-d6,TMS,ppm):δ
155.92,138.81,136.83,130.55,127.80,127.16,126.55,123.27,122.28,121.46,121.05,
118.91,118.75,112.41,111.90,41.98,26.42,18.46.MS(ESI+)m/z:294.1618[M+H]+.。
N- [2- (1H- indoles -3-) ethyl]-N '-(3- aminomethyl phenyls) urea (I -3)
Beige solid；Yield：13.79%；mp:124-136℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ
10.85 (s, 1H, NH), 8.40 (s, 1H, NH), 7.57 (d, J=7.7Hz, 1H, Ar-H), 7.34 (d, J=8.0Hz, 1H, Ar-
), H 7.23 (s, 1H, Ar-H), 7.16 (d, J=11.1Hz, 2H, Ar-H), 7.08 (dd, J=11.3,7.7Hz, 2H, Ar-H),
6.98 (t, J=7.4Hz, 1H, Ar-H), 6.70 (d, J=7.2Hz, 1H, Ar-H), 6.11 (s, 1H, NH), 3.38 (d, J=
6.5Hz,2H,CH2- NH), 2.85 (t, J=7.0Hz, 2H, CH2),2.24(s,3H,CH3).13C NMR(100MHz,DMSO-d6,
TMS,ppm):δ155.74,141.04,138.23,136.84,128.99,127.76,123.27,122.20,121.46(s),
118.89,118.76,118.66,115.31,112.30,111.89,40.29,26.40,21.77.MS(ESI+)m/z:
294.1607[M+H]+.。
N- [2- (1H- indoles -3-) ethyl]-N '-(2- chlorphenyls) urea (I -4)
White solid；Yield：28.23%；mp:176-178℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ
10.86 (s, 1H, NH), 8.17 (d, J=8.3Hz, 1H, Ar-H), 8.04 (s, 1H, NH), 7.57 (d, J=7.8Hz, 1H, Ar-
), H 7.36 (dd, J=15.3,8.1Hz, 2H, Ar-H), 7.24 (t, J=7.9Hz, 1H, Ar-H), 7.18 (s, 1H, NH), 7.07
(t, J=7.0Hz, 2H, Ar-H), 7.03-6.88 (m, 2H, Ar-H), 3.41 (dd, J=12.7,6.3Hz, 2H, CH2-NH),
2.87 (t, J=7.0Hz, 2H, CH2).13C NMR(100MHz,DMSO-d6,TMS,ppm):δ155.32,137.35,136.83,
129.56,127.92,127.77,123.31,122.84,121.63,121.46,121.37,118.86,118.77,112.27,
111.90,40.35,26.24.MS(ESI+)m/z:314.1094[M+H]+.。
N- [2- (1H- indoles -3-) ethyl]-N '-(3- chlorphenyls) urea (I -5)
White solid；Yield：27.42%；mp:149-150℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ
10.85 (s, 1H, NH), 8.72 (s, 1H, NH), 7.69 (s, 1H, Ar-H), 7.57 (d, J=7.7Hz, 1H, Ar-H), 7.35 (d,
J=8.0Hz, 1H, Ar-H), 7.26-7.13 (m, 3H, Ar-H), 7.07 (t, J=7.4Hz, 1H, Ar-H), 6.98 (t, J=
7.3Hz, 1H, Ar-H), 6.92 (d, J=7.7Hz, 1H, Ar-H), 6.22 (s, 1H, NH), 3.45-3.36 (m, 2H, CH2-NH),
2.86 (t, J=6.7Hz, 2H, CH2).13C NMR(100MHz,DMSO-d6,TMS,ppm):δ155.48,142.69,
136.84,133.64,130.74,127.75,123.29,121.48,121.02,118.88,118.77,117.44,116.44,
112.20,111.90,40.31,26.28.MS(ESI+)m/z:314.1058[M+H]+.。
N- [2- (1H- indoles -3-) ethyl]-N '-(4- chlorphenyls) urea (I -6)
Light brown solid；Yield：18.55%；mp:176-178℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ
10.79 (s, 1H, NH), 8.59 (s, 1H, NH), 7.53 (d, J=7.8Hz, 1H, Ar-H), 7.38 (d, J=2.1Hz, 1H, Ar-
), H 7.36 (d, J=2.0Hz, 1H, Ar-H), 7.30 (d, J=8.1Hz, 1H, Ar-H), 7.24-7.21 (m, 1H, Ar-H),
7.20 (d, J=2.0Hz, 1H, Ar-H), 7.13 (d, J=2.2Hz, 1H, Ar-H), 7.06-6.99 (m, 1H, Ar-H), 6.94
(t, J=7.4Hz, 1H, Ar-H), 6.13 (s, 1H, NH), 3.39-3.34 (m, 2H, CH2- NH), 2.81 (t, J=7.2Hz, 2H,
CH2).13C NMR(100MHz,DMSO-d6,TMS,ppm):δ155.56,140.14,136.84,128.96,128.96,
127.75,124.86,123.27,121.46,119.55,119.55,118.87,118.75,112.23,111.89,40.30,
26.31.MS(ESI+)m/z:314.1048[M+H]+.。
N- [2- (1H- indoles -3-) ethyl]-N '-(2- methoxyphenyls) urea (I -7)
White solid；Yield：59.68%；mp:154℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ10.83
(s, 1H, NH), 8.11 (dd, J=7.4,2.3Hz, 1H, Ar-H), 7.92 (s, 1H, NH), 7.56 (d, J=7.8Hz, 1H, Ar-
), H 7.34 (d, J=8.1Hz, 1H, Ar-H), 7.17 (s, 1H, Ar-H), 7.09-7.04 (m, 1H, Ar-H), 7.01-6.97 (m,
1H, Ar-H), 6.95 (dd, J=3.3,1.6Hz, 1H, Ar-H), 6.94-6.93 (m, 1H, Ar-H), 6.91 (s, 1H, NH),
6.86–6.82(m,2H,Ar-H),3.81(s,3H,CH3),3.43–3.35(m,2H,CH2- NH), 2.84 (t, J=7.1Hz, 2H,
CH2).13C NMR(100MHz,DMSO-d6,TMS,ppm):δ155.75,147.81,136.82,130.12,127.79,
123.27,121.44,121.36,120.99,118.86,118.75,118.53,112.36,111.89,111.05,56.13,
41.28,26.39.MS(ESI+)m/z:310.15555[M+H]+.。
N- [2- (1H- indoles -3-) ethyl]-N '-(3- nitrobenzophenones) urea (I -8)
Yellow powder；Yield：14.84%；mp:166-168℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ
10.85 (s, 1H, NH), 9.07 (s, 1H, NH), 8.53 (s, 1H, Ar-H), 7.74 (d, J=8.2Hz, 1H, Ar-H), 7.63 (d,
J=8.1Hz, 1H, Ar-H), 7.58 (d, J=7.8Hz, 1H, Ar-H), 7.50 (t, J=8.1Hz, 1H, Ar-H), 7.35 (d, J
=8.0Hz, 1H, Ar-H), 7.19 (s, 1H, Ar-H), 7.07 (t, J=7.5Hz, 1H, Ar-H), 6.99 (t, J=7.4Hz, 1H,
), Ar-H 6.33 (s, 1H, NH), 3.42 (d, J=6.2Hz, 2H, CH2- NH), 2.88 (t, J=7.0Hz, 2H, CH2).13C NMR
(100MHz,DMSO-d6,TMS,ppm):δ155.44,148.67,142.46,136.84,130.41,127.75,124.10,
123.31,121.49,118.88,118.78,115.90,112.16,111.97,111.91,40.38,26.24.MS(ESI+)
m/z:325.1294[M+H]+.。
N- [2- (1H- indoles -3-) ethyl]-N '-(4- nitrobenzophenones) urea (I -9)
Chinese red powder；Yield：16.41%；mp:174-176℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ
10.85(s,1H,NH),9.30(s,1H,NH),8.16–8.14(m,1H,Ar-H),8.14–8.11(m,1H,Ar-H),7.65–
7.62 (m, 1H, Ar-H), 7.61 (d, J=2.0Hz, 1H, Ar-H), 7.58 (d, J=7.8Hz, 1H, Ar-H), 7.35 (d, J=
8.1Hz, 1H, Ar-H), 7.19 (d, J=2.1Hz, 1H, Ar-H), 7.07 (t, J=7.3Hz, 1H, Ar-H), 6.98 (t, J=
7.4Hz, 1H, Ar-H), 6.44 (s, 1H, NH), 3.43 (dd, J=13.1,7.1Hz, 2H, CH2- NH), 2.88 (t, J=
7.1Hz,2H,CH2).13C NMR(100MHz,DMSO-d6,TMS,ppm):δ154.94,147.79,140.85,136.85,
127.74,125.67,125.67,123.33,121.50,118.86,118.79,117.27,117.27,112.08,119.92,
40.37,26.11.MS(ESI+)m/z:325.1307[M+H]+.。
2nd, the In vitro cell experiment of the compounds of this invention
(1) experiment material
Cell line：A-549 (Non-small cell lung carcinoma cell line), HeLa (human cervical carcinoma cell lines), Hep-G2(human liver cancer
Cell line), WI-38 (human embryonic lung fibroblasts)
Culture medium：Hyclone RPMI-1640 culture mediums, DMEM high glucose mediums, 10% hyclone.
Medicine and preparation：Target compound, is dissolved in DMSO, and dilution obtains 5 concentration by a certain percentage.
(2) experimental method
The cell line that logarithmic phase is grown, with every hole about 103A cell is added in 96 orifice plates, by difference after cell attachment
The solution addition effect of concentration, each concentration set 3 multiple holes.48h is cultivated in incubator, it is 5mg/ that 10 μ L concentration are added per hole
The MTT solution of mL, continues abandoning supernatant after culture 4h, and 150 μ L DMSO are added per hole, and fully shaking dissolves first a ceremonial jade-ladle, used in libation,
Absorbance OD values are measured under microplate reader 570nm.The calculation formula of cell inhibitory rate is：
Cell inhibitory rate %=(control group OD values-medication group OD values)/control group OD value × 100%, then calculate IC50.
(3) experimental result
Inhibiting tumour cells activity is preferably I -9, IC50 in indoles fascaplysin derivatives<90 μM,.The present invention
Fascaplysin derivatives be weaker than positive control Fascaplysin to tumor cell proliferation inhibition activity, but to normal cell
(WI-38) inhibitory activity IC50 values are high, and cytotoxicity selectively increases than decreasing.
The target compound of the present invention is tested with CDK4 molecular dockings, selection of the target compound to this target spot of CDK4
Property, rather than relatively with other target spots, theoretically elaborate that this kind of compound is CDK4 inhibitor, further theoretically
Compound is illustrated to CDK4 enzyme inhibition levels.
(1) experiment material
Calculating platform：(2 Intel to strong E5-2683V3, amount to 28 core, 56 thread to CPU.The farsighted screens of dominant frequency 2.0G
3.0G), memory (128GB DDR4ECC 2133MHZ), hard disk (4TB SATA 6Gb/s are maximum to support 40TB hard disks), GPU meters
Calculate card (2 NVDIA GTX 980 are supported and calculated)
Target compound：Fascaplysin, I -9, with chemdraw softwares smaller ligand is drawn, be used in combination
Chem3D Pro softwares minimize its structural energy, and preserve the form into .mol2, for molecular docking.
Destination protein：CDK4/Cyclin D1PDB ID：2W99
(2) experimental method
Using CDK4/Cyclin D (the PDB ID in PUB：2W99) it is purpose albumen.First, it is the 2W99 downloaded is brilliant
Body structure is opened with LeadIT softwares, this albumin crystal includes two chains, and it is that main chain docks position as activity that we, which select B chains,
Point, early-stage preparations are carried out according to LeadIT docking operations flow by receptor protein, including remove hydrone, additive polarity hydrogen etc..Will
Ligand Fascaplysin, I -9 are docked in 2W99 acceptors, check that it docks result.
(3) experimental result
Reference substance Fascaplysin and target compound I -9 dock result as shown in Figure 1, 2 with CDK4/Cyclin D1：
It was found from two compounds of attached drawing dock result with CDK4/Cyclin D1 simulations, it can enter hydrophobic work
Property chamber, acted on CDK4/Cyclin D1, action site residue is slightly different.Fascaplysin can with hydrophobic active chamber
LEU-178, VAL-176 amino acid residue form 2 hydrogen bonds；Target compound I -9 and CDK4/Cyclin D1 hydrophobic active chambers
In SER-166, GLN-168, VAL-174, VAL-175 amino acid residue formed 4 hydrogen bonds.
Claims (4)
1. such as the compound that formula (I) is shown,
Wherein substituent R1For chlorine, methyl, methoxyl group, nitro.
2. such as formula of compounds process for production thereof described in claim 1 (II), i.e.,：In reaction vessel successively
1,2 dichloroethanes 20ml, triphosgene 2mmol are added, it is under ice bath stirring that corresponding amine 4mmol, triethylamine 16mmol is molten
Be added dropwise in 1,2 dichloroethanes in round-bottomed flask, after 85 DEG C be refluxed 4h, reaction solution can by vacuum distillation
To obtain inter-mediate isocyanate, intermediate adds 1,2 dichloroethanes 20ml, tryptamines 4mmol is added portionwise under stirring, then adds
Enter triethylamine 5mmol, 24h is stirred at room temperature, contact plate monitoring, treats that product point color is no longer deepened, and accessory substance has light point to occur, reaction
Stop, being evaporated under reduced pressure, dried successively with saturated sodium-chloride water solution, the washing of 5% sodium bicarbonate aqueous solution, anhydrous magnesium sulfate,
Chromatographic column purifies to obtain target compound.
3. compound described in claim 1 is used to prepare prevention or treatment and cell cycle protein dependent kinase CDK4 inhibitor
The medicine of related disease, it is described to show compound and its pharmaceutically acceptable salt for Formula (I), including with following acid
The acid-addition salts of formation：Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, naphthalene sulfonic acids, p-methyl benzenesulfonic acid, lactic acid, pyruvic acid, lemon
Lemon acid, tartaric acid, acetic acid, maleic acid, benzene sulfonic acid, butanedioic acid, fumaric acid, salicylic acid, phenylacetic acid or tussol, and contain alkali
Property metal cation, alkaline earth metal cation, ammonium cation salt inorganic base acid salt.
4. compound described in claim 1 is being used to prepare prevention or is treating the medicine of following disease, the disease is:Melanin
Knurl, liver cancer, stomach cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, colorectal cancer, cancer of pancreas, oophoroma, breast cancer,
The cancer of the esophagus, gastrointestinal cancer, it is described to show compound and its pharmaceutically acceptable salt for Formula (I), including with following acid
The acid-addition salts of formation：Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, naphthalene sulfonic acids, p-methyl benzenesulfonic acid, lactic acid, pyruvic acid, lemon
Lemon acid, tartaric acid, acetic acid, maleic acid, benzene sulfonic acid, butanedioic acid, fumaric acid, salicylic acid, phenylacetic acid or tussol, and contain alkali
Property metal cation, alkaline earth metal cation, ammonium cation salt inorganic base acid salt.
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| CN104292170A (en) * | 2014-09-22 | 2015-01-21 | 广西师范大学 | Quinazolinyl-aryl urea derivatives with antitumor function and application thereof |
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