CN106008532B - Alcoxyl yl pyrimidines splice 3- pyrroles's loop coil oxoindole derivative and preparation method and application - Google Patents
Alcoxyl yl pyrimidines splice 3- pyrroles's loop coil oxoindole derivative and preparation method and application Download PDFInfo
- Publication number
- CN106008532B CN106008532B CN201610573327.7A CN201610573327A CN106008532B CN 106008532 B CN106008532 B CN 106008532B CN 201610573327 A CN201610573327 A CN 201610573327A CN 106008532 B CN106008532 B CN 106008532B
- Authority
- CN
- China
- Prior art keywords
- pyrimidines
- alcoxyl
- pyrroles
- loop coil
- splicing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
Abstract
The invention discloses a kind of alcoxyl yl pyrimidines to splice 3- pyrroles's loop coil oxoindole derivative, the present invention is with various substituted alcoxyl yl pyrimidines splicing 3- ethylene linkage oxoindole derivatives and sarcosine, paraformaldehyde, it flows back in organic solvent, carry out 1, 3- dipole 3+2 cycloaddition reaction, it obtains alcoxyl yl pyrimidines and splices 3- pyrroles's loop coil oxoindole derivative, such skeleton includes potential bioactivity pyrimidine scaffold and 3- pyrroles's loop coil Oxoindole skeleton, it is a kind of important medicine intermediate analog and drug molecule analog, chemical combination material resource can be provided for bioactivity screening, screening and pharmaceutical industry to drug have important application value, the present invention carries out tumor growth inhibiting activity screening to three kinds of tumor cell lines for these derivatives, prove that these derivatives are found to have certain inhibition tumour Cells growth activity, it is contemplated that as antineoplastic use.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, especially a kind of alcoxyl yl pyrimidines splice 3- pyrroles's loop coil Oxoindole
Derivative and the preparation method and application thereof.
Background technique
It is extremely heavy having bio-active group to be spliced in a molecular skeleton in organic chemistry and medical chemistry
The research field wanted.(1) polyfunctional group Oxoindole is widely present in natural products and synthetic drug molecule, wherein especially 3-
Pyrroles's loop coil Oxoindole has attracted the wide of many chemists and medical chemistry team because having extensive bioactivity
General concern, for example, natural products loop coil Oxoindole horsfiline and elacomine have multi-biological activity；Important
It is or even unnatural products loop coil Oxoindole III and IV has been demonstrated complete inhibition tsFT210 cell, is blocking cell point
The G2/M phase split is a kind of important non-peptide p53-MDM2 binding inhibitors.P53-MDM2 binding inhibitors are a kind of to treat cancer
The new treatment of disease.(2) quite a lot of antitumor or viral infection resisting drug that lists or will list at present is all that alkoxy is phonetic
Pyridine derivative forms.Such as: Zidovudine (zidovudine, AZT), ddC (dideoxycytidine) and Lamivudine (rummy husband
It is fixed) etc. be hiv reverse transcriptase inhibitor；Alkoxy pyrimidine compound V-X is drug molecule or there is extensive bioactivity to divide
Son.There is potential bioactivity in view of 3- ethylene linkage Oxoindole framework compound and alkoxy pyrimidine scaffold compound.Therefore,
Alkoxy pyrimidine scaffold is spliced on 3- ethylene linkage Oxoindole framework compound, a series of new potential more active functions are synthesized
The pyrimidine that group replaces splices 3- pyrroles's loop coil oxoindole derivative, chemical combination material resource can be provided for bioactivity screening, to medicine
The screening of object and pharmaceutical industry have important application value.(as shown in Fig. 7).
Summary of the invention
The object of the present invention is to provide a kind of alcoxyl yl pyrimidines splicing 3- pyrroles's loop coil oxoindole derivative and its preparations
Method and application, it is a kind of important medicine intermediate analog and drug molecule analog, to drug screening and pharmacy row
Industry has important application value, and the very economical simplicity of its synthetic method.
The present invention is implemented as follows: a kind of alcoxyl yl pyrimidines splice 3- pyrroles's loop coil oxoindole derivative, the chemical combination
Object has the structure of following general formula (I):
In formula, R1For alkyl or hydrogen or phenyl；R2For alkyl or halogen or H；R3For alkyl；R4For halogen or alkoxy or
H；R5For halogen or alkoxy.
Alcoxyl yl pyrimidines splice the preparation method of 3- pyrroles's loop coil oxoindole derivative, phonetic by various substituted alkoxies
3- ethylene linkage oxoindole derivative and sarcosine and paraformaldehyde are spliced in pyridine, are in molar ratio the ratio of 2:3:6 in organic solvent
Middle reflux carries out 1,3- dipole 3+2 cycloaddition reaction, and it is derivative to obtain alcoxyl yl pyrimidines splicing 3- pyrroles's loop coil Oxoindole
Object.
The preparation method of alcoxyl yl pyrimidines splicing 3- pyrroles's loop coil oxoindole derivative, it is characterised in that: institute
The organic solvent stated be acetonitrile, methanol, ethyl alcohol, propyl alcohol, isopropanol, ether, tetrahydrofuran, benzene,toluene,xylene, trimethylbenzene,
Dioxane, glycol dimethyl ether, isopropyl ether, chloroform, methylene chloride or nitrobenzene.
The preparation method of alcoxyl yl pyrimidines splicing 3- pyrroles's loop coil oxoindole derivative, it is characterised in that: each
The alcoxyl yl pyrimidines splicing 3- ethylene linkage oxoindole derivative and sarcosine that kind replaces, paraformaldehyde, in molar ratio for 2:3:6's
Ratio, reaction temperature in organic solvent are 50-100 DEG C, and the reaction time is 5-20 hours.
The alcoxyl yl pyrimidines splice 3- pyrroles's loop coil oxoindole derivative, it is characterised in that: swollen in preparation prevention and treatment
Application in tumor disease medicament.
Reaction principle of the invention is as follows:
In formula, R1For alkyl or hydrogen or phenyl；R2For alkyl or halogen or H；R3For alkyl；R4For halogen or alkoxy or
H；R5For halogen or alkoxy.
By using above-mentioned technical proposal, with various substituted alcoxyl yl pyrimidines splicing 3- ethylene linkage oxoindole derivatives with
Sarcosine and paraformaldehyde, flow back in organic solvent in specific proportions, carry out 1,3- dipole 3+2 cycloaddition reaction, obtain
Alcoxyl yl pyrimidines splice 3- pyrroles's loop coil oxoindole derivative, such skeleton includes the active 3- pyrroles's loop coil oxygen of multi-biological
Change indoles skeleton and be spliced to alkoxy pyrimidine scaffold, chemical combination material resource can be provided for bioactivity screening, to multiple target point multipurpose
The screening of medicine and pharmaceutical industry have important application value.Operation of the present invention is simple and easy, and Material synthesis is cheap and easily-available, can be with
It is carried out in various organic solvents, it may have preferable air stability, applicability is wide, has well for various substituent groups
Compatibility.
Detailed description of the invention
Attached drawing 1 and attached drawing 2 are the compound 3a spectral data of the embodiment of the present invention 1；
Attached drawing 3 and attached drawing 4 are the compound 3b spectral data of the embodiment of the present invention 1；
Attached drawing 5 and attached drawing 6 are the compound 3c spectral data of the embodiment of the present invention 1；
Attached drawing 7 is the synthesis application of the compound of the present invention；
Attached drawing 8 is compound 3g, 3j and 3o the monocrystalline figure of the embodiment of the present invention 1.
Specific embodiment
The embodiment of the present invention 1: 89.1mg bi-methoxy pyrimidine splicing 3- ethylene linkage oxidation Yin is sequentially added in reaction tube
Diindyl 1a (0.3mmol), 53.4mg sarcosine 2 (0.6mmol) and 27.0mg paraformaldehyde (0.9mmol) and 8.0mL toluene solution,
Heating reflux reaction 12h, direct loading are purified through column chromatography (eluant, eluent: V (petroleum ether): V (ethyl acetate)=3:1)
94.5mg compound 3a, white solid, fusing point: 107.5-109.3 DEG C；Yield 89%, > 20:1dr.Nuclear magnetic resonance and high-resolution
The results such as mass spectrometric measurement are as follows:1H NMR(CDCl3, 400MHz) and δ: 2.48 (s, 3H), 2.63 (d, J=8.0Hz, 1H), 3.08-
3.10(m,1H),3.14-3.17(m,4H),3.69-6.70(m,1H),3.78(s,6H),4.14-4.18(m,1H),6.62(d,
J=8.0Hz, 1H), 6.76-6.79 (m, 1H), 7.03-7.09 (m, 2H), 8.04 (s, 1H)；13C NMR(CDCl3,100MHz)
δ:26.3,42.4,44.8,53.9,58.3,59.7,66.8,102.3,107.2,121.7,124.1,127.9,131.4,
143.4,154.7,168.3,168.4,180.4；HRMS(ESI-TOF)m/z:Calcd.for C19H22N4NaO3[M+Na]+:
377.1590；Found:377.1591.
For the preparation method of compound 3b-3t with compound 1, feed ratio is identical as compound 3a, and compound 3b- can be obtained
3t, reaction yield and dr value are shown in Tables 1 and 2, but it is emphasized that the compound of the present invention is not limited to represented by Tables 1 and 2
Content.
Table 1 is the chemical structure and its external activity test that alcoxyl yl pyrimidines splice 3- pyrroles's loop coil oxoindole derivative
As a result
Table 2 is the chemical structure and its external activity test that alcoxyl yl pyrimidines splice 3- pyrroles's loop coil oxoindole derivative
As a result
The present embodiment prepare compound 3b: white solid, yield 79%；18:1dr；Fusing point: 82.9-84.6 DEG C；Nuclear-magnetism is total
The results such as vibration and high resolution mass spectrum test are as follows:1H NMR(CDCl3,400MHz)δ:2.93-2.95(m,3H),3.62-3.65
(m, 2H), 3.84 (s, 7H), 4.27-4.32 (m, 2H), 6.76-6.79 (m, 1H), 6.85-6.86 (m, 1H), 6.94 (d, J=
8.0Hz,1H),7.02-7.06(m,1H),8.14(s,1H),9.30(br s,1H)；13C NMR(CDCl3,100MHz)δ:
29.7,42.7,43.2,54.1,57.9,58.9,109.9,122.0,124.2,128.7,130.9,141.0,155.5,
168.1；HRMS(ESI-TOF)m/z:Calcd.for C18H20N4NaO3[M+Na]+:363.1433；Found:363.1430.
The present embodiment prepare compound 3c: white solid, yield 90%；>20:1dr；Fusing point: 144.4-145.8 DEG C.Core
The results such as magnetic resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3, 400MHz) and δ: 2.56 (s, 3H), 2.80 (d, J=
9.6Hz, 1H), 3.11-3.19 (m, 1H), 3.25 (d, J=9.6Hz, 1H), 3.78 (s, 7H), 4.30-4.35 (m, 1H), 4.74
(d, J=15.6Hz, 1H), 5.04 (d, J=15.6Hz, 1H), 6.53 (d, J=7.9Hz, 1H), 6.78-6.81 (m, 1H),
6.96-6.98(m,1H),7.19-7.22(m,3H),7.23-7.30(m,3H),8.12(s,1H)；13C NMR(CDCl3,
100MHz)δ:42.3,43.7,44.1,53.8,58.4,59.2,66.8,101.8,108.2,121.6,124.5,127.1,
127.5,127.8,128.7,136.0,142.6,154.8,168.3,180.0；HRMS(ESI-TOF)m/z:Calcd.for
C25H26N4NaO3[M+Na]+:453.1903；Found:453.1907.
The present embodiment prepare compound 3d: yellow solid, yield 87%；>20:1dr；Fusing point: 133.3-134.5 DEG C.Core
The results such as magnetic resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3, 400MHz) and δ: 2.51 (s, 3H), 2.89 (d, J=
9.6Hz, 1H), 3.11-3.14 (m, 1H), 3.32 (d, J=9.6Hz, 1H), 3.83-3.84 (m, 7H), 4.30-4.35 (m,
1H), 6.71 (d, J=8.1Hz, 1H), 6.84-6.86 (m, 1H), 7.01-7.02 (m, 1H), 7.26-7.27 (m, 1H), 7.38-
7.41(m,3H),7.48-7.52(m,2H),8.13(s,1H)；13C NMR(CDCl3,100MHz)δ:42.2,45.0,54.0,
58.9,59.2,66.8,101.8,108.6,122.0,124.6,125.8,127.5,127.7,129.3,130.9,134.8,
142.9,154.8,168.3,179.1；HRMS(ESI-TOF)m/z:Calcd.for C24H24N4NaO3[M+Na]+:
439.1746；Found:439.1747.
The present embodiment prepare compound 3e: yellow solid, yield 86%；>20:1dr；Fusing point: 152.5-154.0 DEG C.Core
The results such as magnetic resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3, 400MHz) and δ: 2.51 (s, 3H), 2.73 (d, J=
9.6Hz,1H),2.95-2.99(m,1H),3.09-3.13(m,1H),3.15(s,3H),3.74-3.77(m,1H),3.85(s,
6H), 4.22-4.26 (m, 1H), 6.52 (d, J=7.8Hz, 1H), 7.03-7.06 (m, 1H), 7.27-7.31 (m, 1H), 8.10
(s,1H)；13C NMR(CDCl3,100MHz)δ:26.3,42.0,44.7,53.9,58.6,58.7,65.8,101.7,107.8,
125.0,126.8,127.5,133.1,141.8,154.9,168.1,179.2；HRMS(ESI-TOF)m/z:Calcd.for
C19H21ClN4NaO3[M+Na]+:411.1200；Found:411.1202.
The present embodiment prepare compound 3f: yellow solid, yield 89%；>20:1dr；Fusing point: 146.5-148.4 DEG C.Core
The results such as magnetic resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3, 400MHz) and δ: 2.47 (s, 3H), 2.70 (d, J=
9.6Hz, 1H), 2.90-2.95 (m, 1H), 3.08 (d, J=9.5Hz, 1H), 3.12 (s, 3H), 3.71-3.74 (m, 1H), 3.83
(s, 6H), 4.18-4.22 (m, 1H), 6.46 (d, J=8.4Hz, 1H), 7.14-7.17 (m, 1H), 7.42 (d, J=4.0Hz,
1H),8.08(s,1H)；13C NMR(CDCl3,100MHz)δ:26.4,42.2,44.8,54.1,58.7,58.8,65.9,
101.8,108.5,114.3,127.9,130.6,133.6,142.4,155.0,168.2,179.2；HRMS(ESI-TOF)m/z:
Calcd.for C19H21BrN4NaO3[M+Na]+:455.0695；Found:455.0697.
The present embodiment prepare compound 3g: yellow solid, yield 80%；>20:1dr；Fusing point: 88.5-90.2 DEG C.Nuclear-magnetism
The results such as resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3,400MHz)δ:2.47-2.49(m,3H),2.73(d,J
=9.2Hz, 1H), 3.03-3.08 (m, 1H), 3.17 (d, J=9.6Hz, 1H), 3.70-3.73 (m, 1H), 3.75 (s, 6H),
4.25-4.30 (m, 1H), 5.25 (d, J=16.2Hz, 1H), 5.41 (d, J=16.2Hz, 1H), 6.68-6.73 (m, 1H),
6.92-6.95(m,1H),7.12-7.17(m,2H),7.22-7.26(m,4H),8.13(s,1H)；13C NMR(CDCl3,
100MHz)δ:42.3,44.7,44.8,53.9,58.2,59.2,67.6,101.9,114.5,122.6,123.4,126.5,
127.1,128.6,130.4,134.3,138.0,138.7,155.0,168.3,180.6；HRMS(ESI-TOF)m/z:
Calcd.for C25H25ClN4O3[M+Na]+:464.1615；Found:464.1617.
The present embodiment prepare compound 3h: yellow solid, yield 87%；19:1dr；Fusing point: 69.5-71.2 DEG C.Nuclear-magnetism is total
The results such as vibration and high resolution mass spectrum test are as follows:1H NMR(CDCl3, 400MHz) and δ: 2.91 (s, 3H), 2.80 (d, J=9.6Hz,
1H), 2.93-2.96 (m, 1H), 3.14 (d, J=9.4Hz, 1H), 3.78-3.80 (m, 7H), 4.35-4.39 (m, 1H), 4.77-
4.89 (m, 2H), 6.36 (d, J=7.8Hz, 1H), 6.90-6.97 (m, 1H), 7.07-7.10 (m, 2H), 7.24-7.28 (m,
4H),7.42-7.43(m,1H),8.13(s,1H)；13C NMR(CDCl3,100MHz)δ:42.2,43.9,44.2,54.0,
58.3,58.9,66.4,101.5,109.1,125.7,127.0,127.1,127.7,128.9,129.0,133.1,135.6,
141.2,155.2,168.3,168.4,179.1；HRMS(ESI-TOF)m/z:Calcd.for C25H25ClN4NaO3[M+Na]+:
487.1513；Found:487.1513.
The present embodiment prepare compound 3i: yellow solid, yield 84%；>20:1dr；Fusing point: 138.3-140.1 DEG C.Core
The results such as magnetic resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3,400MHz)δ:2.18(s,3H),2.56(s,3H),
2.81 (d, J=9.6Hz, 1H), 3.09-3.13 (m, 1H), 3.25 (d, J=9.6Hz, 1H), 3.78-3.80 (m, 7H), 4.30-
4.33 (m, 1H), 4.74 (d, J=15.6Hz, 1H), 4.99 (d, J=15.6Hz, 1H), 6.40 (d, J=7.9Hz, 1H),
6.75-6.78(m,1H),7.07(s,1H),7.17-7.19(m,2H),7.26-7.28(m,3H),8.12(s,1H)；13C NMR
(CDCl3,100MHz)δ:21.0,42.3,43.7,44.1,53.8,58.4,59.0,66.7,101.8,107.9,125.5,
127.0,127.4,128.0,128.6,130.9,136.1,140.2,154.8,168.3,179.9；HRMS(ESI-TOF)m/z:
Calcd.for C26H28N4NaO3[M+Na]+:467.2059；Found:467.2057.
The present embodiment prepare compound 3j: white solid, yield 90%；>20:1dr；Fusing point: 177.2-179.0 DEG C.Core
The results such as magnetic resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3,400MHz)δ:2.11(s,3H),2.51(s,3H),
2.75 (d, J=9.6Hz, 1H), 3.08-3.10 (m, 1H), 3.23 (d, J=9.4Hz, 1H), 3.73-3.76 (m, 1H), 3.78
(s, 6H), 4.28-4.32 (m, 1H), 5.02 (d, J=16.8Hz, 1H), 5.26-5.33 (m, 1H), 6.68-6.71 (m, 2H),
7.02-7.04(m,2H),7.18-7.19(m,1H),7.23-7.26(m,3H),8.11(s,1H)；13C NMR(CDCl3,
100MHz)δ:18.8,42.4,44.6,45.0,53.9,57.8,59.4,67.8,102.1,118.8,121.7,122.7,
125.7,125.8,125.9,127.1,128.9,129.0,131.8,131.9,138.2,140.7,154.8,168.4,
181.2；HRMS(ESI-TOF)m/z:C26H28N4NaO3[M+Na]+:467.2059；Found:467.2062.
The present embodiment prepare compound 3k: white solid, yield 80%；>20:1dr；Fusing point: 139.1-140.9 DEG C.Core
The results such as magnetic resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3,400MHz)δ:1.29-1.34(m,6H),2.50(s,
3H), 2.76 (d, J=9.2Hz, 1H), 3.01-3.02 (m, 1H), 3.19-3.21 (m, 1H), 3.79-3.84 (m, 1H), 4.10-
4.26 (m, 4H), 4.35-4.39 (m, 1H), 4.73 (d, J=15.6Hz, 1H), 5.01 (d, J=15.6Hz, 1H), 6.45 (d, J
=8.0Hz, 1H), 6.75-6.78 (m, 1H), 6.91-6.95 (m, 1H), 7.13-7.15 (m, 2H), 7.22-7.26 (m, 3H),
7.34 (d, J=11.2Hz, 1H), 8.05 (s, 1H)；13C NMR(CDCl3,100MHz)δ:14.6,42.2,43.7,44.2,
58.6,59.0,62.7,67.2,101.8,102.9,108.4,121.6,124.8,127.0,127.1,127.5,127.8,
128.8,131.4,136.1,142.7,154.9,168.1,180.0；HRMS(ESI-TOF)m/z:C27H30N4NaO3[M+Na]+:
481.2216；Found:481.2218.
The present embodiment prepare compound 3l: yellow solid, yield 82%；>20:1dr；Fusing point: 216.5-217.9 DEG C.Core
The results such as magnetic resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3,400MHz)δ:0.96-0.99(m,6H),1.73-
1.80(m,4H),2.48(s,3H),2.63-2.66(m,1H),3.13-3.15(m,1H),3.19-3.22(m,1H),3.74-
3.76(m,1H),4.10-4.19(m,4H),4.24-4.26(m,1H),6.73-6.77(m,2H),6.96-6.99(m,1H),
7.12 (d, J=7.8Hz, 1H), 8.02 (s, 1H), 9.16 (br s, 1H)；13C NMR(CDCl3,100MHz)δ:10.8,22.3,
34.0,42.2,44.4,51.9,58.7,68.6,103.0,109.4,121.6,124.4,127.9,131.5,141.0,
154.7,168.2,183.5；HRMS(ESI-TOF)m/z:C22H28N4NaO3[M+Na]+:419.2059；Found:419.2060.
The present embodiment prepare compound 3m: white solid, yield 80%；>20:1dr；Fusing point: 175.2-177.0 DEG C.Core
The results such as magnetic resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3,400MHz)δ:0.90-0.93(m,6H),1.41-
1.46 (m, 4H), 1.70-1.75 (m, 4H), 2.48 (s, 3H), 2.64 (d, J=8.4Hz, 1H), 3.09-3.14 (m, 1H),
3.17-3.21(m,1H),3.71-3.74(m,1H),4.11-4.18(m,3H),4.21-4.26(m,2H),6.72-6.75(m,
2H), 6.96-7.02 (m, 1H), 7.12 (d, J=8.1Hz, 1H), 8.03 (s, 1H), 8.72 (br s, 1H)；13C NMR
(CDCl3,100MHz)δ:13.9,19.4,31.0,34.0,42.2,44.5,51.9,58.7,66.8,103.0,109.2,
121.7,124.5,127.9,140.8,154.7,168.2,183.2；HRMS(ESI-TOF)m/z:C24H32N4NaO3[M+Na]+:
447.2372；Found:447.2375.
The present embodiment prepare compound 3n: white solid, yield 76%；>20:1dr；Fusing point: 182.7-184.7 DEG C.Core
The results such as magnetic resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3,400MHz)δ:0.88-0.90(m,12H),1.60-
1.68 (m, 4H), 1.70-1.77 (m, 2H), 2.47 (s, 3H), 2.63 (d, J=8.4Hz, 1H), 3.08-3.12 (m, 1H),
3.18 (d, J=8.1Hz, 1H), 3.69-3.72 (m, 1H), 4.13-4.18 (m, 2H), 4.23-4.31 (m, 3H), 6.73-6.78
(m,2H),6.97-6.99(m,1H),7.10-7.11(m,1H),8.03(s,1H),9.21(br s,1H)；13C NMR(CDCl3,
100MHz)δ:22.4,22.7,25.1,37.6,42.2,44.5,58.8,65.5,102.1,109.4,121.6,124.4,
127.9,131.7,141.0,154.7,168.2,183.6；HRMS(ESI-TOF)m/z:C26H36N4NaO3[M+Na]+:
475.2685；Found:475.2687.
The present embodiment prepare compound 3o: yellow solid, yield 88%；14:1dr；Fusing point: 134.2-136.1 DEG C.Nuclear-magnetism
The results such as resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3, 400MHz) and δ: 2.48 (s, 3H), 2.79 (d, J=
12.4Hz, 1H), 2.88-2.92 (m, 1H), 3.01 (d, J=12.4Hz, 1H), 3.53 (s, 3H), 3.77-3.82 (m, 1H),
3.92(s,3H),4.36-4.40(m,1H),6.68-6.72(m,1H),6.97-7.00(m,1H),7.21-7.25(m,1H),
8.19(s,1H)；13C NMR(CDCl3,100MHz)δ:30.0,41.9,48.4,54.7,58.4,58.6,66.6,115.1,
117.7,122.5,123.1,130.6,133.5,139.3,155.4,160.1,168.5,179.7；HRMS(ESI-TOF)m/z:
Calcd.for C18H18Cl2N4NaO2[M+Na]+:415.0705；Found:415.0707.
The present embodiment prepare compound 3p: yellow solid, yield 81%；17:1dr；Fusing point: 148.2-150.1 DEG C.Nuclear-magnetism
The results such as resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3,400MHz)δ:1.46-1.50(m,3H),2.43(s,
3H),2.77-2.80(m,2H),2.91-2.93(m,1H),3.09(s,3H),3.75-3.79(m,1H),4.34-4.45(m,
3H),6.47-6.51(m,1H),6.70-6.75(m,1H),7.15-7.21(m,1H),8.11(s,1H)；13C NMR(CDCl3,
100MHz)δ:14.3,26.7,41.6,48.2,58.2,59.2,63.8,65.9,107.9,112.6,112.9,114.2,
114.4,117.5,132.5,132.6,139.4,155.4,155.5,157.5,159.9,160.5,167.9,178.8；HRMS
(ESI-TOF)m/z:C19H20ClFN4NaO2[M+Na]+:413.1157；Found:413.1157.
The present embodiment prepare compound 3q: yellow solid, yield 79%；>20:1dr；Fusing point: 117.1-118.7 DEG C.Core
The results such as magnetic resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3,400MHz)δ:1.49-1.53(m,3H),2.49(s,
3H),2.85-2.89(m,2H),3.02-3.03(m,1H),3.81-3.84(m,1H),4.37-4.40(m,1H),4.46-4.53
(m, 2H), 4.68 (d, J=15.8Hz, 1H), 4.98 (d, J=16.0Hz, 1H), 6.41-6.43 (m, 1H), 6.63-6.66 (m,
1H),7.21-7.24(m,6H),8.19(s,1H)；13C NMR(CDCl3,100MHz)δ:14.3,41.7,44.4,47.9,
58.2,59.3,63.8,66.5,100.0,109.1,109.2,113.1,114.2,114.5,117.4,127.4,127.8,
128.8,128.9,132.5,135.4,138.6,155.5,157.4,159.8,160.7,167.9,168.0,178.8；HRMS
(ESI-TOF)m/z:C25H24ClFN4NaO2[M+Na]+:489.1470；Found:489.1474.
The present embodiment prepare compound 3r: yellow solid, yield 81%；18:1dr；Fusing point: 163.5-165.2 DEG C.Nuclear-magnetism
The results such as resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3,400MHz)δ:1.49-1.53(m,3H),2.52(s,
3H), 2.93-3.00 (m, 2H), 3.14 (d, J=9.2Hz, 1H), 3.87-3.91 (m, 1H), 4.39-4.54 (m, 3H), 6.63
(d, J=7.8Hz, 1H), 6.82-6.86 (m, 1H), 6.98-7.02 (m, 1H), 7.35-7.49 (m, 6H), 8.19 (s, 1H)；13C
NMR(CDCl3,100MHz)δ:14.3,41.9,48.6,58.6,59.1,63.8,66.9,109.1,117.9,122.2,
124.8,126.4,128.0,128.2,129.6,134.6,143.4,155.4,160.6,168.2,178.7；HRMS(ESI-
TOF)m/z:C24H23ClN4NaO2[M+Na]+:457.1407；Found:457.1409.
The present embodiment prepare compound 3s: yellow solid, yield 80%；>20:1dr；Fusing point: 114.5-116.2 DEG C.Core
The results such as magnetic resonance and high resolution mass spectrum test are as follows:1H NMR(CDCl3,400MHz)δ:2.49(s,3H),2.73-2.75(m,
1H),3.01-3.08(m,1H),3.19-3.23(m,1H),3.67-3.72(m,1H),3.73(s,6H),3.80(s,3H),
4.22-4.25 (m, 1H), 4.75 (d, J=15.8Hz, 1H), 4.96 (d, J=15.2Hz, 1H), 6.49 (d, J=7.8Hz,
1H),6.78-6.80(m,1H),6.93-6.95(m,1H),7.15-7.19(m,3H),7.21-7.26(m,4H)；13C NMR
(CDCl3,100MHz)δ:42.5,43.8,44.1,53.8,54.5,58.5,59.3,67.0,94.2,108.3,121.7,
124.8,127.1,127.2,127.3,127.5,127.8,128.8,136.2,142.7,162.5,169.9,180.3；HRMS
(ESI-TOF)m/z:C26H28N4NaO4[M+Na]+:483.2008；Found:483.2008.
The present embodiment prepare compound 3t: yellow solid, yield 75%；17:1dr；Fusing point: 88.3-89.8 DEG C.Nuclear-magnetism is total
The results such as vibration and high resolution mass spectrum test are as follows:1H NMR(CDCl3, 400MHz) and δ: 2.52 (s, 3H), 2.81 (d, J=7.8Hz,
1H), 2.93-2.96 (m, 1H), 3.17 (d, J=7.8Hz, 1H), 3.73-3.77 (m, 1H), 3.81 (s, 6H), 3.86 (s,
3H), 4.34-4.38 (m, 1H), 4.82-4.89 (m, 2H), 6.38 (d, J=7.2Hz, 1H), 6.93-6.94 (m, 1H), 7.10-
7.12(m,2H),7.24-7.28(m,3H),7.47-7.48(m,1H)；13C NMR(CDCl3,100MHz)δ:42.1,43.6,
43.9,53.8,54.4,58.1,58.8,66.2,93.7,108.9,125.7,126.7,126.8,126.9,127.4,127.5,
128.6,128.7,133.2,135.5,141.1,162.5,169.7,179.1；HRMS(ESI-TOF)m/z:C26H27ClN4NaO4
[M+Na]+:517.1619；Found:517.1621.
Formula (1) compound of the invention has important bioactivity, Human Prostate Cancer Cells (PC-3), human lung carcinoma cell
(A549) and the cell toxicity test of human leukemia cell (K562) totally three plants of tumour cells shows: shown in such formula (1)
Alcoxyl yl pyrimidines splicing 3- pyrroles's loop coil oxoindole derivative of structure is inhibited to growth of tumour cell, it is possible to
Develop into new prevention and treatment tumour medicine.But it is emphasized that the compound of the present invention is not limited to human lung carcinoma cell (A549), people
The cytotoxicity that prostate gland cancer cell (PC-3) and human leukemia cell (K562) indicate.
Pharmacological Examples 1: compound 3a-3t is to the cytotoxicity of PC-3 cell, but it is emphasized that chemical combination of the invention
Object is not limited to compound 3a-3t to the cytotoxicity of PC-3 (human prostata cancer).
The RPMI-1640 culture medium culture of PC-3 (human prostata cancer) cell contains 10% fetal calf serum in culture medium,
The streptomysin of 100U/mL penicillin and 100U/mL.Cell is added in 96 holes with the concentration of every 5000 cells in hole, at 37 DEG C
Containing 5%CO2It is cultivated 24 hours in the incubator of humid air.
The measurement of cell survival rate improvement mtt assay.Cell is after incubation in 24 hours, compound that will newly match respectively
The dimethyl sulphoxide solution of 3a-3t is added in each hole with concentration gradient, and making compound ultimate density in hole is respectively 5 μm of ol/
L, 10 μm of ol/L, 20 μm of ol/L, 40 μm of ol/L and 80 μm of ol/L.After 48 hours, the phosphorus of 10 μ L MTT (5mg/mL) is added in every hole
Phthalate buffer is further continued for after 37 DEG C are cultivated 4 hours, and centrifugation removes unconverted MTT in 5 minutes, and 150 μ L bis- are added in every hole
Methyl sulfoxide.With the MTT crystal formazan (formazan) of dissolving and reducing, OD value is measured in 490nm wavelength with microplate reader.Wherein change
Object 3a-3t is closed to PC-3 cell 503nhibiting concentration IC50It is obtained by spss software (19 version) analysis.Compound 3a-3t is to PC-3
The IC of tumour cell50To see Tables 1 and 2；And positive control cis-platinum is to the IC of PC-3 tumour cell50For 24.4 μm of ol/L.
Experiment conclusion: PC-3 cell is that the effective tool for the cytotoxicity for testing compound on tumor cell and evaluation refer to
Mark.This experiment shows the splicing 3- pyrroles's loop coil oxoindole derivative of alcoxyl yl pyrimidines shown in such formula (1) to PC-3 cell
With stronger cytotoxicity, part of compounds and the same order of magnitude of oncotherapy fiest-tire medication cis-platinum, it is possible to develop into new
The drug with antitumor action.
Pharmacological Examples 2: compound 3a-3t is to the cytotoxicity of A549 cell, but it is emphasized that chemical combination of the invention
Object is not limited to compound 3a-3t to the cytotoxicity of A549 cell.
A549 (Non-small cell lung carcinoma lung cancer) DMEM culture medium culture contains 10% fetal calf serum in culture medium,
The penicillin and 100U/mL streptomysin of 100U/mL.Cell is added in 96 holes with the concentration of every 4000 cells in hole, at 37 DEG C
Containing 5%CO2It is cultivated 24 hours in the incubator of humid air.
The measurement of cell survival rate improvement mtt assay.Specific method such as Pharmacological Examples 1.Compound 3a-3t is swollen to A549
The IC of oncocyte50To see Tables 1 and 2；And the positive according to cis-platinum to the IC of A549 tumour cell50For 28.1 μm of ol/L.
Experiment conclusion: A549 cell is that the effective tool for the cytotoxicity for testing compound on tumor cell and evaluation refer to
Mark.This experiment shows the splicing 3- pyrroles's loop coil oxoindole derivative of alcoxyl yl pyrimidines shown in such formula (1) to A549 cell
With stronger cytotoxicity, part of compounds and the same order of magnitude of oncotherapy fiest-tire medication cis-platinum, it is possible to develop into new
The drug with antitumor action.
Pharmacological Examples 3: compound 3a-3t is to the cytotoxicity of K562 cell, but it is emphasized that chemical combination of the invention
Object is not limited to compound 3a-3t to the cytotoxicity of A549 cell.
K562 (people's chronic myelogenous leukemia cell) RPMI-1640 culture medium culture contains 10% tire ox in culture medium
Serum, the penicillin and 100U/mL streptomysin of 100U/mL.Cell is added in 96 holes with the concentration of every 5000 cells in hole,
37 DEG C contain 5%CO2It is cultivated 24 hours in the incubator of humid air.
The measurement of cell survival rate improvement mtt assay.Specific method such as Pharmacological Examples 1.Compound 3a-3t is thin to K562
The IC of born of the same parents50To see Tables 1 and 2；And positive control cis-platinum is to the IC of K562 tumour cell50For 26.8 μm of ol/L.
Experiment conclusion: K562 cell is that the effective tool for the cytotoxicity for testing compound on tumor cell and evaluation refer to
Mark.This experiment shows the splicing 3- pyrroles's loop coil oxoindole derivative of alcoxyl yl pyrimidines shown in such formula (1) to K562 cell
With stronger cytotoxicity, part of compounds and the same order of magnitude of oncotherapy fiest-tire medication cis-platinum, it is possible to develop into new
The drug with antitumor action.
We can see that these compounds all show centainly this three plants of tumour cells from the above Pharmacological Examples
Cytotoxicity.But it is emphasized that the compound of the present invention is not limited to Human Prostate Cancer Cells (PC-3), human lung carcinoma cell
(A549) and human leukemia cell (K562) indicate cytotoxicity.It can be seen that these compounds, which have, is developed into antineoplastic
The potentiality of object are worth continuing deeper into research and.
Claims (5)
1. a kind of alcoxyl yl pyrimidines splice 3- pyrroles's loop coil oxoindole derivative, it is characterised in that: the compound has as logical
Structure shown in formula (I):
Specially such as one of flowering structure:
2. a kind of preparation method of alcoxyl yl pyrimidines splicing 3- pyrroles's loop coil oxoindole derivative as described in claim 1,
It is characterized by: various substituted alcoxyl yl pyrimidines splicing 3- ethylene linkage oxoindole derivatives and sarcosine and paraformaldehyde, are pressed
Molar ratio is that the ratio of 2:3:6 flows back in organic solvent, carries out 1,3- dipole 3+2 cycloaddition reaction, it is phonetic to obtain alkoxy
3- pyrroles's loop coil oxoindole derivative is spliced in pyridine.
3. the preparation method of alcoxyl yl pyrimidines splicing 3- pyrroles's loop coil oxoindole derivative according to claim 2,
Be characterized in that: the organic solvent is acetonitrile, methanol, ethyl alcohol, propyl alcohol, isopropanol, ether, tetrahydrofuran, benzene, toluene, two
Toluene, trimethylbenzene, dioxane, glycol dimethyl ether, isopropyl ether, chloroform, methylene chloride or nitrobenzene.
4. the preparation method of alcoxyl yl pyrimidines splicing 3- pyrroles's loop coil oxoindole derivative according to claim 2,
Be characterized in that: various substituted alcoxyl yl pyrimidines splicing 3- ethylene linkage oxoindole derivatives and sarcosine, paraformaldehyde, by mole
Than the ratio for 2:3:6, reaction temperature in organic solvent is 50-100 DEG C, and the reaction time is 5-20 hours.
5. a kind of alcoxyl yl pyrimidines splicing 3- pyrroles's loop coil oxoindole derivative as described in claim 1 prevents and treats people in preparation
Application in prostate cancer, human lung cancer and human leukemia drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610573327.7A CN106008532B (en) | 2016-07-20 | 2016-07-20 | Alcoxyl yl pyrimidines splice 3- pyrroles's loop coil oxoindole derivative and preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610573327.7A CN106008532B (en) | 2016-07-20 | 2016-07-20 | Alcoxyl yl pyrimidines splice 3- pyrroles's loop coil oxoindole derivative and preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106008532A CN106008532A (en) | 2016-10-12 |
| CN106008532B true CN106008532B (en) | 2019-06-07 |
Family
ID=57116750
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610573327.7A Active CN106008532B (en) | 2016-07-20 | 2016-07-20 | Alcoxyl yl pyrimidines splice 3- pyrroles's loop coil oxoindole derivative and preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106008532B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107935910B (en) * | 2017-11-23 | 2021-10-19 | 贵州大学 | Spliced 3-oxindole compound containing 1' -indanol and preparation method and application thereof |
| EP3511334A1 (en) * | 2018-01-16 | 2019-07-17 | Adamed sp. z o.o. | 1,2,3',5'-tetrahydro-2'h-spiro[indole-3,1'-pyrrolo[3,4-c]pyrrole]-2,3'-dione compounds as therapeutic agents activating tp53 |
| CN110305141B (en) * | 2019-07-18 | 2022-01-11 | 深圳市三启药物开发有限公司 | Spiro (3, 3' -isopropyl pyrrole alkoxylated indole) liver X receptor regulator and preparation method and application thereof |
| CN110330498B (en) * | 2019-07-18 | 2022-03-08 | 麻王医药(深圳)有限公司 | Spiro (3, 3' -phenylpyrrole alkoxylated indole) liver X receptor regulator and preparation method and application thereof |
| CN110680838B (en) * | 2019-11-21 | 2021-10-01 | 海门茂发美术图案设计有限公司 | Application of vegetarian calycanthine in resisting prostate cancer |
| CN114057755B (en) * | 2021-10-17 | 2022-08-30 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Preparation method and application of iridoid aglycone-based spiro indolone compound |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008144507A2 (en) * | 2007-05-16 | 2008-11-27 | President And Fellows Of Harvard College | Spirooxindole inhibitors of aurora kinase |
| WO2009023773A2 (en) * | 2007-08-15 | 2009-02-19 | University Of Miami | Galactokinase inhibitors |
| WO2009154697A2 (en) * | 2008-05-28 | 2009-12-23 | Massachusetts Institute Of Technology | Disc-1 pathway activators in the control of neurogenesis |
| WO2010075282A1 (en) * | 2008-12-22 | 2010-07-01 | University Of Washington | Molecular inhibitors of the wnt/beta-catenin pathway |
| CN104650096A (en) * | 2015-02-12 | 2015-05-27 | 贵州大学 | Compound containing isopentene ketone group five-membered ring pyrrole spiro ring oxoindole as well as preparation method and application of compound |
| CN105585570A (en) * | 2015-12-15 | 2016-05-18 | 贵州大学 | Isoxazole and pyrrolidinyl spirooxindole spliced compound and preparation method and application thereof |
| CN105693732A (en) * | 2016-01-20 | 2016-06-22 | 贵州大学 | Turmerone framework spliced 3-pyrrolespirooxindoles compound as well as preparation method and application of turmerone framework spliced 3-pyrrolespirooxindoles compound |
-
2016
- 2016-07-20 CN CN201610573327.7A patent/CN106008532B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008144507A2 (en) * | 2007-05-16 | 2008-11-27 | President And Fellows Of Harvard College | Spirooxindole inhibitors of aurora kinase |
| WO2009023773A2 (en) * | 2007-08-15 | 2009-02-19 | University Of Miami | Galactokinase inhibitors |
| WO2009154697A2 (en) * | 2008-05-28 | 2009-12-23 | Massachusetts Institute Of Technology | Disc-1 pathway activators in the control of neurogenesis |
| WO2010075282A1 (en) * | 2008-12-22 | 2010-07-01 | University Of Washington | Molecular inhibitors of the wnt/beta-catenin pathway |
| CN104650096A (en) * | 2015-02-12 | 2015-05-27 | 贵州大学 | Compound containing isopentene ketone group five-membered ring pyrrole spiro ring oxoindole as well as preparation method and application of compound |
| CN105585570A (en) * | 2015-12-15 | 2016-05-18 | 贵州大学 | Isoxazole and pyrrolidinyl spirooxindole spliced compound and preparation method and application thereof |
| CN105693732A (en) * | 2016-01-20 | 2016-06-22 | 贵州大学 | Turmerone framework spliced 3-pyrrolespirooxindoles compound as well as preparation method and application of turmerone framework spliced 3-pyrrolespirooxindoles compound |
Non-Patent Citations (2)
| Title |
|---|
| 3-取代氧化吲哚的合成及其抗肿瘤活性研究;黄璇 等;《贵州大学学报(自然科学版)》;20141231;第31卷(第6期);第34-37页 |
| A Library of Spirooxindoles Based on a Stereoselective Three-Component Coupling Reaction;Michael M.-C. Lo et al.;《J. AM. CHEM. SOC.》;20041119;第126卷;第16077-16086页 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106008532A (en) | 2016-10-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106008532B (en) | Alcoxyl yl pyrimidines splice 3- pyrroles's loop coil oxoindole derivative and preparation method and application | |
| CN103588771B (en) | There is the miazines antineoplastic compound of activity of hedgehog path antagonist | |
| Martín et al. | Isolation and first total synthesis of PM050489 and PM060184, two new marine anticancer compounds | |
| Liu et al. | Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors | |
| Chang et al. | Crambescidin 826 and dehydrocrambine A: new polycyclic guanidine alkaloids from the marine sponge Monanchora sp. that inhibit HIV-1 fusion | |
| CN105693732B (en) | Turmerone skeleton splices 3- pyrroles's loop coil oxidized indole compounds and preparation method and application | |
| Dofe et al. | Synthesis, antimicrobial evaluation, and molecular docking studies of novel chromone based 1, 2, 3-triazoles | |
| CN106866686A (en) | Isoxazole splices double volution Oxoindole compounds of 3,3 ' pyrroles and preparation method and application | |
| CN104276994B (en) | 3,3 ' disubstituted Oxoindoles and 3 ethylene linkage Oxoindoles splicing derivative and preparation method and application | |
| Bernal et al. | Synthesis and anticancer activity of new tetrahydroquinoline hybrid derivatives tethered to isoxazoline moiety | |
| CN107935910B (en) | Spliced 3-oxindole compound containing 1' -indanol and preparation method and application thereof | |
| CN107383030A (en) | Turmerone splices double loop coil Oxoindole compounds of 3,3 ' pyrroles and preparation method and application | |
| CN108676026A (en) | Main group metal complexes and its preparation with cancer cell killing power and application | |
| Xie et al. | The application of tandem Aza‐Wittig reaction to synthesize artemisinin–guanidine hybrids and their anti‐tumor activity | |
| Liu et al. | Synthesis, characterization and bioactivity determination of ferrocenyl urea derivatives | |
| Bold et al. | Synthesis of Morpholine‐Based Analogues of (−)‐Zampanolide and Their Biological Activity | |
| CN110156796A (en) | Isoxazole splices double loop coil Oxoindole compounds of 3,3 '-thio pyrrolinones and preparation method and application | |
| Dei et al. | Design and synthesis of aminoester heterodimers containing flavone or chromone moieties as modulators of P-glycoprotein-based multidrug resistance (MDR) | |
| Dobbelaar et al. | Povarov reactions of exo-glycals: preparation of C-linked, quinoline analogues | |
| Bashandy et al. | Design and synthesis of some novel hydrazide, 1, 2-dihydropyridine, chromene derivatives carrying biologically active sulfone moieties with potential anticancer activity | |
| Khaybullin et al. | Synthesis and anticancer evaluation of complex unsaturated isosteviol-derived triazole conjugates | |
| CN104825453A (en) | Application of cinchona alkaloid derivatives as cytotoxic compounds | |
| CN104059053B (en) | One class amide side chains contains synthesis and the application thereof of the naphthalimide derivative of 1,2,3-triazoles | |
| CN104693194B (en) | 3 (2 acrylate) 3 ˊ nitro isoxazole Oxoindole compounds and preparation method and application | |
| Fu et al. | Design, synthesis and antiproliferative evaluation of 3-aminopropyloxy derivatives of chalcone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |