CN107840818A - Fluorine-containing titanium dioxide benzazolyl compounds and its application - Google Patents
Fluorine-containing titanium dioxide benzazolyl compounds and its application Download PDFInfo
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- 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
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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Abstract
The invention belongs to technical field of medicine synthesis, specially fluorine-containing titanium dioxide benzazolyl compounds and its application.Wherein, the structural formula of fluorine-containing titanium dioxide benzazolyl compounds is as follows：
Description
Technical field
The invention belongs to technical field of medicine synthesis, specially fluorine-containing titanium dioxide benzazolyl compounds and its application.
Background technology
Prostate cancer refers to the epithelial malignancy in prostate occurs, and is most common pernicious swollen in male genetic
Knurl, fall ill with the age and increase, be only second to lung cancer, be second largest reason of the male because of cancer mortality.In the U.S., the forefront of male
Gland cancer neopathy rate account for first of all cancers of male, its fatal rate then occupy second；2012, China's tumour was stepped on
Remember regional prostate-cancer incidence for 9.92/10 ten thousand, the 6th of the row male malignancy incidence of disease.With other numerous tumours one
Sample, the direct pathogenic factor of prostate cancer are still not clear.But according to existing literature, one of most important factor is heredity.In addition not
Negligible is that extrinsic factor also plays very important effect in the pathogenic process of prostate cancer.In the last few years, with
The development of society, living standards of the people improve constantly, relatively past there occurs very big change in terms of dietary structure, along with population is old
Ageization and hormone is improper the reason such as uses, the prostate-cancer incidence cumulative year after year of Chinese male, causes the attention of the people.
At present, the method for treating prostate cancer mainly has：Radiotherapy, operative treatment, hormonotherapy and chemicals are treated
Method.Radiotherapy, operative treatment and hormonotherapy can play certain control action to prostate cancer, but generally not
It can effect a radical cure, conditions of patients may proceed to develop, deteriorate.Clinically, when above-mentioned three kinds for the treatment of method effects are undesirable, chemical drugs
Thing treatment just becomes the most important means for the treatment of prostate cancer.At present, the active medicine of clinical treatment prostate cancer only office
It is limited to the several drugses such as Docetaxel, Cabazitaxel.So Development of Novel low toxicity efficiently anti-prostate cancer active medicine just into
For a significant challenge of medicine research and development industry.
3- alkane alkenyl Oxoindoles and 3,3 '-two substitution Oxoindole structures are the core bones of many natural products and medicine
Frame.Such as：Sunitinib I are that a kind of tyrosine kinase inhibitor can be used to treat clear-cell carcinoma and gastrointestinal stromal tumors
(Eur.J.Org.Chem.,2010,4527–4547.)；MI-219VI is a kind of MDM2-P53 interaction inhibitors, for cancer
The treatment (Proc.Natl.Acad.Sci.U.S.A., 2008,105,3933-3938) of disease.In addition, introduced into organic molecule
Fluorine atom or fluoro-containing group tend to change chemistry, physics and the biological property of parent compound.At present to physiologically active molecule
Middle fluorine atom or the fluoro-containing group of introducing has turned into a Critical policies of new drug development.
In view of having now been found that a large amount of marine natural products contain titanium dioxide indole structure and with good anticancer etc.
Physiologically active (J.Org.Chem., 1988,53,3116-3118；J.Org.Chem.,1992,57,4772–
4775.Proc.Natl.Acad.Sci.U.S.A.,2007,104,2068–2073.).It is a kind of fluorine-containing it is therefore desirable to explore
Have 3- alkane alkenyl Oxoindoles and 3, the active anticancer of 3 '-two substitution Oxoindole structure class compounds, so as to for clinically concurrently
Treat prostate cancer and a kind of effective means is provided.
The content of the invention
The present invention is based on above technical problem, there is provided fluorine-containing titanium dioxide benzazolyl compounds, the compound have excellent suppression
System suppresses the effect of prostate carcinoma cell growth, can be used to treat in the medicine of prostate cancer disease by the compound, for clinic
Upper treatment prostate cancer provides may.
In order to realize above goal of the invention, concrete technical scheme of the invention is as follows：
Fluorine-containing titanium dioxide benzazolyl compounds, shown in its structural formula such as formula (I)：
Wherein, R1And R2It is former with alkyl, halogen on described phenyl ring for one kind in phenyl ring, alkyl and acyl group or its combination
Son, nitro, ester group, methoxyl group or hydroxyl substituent are substituted, and the position of substituent is ortho position, meta or para position.Described
Alkyl is methyl, ethyl, isopropyl, the tert-butyl group, pi-allyl or propargyl.Described acyl group is acetyl group, 2,2- dimethyl propylenes
Acyl group.3 in structure are chiral carbons, and it is configured as R configurations or S configurations.
Preferably, described fluorine-containing titanium dioxide benzazolyl compounds are specially：
Application of the above-described fluorine-containing titanium dioxide benzazolyl compounds in antiprostate cancer is prepared.The present invention passes through
External MTT antineoplastic activity evaluation finds that growth of the fluorine-containing titanium dioxide indoles to human prostate cancer cell line has significant suppression
Make and use, the IC50 values and positive drug taxol for there are three compounds approach.Best can be up to 8.49 μM.Therefore, Ji Gehan
Fluorodioxy indoles can be used to prepare antiprostate cancer, have good development prospect.
The positive effect of the present invention is embodied in：
(1), the purposes of the novel fluorine-containing titanium dioxide benzazolyl compounds of a class formation is provided.
(2), there is the effect of excellent suppression prostate carcinoma cell growth, available for the treatment of prostate cancer disease, be
Clinical treatment prostate cancer provides a kind of effective means.
Embodiment
The present invention is expanded on further with reference to specific embodiment and comparative example.It will be appreciated that these embodiments are only used for
Illustrate the present invention rather than limitation the scope of the present invention.It should also be understood that be, after the content of the invention lectured has been read,
Those skilled in the art can make various changes or modifications to the present invention, and these equivalent form of values equally fall within right appended by the application
Claim limited range.
The preparation method of involved fluorine-containing titanium dioxide benzazolyl compounds is referring to document (Liu Y.et in following examples
al.,2016.Synthesis of 3-Fluoroalkenyl-3-trifluoromethyl-2-oxindoles by the
Reaction of Indoline-2,3-diones with Difluoromethylene Phosphabetaine.
Chemical Communications 52(35),5969–5972.)。
Embodiment 1：
Compound 1- ethyls -3- ((1- ethyl -5- methoxyl group -2- indoline -3- subunits) fluoro ethyl -5- methoxyl groups -3-
The preparation of (trifluoromethyl) indol-2-one：
1- ethyl -5- Methoxv-indole quinolines -2,3- two is sequentially added into the there-necked flask of a dry oxygenless nitrogen protection
Ketone (2.05g, 10mmol), 2,2- bis- fluoro- 2- (triphenyl phosphorus base) acetate (1.96g, 10mmol), anhydrous N-methyl pyrroles
Alkanone 50ml, following reaction bottle are placed in 80 DEG C of oil bath and are sufficiently stirred.Reaction end is confirmed by thin-layered chromatography
Afterwards, reaction bulb is cooled to room temperature, adds appropriate aqueous solution quenching reaction, add ethyl acetate aqueous phase extracted, merge organic
Phase, organic phase are washed with the saturation NaCl aqueous solution, anhydrous sodium sulfate drying, filtering, rotary evaporation recycling design, residue post
Afterwards, yellow solid 1.89g, yield 79% are obtained.
mp 167–168℃；1H NMR(400MHz,CDCl3)δ7.39(s,1H),6.98(s,1H),6.97–6.88(m,
2H), 6.86 (d, J=8.5Hz, 1H), 6.67 (d, J=8.4Hz, 1H), 4.00 (td, J=13.7,6.7Hz, 1H), 3.84 (s,
3H), 3.79 (s, 3H), 3.75 (d, J=7.3Hz, 1H), 3.56 (d, J=7.0Hz, 2H), 1.39 (t, J=6.9Hz, 3H),
1.12 (t, J=6.9Hz, 3H)19F NMR(377MHz,CDCl3) δ -68.32 (s, 3F), -87.60 (q, J=20.8Hz, 1F)
.13C NMR (101MHz, CDCl3) δ 166.4 (d, J=6.2Hz), 164.0 (d, J=19.6Hz), 161.2,158.3,
155.9,155.5 (d, J=5.5Hz), 139.3,135.4,122.8 (qd, J=280.9,3.0Hz), 122.6,120.8,
115.5 (d, J=2.5Hz), 115.1,112.2,111.9 (d, J=13.7Hz), 108.9,108.4,61.3-59.9 (m),
56.0,55.8,36.1,34.4,12.6,12.3.IR(KBr)max 3061,2929,1728,1655,1491,1218,1176,
1030,811,687cm-1；MS(EI)m/z 478.1[M]+；HRMS(EI)m/z[M]+calcd for C24H22F4N2O4,
478.1516；Found,478.1510.
Embodiment 2：
The fluoro- 3- of compound 5- (fluorine (the fluoro- 2- oxos -1- Phenylindoles quinoline -3- subunits of 5-) methyl) -1- phenyl-(fluoroform
Base) indol-2-one preparation：
The fluoro- 1- Phenylindoles quinoline -2,3- diketone of 5- is sequentially added into the there-necked flask of a dry oxygenless nitrogen protection
(2.41g, 10mmol), 2,2- bis- fluoro- 2- (triphenyl phosphorus base) acetate (1.96g, 10mmol), anhydrous N-methyl pyrrolidines
Ketone 50ml, following reaction bottle are placed in 80 DEG C of oil bath and are sufficiently stirred.After confirming reaction end by thin-layered chromatography,
Reaction bulb is cooled to room temperature, appropriate aqueous solution quenching reaction is added, adds ethyl acetate aqueous phase extracted, merge organic phase,
Organic phase is washed with the saturation NaCl aqueous solution, anhydrous sodium sulfate drying, filtering, rotary evaporation recycling design, after residue post, is obtained
To yellow solid 1.73g, yield 63%.
mp 248–249℃；1H NMR(400MHz,CDCl3) δ 7.62 (d, J=8.2Hz, 1H), 7.58-7.53 (m, 4H),
7.48 (dd, J=14.3,7.2Hz, 3H), 7.39 (t, J=7.3Hz, 1H), 7.33-7.28 (m, 2H), 7.24 (d, J=
7.0Hz,1H),7.09–6.98(m,2H),6.79–6.71(m,2H).19F NMR(377MHz,CDCl3)δ-68.17(s,3F),-
84.83 (q, J=20.6Hz, 1F) ,-118.64-- 119.01 (m, 1F) ,-119.28-- 119.75 (m, 1F)13C NMR
(101MHz,CDCl3) δ 166.0 (d, J=4.5Hz), 163.9 (d, J=19.2Hz), 162.1,160.4 (d, J=3.9Hz),
159.2,158.0,143.1,138.5,133.9 (d, J=30.4Hz), 129.8,129.6,128.9,128.2,127.3,
126.4,122.7 (qd, J=284.5,2.8Hz), 120.6 (d, J=9.6Hz), 117.4 (d, J=23.3Hz), 116.7 (d, J
=24.0Hz), 113.3 (d, J=13.4Hz), 113.1,112.85,112.96,110.6 (d, J=7.9Hz), 110.1 (d, J
=8.1Hz), 61.3-60.57 (m) .IR (KBr) max 3063,2924,1749,1658,1606,1488,1364,1196,
817,747,695cm-1；MS(EI)m/z 550.1[M]+；HRMS(EI)m/z[M]+calcd for C30H16F6N2O2,
550.1116；Found,550.1119.
Embodiment 3：
Compound 1- benzyls -3- ((1- benzyl -2--oxindole quinoline -3- subunits) methyl fluoride) -3- (trifluoromethyl) indoles -
The preparation of 2- ketone：
Sequentially added into the there-necked flask of a dry oxygenless nitrogen protection 1- benzylindole quinoline -2,3- diketone (2.37g,
10mmol), bis- fluoro- 2- of 2,2- (triphenyl phosphorus base) acetate (1.96g, 10mmol), dry N-methylpyrrolidone 50ml,
Following reaction bottle is placed in 80 DEG C of oil bath and is sufficiently stirred.After confirming reaction end by thin-layered chromatography, it will react
Bottle is cooled to room temperature, adds appropriate aqueous solution quenching reaction, adds ethyl acetate aqueous phase extracted, merge organic phase, organic phase
Washed, anhydrous sodium sulfate drying, filtered, rotary evaporation recycling design with the saturation NaCl aqueous solution, after residue post, obtain yellow
Solid 1.98g, yield 73%.
mp 178–179℃；1H NMR(400MHz,CDCl3) δ 7.82 (d, J=7.5Hz, 1H), 7.47-7.42 (m, 3H),
7.38 (t, J=7.2Hz, 2H), 7.30 (dt, J=17.2,8.4Hz, 5H), 7.21 (t, J=7.8Hz, 1H), 7.16 (d, J=
7.1Hz, 2H), 7.10 (dd, J=14.1,7.0Hz, 2H), 6.83 (d, J=7.9Hz, 1H), 6.64 (d, J=7.8Hz, 1H),
5.57 (d, J=16.0Hz, 1H), 4.86 (d, J=15.9Hz, 1H), 4.70 (t, J=16.1Hz, 2H)19F NMR(377MHz,
CDCl3) δ -67.84 (s, 3F), -86.71 (q, J=20.3Hz, 1F)13C NMR(101MHz,CDCl3) δ 167.8 (d, J=
4.5Hz), 165.0 (d, J=20.1Hz), 161.8,158.9,146.2,141.4,135.5 (d, J=8.5Hz), 130.8,
130.0 (d, J=2.5Hz), 128.8,128.7,127.6 (d, J=4.1Hz), 127.2,127.1,125.5,125.3,
(124.8,123.1,123.0 q, J=285.9Hz), 122.7,121.4,120.0,113.8 (d, J=17.6Hz), 109.7,
109.1,61.5–60.3(m),45.5,43.5.IR(KBr)max 3060,2925,1740,1660,1607,1480,1353,
1252,1179,947,743,698cm-1；MS(EI)m/z 542.0[M]+；HRMS(EI)m/z[M]+calcd for
C32H22F4N2O2,542.1617；Found,542.1614.
Embodiment 4：
Compound 3- (fluorine (5- methyl -2- oxos -1- (2- propargyls) indoline -3- subunits) methyl) -5- methyl isophthalic acids -
The preparation of (2- propargyls) -3- (trifluoromethyl) indol-2-one：
Sequentially added into the there-necked flask of a dry oxygenless nitrogen protection 1- benzylindole quinoline -2,3- diketone (1.99g,
10mmol), bis- fluoro- 2- of 2,2- (triphenyl phosphorus base) acetate (1.96g, 10mmol), dry N-methylpyrrolidone 50ml,
Following reaction bottle is placed in 80 DEG C of oil bath and is sufficiently stirred.After confirming reaction end by thin-layered chromatography, it will react
Bottle is cooled to room temperature, adds appropriate aqueous solution quenching reaction, adds ethyl acetate aqueous phase extracted, merge organic phase, organic phase
Washed, anhydrous sodium sulfate drying, filtered, rotary evaporation recycling design with the saturation NaCl aqueous solution, after residue post, obtain yellow
Solid 2.03g, yield 74%.
mp 192–193℃；1H NMR(400MHz,CDCl3) δ 7.64 (s, 1H), 7.28 (d, J=7.9Hz, 1H), 7.22
(s, 1H), 7.16 (t, J=6.3Hz, 2H), 6.91 (d, J=7.9Hz, 1H), 4.96 (d, J=17.8Hz, 1H), 4.39-4.24
(m,3H),2.40(s,3H),2.35(s,4H),2.19(s,1H).19F NMR(377MHz,CDCl3)δ-68.07(s,3F),-
86.76 (q, J=20.3Hz, 1F)13C NMR(101MHz,CDCl3) δ 166.5 (d, J=4.2Hz), 163.86 (d, J=
20.4Hz), 161.5,158.6,142.6,138.2,133.2,132.6,131.4,130.4 (d, J=2.7Hz), 126.1 (d, J
=13.5Hz), 125.6,122.74 (qd, J=283.0,2.6Hz), 121.1,119.9 (d, J=1.4Hz), 113.7 (d, J=
17.9Hz),109.4,108.9,76.7,72.8,72.5,60.89–60.10(m),30.8,29.0,21.2,21.0.IR
(KBr)max 3297,2922,1742,1660,1610,1494,1433,1343,1194,966,811,667cm-1；MS(EI)m/z
466.0[M]+；HRMS(EI)m/z[M]+calcd for C26H18F4N2O2,466.1304；Found,466.1308.
Embodiment 5：
Pressed down using a kind of growth of the mtt assay evaluation fluorine-containing titanium dioxide benzazolyl compounds of compound to human prostate cancer cell line
Make and use.
Its pharmaceutical activity is further illustrated below by pharmacodynamic experiment.
Subject cell：PC-3
Experiment material：10% hyclone：GIBCO；RPMI-1640：GIBCO；MTT cleans nutrient solution and positive drug Japanese yew
Alcohol：sigma
Method：In 5%CO2With 37 DEG C, cultivate in RPMI-1640 (GIBCO) culture medium of 10% hyclone (GIBCO)
Cancer cell.100 μ l cells are planted in 96 orifice plates with 3 × 10 4 cell/ml concentration.Previously prepared debita spissitudo
The compound of (6.25,12.5,25,50, or 100 μm of ol L-1), and each hole (every kind of concentration compound was added at second day
Four repeating holes), while update culture medium (culture medium be 90 μ l relative to the volume species of compound：10μl).48 hours
Afterwards, nutrient solution is cleaned with 90 μ lRPMI-1640 culture mediums and 10 μ l5mg/ml MTT, to avoid the interference of compound and serum.
Flat board is incubated under the conditions of original 4 hours, then carefully takes out culture medium, and 150 μ lDMSO are added in each hole, in room
The lower dissolving crystal of temperature 10 minutes.96 orifice plates are finally transferred to reader and measure the absorbance at 490nm.Pass through GraphPad
The softwares of Prism 5 calculate IC50 values.
As a result：Representative compound Activity Results are as shown in the table
Table：Fluorine-containing titanium dioxide benzazolyl compounds compound suppresses the growth activity of human prostate cancer cell line
Note：Taxol is positive drug.
Conclusion：
1) IC50 that positive drug taxol suppresses Human Prostate Cancer Cells growth is 13.9 μM
2) activity of test-compound 8,18,19 and 31 approaches with positive drug.
Example described above is only the preferred embodiment of this patent, but the protection domain of this patent is not limited thereto.
It should be pointed out that for those skilled in the art, on the premise of this patent principle is not departed from, according to this specially
The technical scheme and its inventional idea of profit, can also make some improvements and modifications, and these improvements and modifications also should be regarded as this specially
The protection domain of profit.
Claims (6)
1. fluorine-containing titanium dioxide benzazolyl compounds, it is characterised in that：Shown in its structural formula such as formula (I)：
Wherein, R1And R2For one kind in phenyl ring, alkyl and acyl group or its combination, described phenyl ring alkyl, halogen atom, nitro,
Ester group, methoxyl group or hydroxyl substituent are substituted, and the position of substituent is ortho position, meta or para position.
2. fluorine-containing titanium dioxide benzazolyl compounds according to claim 1, it is characterised in that：Described alkyl is methyl, second
Base, isopropyl, the tert-butyl group, pi-allyl or propargyl.
3. fluorine-containing titanium dioxide benzazolyl compounds according to claim 1, it is characterised in that：Described acyl group be acetyl group or
2,2- Dimethylpropanoyls.
4. fluorine-containing titanium dioxide benzazolyl compounds according to claim 1, it is characterised in that：3 in the structure are hands
Property carbon, it is configured as R configurations or S configurations.
5. the fluorine-containing titanium dioxide benzazolyl compounds as described in any one claim in Claims 1-4, it is characterised in that should
Compound is：
6. as described in any one claim in claim 1 to claim 4 prepared by fluorine-containing titanium dioxide benzazolyl compounds
Application in antiprostate cancer.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1247803A2 (en) * | 1996-08-23 | 2002-10-09 | Sugen, Inc. | Indolinone compounds suitable for modulation of protein kinases |
| CN105481752A (en) * | 2015-12-16 | 2016-04-13 | 四川理工学院 | Preparation method for 3-fluoro alkenyl oxoindole-spiro-3,3'-trifluoromethyl oxoindole compounds |
-
2017
- 2017-11-28 CN CN201711210798.2A patent/CN107840818A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1247803A2 (en) * | 1996-08-23 | 2002-10-09 | Sugen, Inc. | Indolinone compounds suitable for modulation of protein kinases |
| CN105481752A (en) * | 2015-12-16 | 2016-04-13 | 四川理工学院 | Preparation method for 3-fluoro alkenyl oxoindole-spiro-3,3'-trifluoromethyl oxoindole compounds |
Non-Patent Citations (2)
| Title |
|---|
| YINGLE LIU ET AL.: "Synthesis of 3-fluoroalkenyl-3-trifluoromethyl-2-oxindoles by the reaction of indoline-2,3-diones with difluoromethylene phosphabetaine", 《CHEM.COMM.》 * |
| YINGLE LIU ET AL.: "Synthesis of 3-fluoroalkenyl-3-trifluoromethyl-2-oxindoles by the reaction of indoline-2,3-diones", 《CHEM.COMM.》 * |
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Application publication date: 20180327 |