CN101250189B - Bisfatty amido substituted quinazolone derivatives as well as preparation method and use thereof as anti-cancer drugs - Google Patents
Bisfatty amido substituted quinazolone derivatives as well as preparation method and use thereof as anti-cancer drugs Download PDFInfo
- Publication number
- CN101250189B CN101250189B CN2008100270043A CN200810027004A CN101250189B CN 101250189 B CN101250189 B CN 101250189B CN 2008100270043 A CN2008100270043 A CN 2008100270043A CN 200810027004 A CN200810027004 A CN 200810027004A CN 101250189 B CN101250189 B CN 101250189B
- Authority
- CN
- China
- Prior art keywords
- reaction
- preparation
- fat
- hours
- quinzolone derivatives
- 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.)
- Expired - Fee Related
Links
Abstract
The invention discloses a dual fatty ammonia substituted quinazolinone derivative, represented as formula (I), wherein n is 1, 2, 3, 4 or 5, R1 and R2 are same or different, selected from the alkyl ofH and C1-6, and naphthenic group, piperidyl, morpholinyl, piperazinyl or quinoxaline of C3-6. The derivative has strong interaction on the telomere DNA rich with guanine and c-myc DNA of proto-oncogene, strong inhibition on telomere/telomerase of cancer cell and strong inhibition on the c-myc expression of proto-oncogene. The derivative has low toxicity and side effect, which can be developed toa new anti-tumor drug. The derivative has simple preparation method, cheap materials and strong inhibition on various cancer cell lines, which can be prepared into anti-tumor drug, with wide application.
Description
Technical field
The present invention relates to oxadiazole derivatives as comt inhibitors, be specifically related to a kind of pair of fat amido and replace Quinzolone derivatives and preparation method thereof and application as cancer therapy drug.
Background technology
Cancer is one of principal disease that threatens human health and life security.The research and development of cancer therapy drug are the focuses that chemist and medicine scholar pay close attention to always.Seek efficient, highly selective, cancer therapy drug that toxic side effect is little is one of important directions of drug development research.
Synthesizing cancer therapy drug for target spot designs with DNA, at the special higher structure design synthesized micromolecule inhibitor of telomeric dna with important physiological significance and proto-oncogene DNA, is the important method of development new type anticancer medicine particularly.With telomeric dna, and the interactional micromolecular compound of proto-oncogene c-myc DNA has some common constitutional featuress: the almost plane aromatic ring structure with three or more; Article one, or several under physiological condition with the side chain of lotus on schedule.Their antitumous effect mechanism mainly is by interacting the telomerase activation of anticancer, or c-myc expression of gene, thereby the propagation of anticancer with telomeric dna or proto-oncogene c-myc DNA.
Quinazolone is a kind of alkaloid, is the effective constituent in the Root of Indigowoad.Quinazolone has good anti-inflammatory action, and certain antitumour activity is also arranged.But quinazolone itself interacts very weak with telomeric dna or proto-oncogene c-myc DNA.Therefore, be that structure of modification is carried out on the basis with the parent nucleus of quinazolone, be a feasible way of finding to have better antitumour activity lead compound.
Have not yet to see the report that relevant two fat amido replaces Quinzolone derivatives and anticancer function thereof.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, the two fatty amido that provides a class to have antitumour activity replaces Quinzolone derivatives.This derivative has very strong interaction with the telomeric dna and the proto-oncogene c-myc DNA that are rich in guanine.
Another object of the present invention is to provide the preparation method of above-mentioned Quinzolone derivatives.
Another object of the present invention is to provide the application of above-mentioned Quinzolone derivatives in the preparation cancer therapy drug.
Above-mentioned purpose of the present invention is achieved by the following technical programs:
The present invention is according to the constitutional features of some and telomeric dna or the interactional micromolecular compound of c-myc DNA, under the situation that keeps the quinazolone precursor skeleton, different positions is introduced two fat amido side chains, obtain having a very class isaindigotone derivative of strong interaction with telomeric dna or proto-oncogene c-myc DNA, we are called two fat amidos and replace the quinazolone analog derivative, and this pair fat amido replaces the chemical formula of Quinzolone derivatives suc as formula shown in (I):
Wherein, n=1,2,3,4 or 5;
R
1, R
2Can be identical, also can be different, be selected from H, C respectively
1-6Alkyl, C
3-6Cycloalkyl, piperidyl, morpholinyl, piperazinyl, Bi Evil quinoline base.
The preparation method of above-mentioned pair of fat amido replacement Quinzolone derivatives is as follows:
(4)
Carry out substitution reaction with substituted amine compound, products therefrom is two fat amidos and replaces Quinzolone derivatives.
Flow process is as follows:
In the above-mentioned steps (4), the molecular formula of substituted amine compound is R
1-NH-R
2, R
1-NH
2Or R
2-NH
2, R wherein
1, R
2Can be identical, also can be different, be selected from H, C respectively
1-6Alkyl, C
3-6Cycloalkyl, piperidyl, morpholinyl, piperazinyl, Bi Evil quinoline base.
In the above-mentioned steps (1),
With the molar ratio of pyrrolidone be 2: 1; The ring closure reaction solvent is a toluene; The catalyzer of ring closure reaction is a phosphorus oxychloride; The temperature of reaction of ring closure reaction is 40 ℃~110 ℃, and the reaction times is 5~12 hours.
In the above-mentioned steps (2),
With
The molar ratio of reaction is 1: 8~10; The condensation reaction solvent is a diacetyl oxide; The reaction times of condensation reaction is 24~32 hours; The reduction reaction solvent is an ethanol; The reductive agent of reduction reaction is nine water cure sodium; The reduction reaction time is 4~8 hours.
In the above-mentioned steps (3),
With Cl (CH
2)
nThe molar ratio of COCl reaction is 1: 10~1: 20; The alkylated reaction time is 3~6 hours.
In the above-mentioned steps (4),
The molar ratio that reacts with substituted amine compound is 1: 10; The substitution reaction solvent is an ethanol; Reaction times is 2~3 hours.
The of the present invention pair of fat amido replaces Quinzolone derivatives and acceptable auxiliary agent combined preparation cancer therapy drug pharmaceutically, and cancer therapy drug is tablet, pill, capsule, injection, suspension agent or emulsion etc.
Compared with prior art, the present invention has following beneficial effect: 1. of the present invention pair of fat amido replaces Quinzolone derivatives and has very strong interaction with the telomeric dna and the proto-oncogene c-myc DNA that are rich in guanine, telomere/Telomerase in the cancer cells is had the good restraining activity, the expression of proto-oncogene c-myc is had very strong restraining effect; 2. the present invention as lead compound, carries out structural modification with the quinazolone mother nucleus structure, and the two fat amidos that obtain replace Quinzolone derivatives and have good antitumor activity and lower toxic side effect, have the prospect that develops into the new type anticancer medicine; 3. of the present invention pair of fat amido replaces Quinzolone derivatives, and its preparation method is simple, and raw material is inexpensive, and multiple JEG-3 is had significant inhibitory effect, is prepared as cancer therapy drug, has the very big market space.
Embodiment
Synthesizing of embodiment 1 compound 2
0.01mol exsiccant 4-nitro-2-benzaminic acid and 0.005mol pyrrolidone are dissolved in the 250ml toluene, drip the phosphorus oxychloride of 2ml under the room temperature, be warming up to 110 ℃ and under this temperature, reacted 5~12 hours.Reaction solution is slowly poured in the frozen water, regulates pH=7, and suction filtration gets the yellow solid powder, the crude product acetone recrystallization, and getting the light yellow solid powder is compound 2, its chemical formula is suc as formula shown in (IIa):
Productive rate: 60%;
1H-NMR (300MHz, CDCl
3) δ (ppm): 2.30-2.40 (m, 2H); 3.23 (t, J=7.8Hz, 2H); 4.24 (t, J=7.2Hz, 2H); 8.17 (dd, J=8.7,2.1Hz, 1H); 8.40 (d, J=8.7Hz, 1H); 8.45 (d, J=2.1Hz, 1H); ESI-MS m/z:232[M+H]
+.
Synthesizing of embodiment 2 compounds 2
Method is with embodiment 1, and different is that getting faint yellow solid is compound 2 with 5-nitro-2-aminobenzoic acid substitution 4-nitro-2-benzaminic acid, and its chemical formula is suc as formula shown in (IIb):
Productive rate: 65%;
1H-NMR (300MHz, CDCl
3) δ (ppm): 2.29-2.40 (m, 2H); 3.23 (t, J=7.8Hz, 2H); 4.24 (t, J=7.2Hz, 2H); 7.72 (d, J=8.7Hz, 1H); 8.48 (dd, J=8.7,2.7Hz, 1H); 9.11 (d, J=2.7Hz, 1H); ESI-MS m/z:232[M+H]
+.
Synthesizing of embodiment 3 compounds 3
In molar ratio, the compound 2 of 0.001mol embodiment 1 preparation and the 4-nitrobenzaldehyde of 8~10 times of amounts are dissolved in the 10ml diacetyl oxide, back flow reaction 24~32 hours is cooled to room temperature, and suction filtration, solid are with ethanol, chloroform, washing with acetone repeatedly.The intermediate product that obtains is dissolved in 10ml ethanol and is heated to backflow nearly, past adding is dissolved with the 16ml aqueous solution of 0.004mol nine water cure sodium and 0.01mol sodium hydroxide, refluxes 4~8 hours, is cooled to room temperature, standing over night.Rotary evaporation falls ethanol, and cooling is put 0~5 ℃ more afterwards, and suction filtration obtains the thick product of garnet after the washing repeatedly.Thick product ethanol/acetone recrystallization, getting orange red solid is compound 3, its chemical formula is suc as formula shown in (IIIa):
Productive rate: 60%;
1H-NMR (500MHz, DMSO-d
6) δ (ppm): 3.11-3.14 (m, 2H); 4.05 (t, J=7.5Hz, 2H); 5.64 (br s, 2H); 5.95 (br s, 2H); 6.62-6.66 (m, 4H); 7.34 (d, J=8.5Hz, 2H); 7.48 (br s, 1H); 7.75 (d, J=8.5Hz, 1H); ESI-MS m/z:305[M+H]
+.
Synthesizing of embodiment 4 compounds 3
Method is with embodiment 3, and different is the compound 2 that replaces embodiment 1 preparation with the compound 2 of embodiment 2 preparations, and getting orange red solid is compound 3, and its chemical formula is suc as formula shown in (IIIb):
Productive rate: 62%;
1H-NMR (500MHz, DMSO-d
6) δ (ppm): 3.13-3.16 (m, 2H); 4.11 (t, J=7.5Hz, 2H); 5.56 (br s, 4H); 6.64 (d, J=8.5Hz, 2H); 7.07 (dd, J=8.5,2.5Hz, 1H); 7.22 (d, J=2.5Hz, 1H); 7.31 (d, J=8.5Hz, 2H); 7.40 (d, J=8.5Hz, 1H); 7.42 (br s, 1H); ESI-MS m/z:305[M+H]
+.
Synthesizing of embodiment 5 compounds 4
The compound 3 of 0.005mol embodiment 3 preparations is suspended in the 3-chlorpromazine chloride of 10ml, back flow reaction 3~6 hours, after reaction is finished, cooling is put 0~5 ℃, suction filtration, solid washs 2 times with ether, crude product DMF/ ethyl alcohol recrystallization, get yellow solid and be compound 4, its chemical formula is suc as formula shown in (IVa):
Productive rate: 75%;
1H-NMR (300MHz, DMS0-d
6) δ (ppm): 2.84-2.93 (m, 4H); 3.23-3.27 (m, 2H); 3.87-3.94 (m, 4H); 4.16 (t, J=6.6Hz, 2H); 7.53 (dd, J=8.7,2.1Hz, 1H); 7.63 (d, J=8.7Hz, 2H); 7.70 (br s, 1H); 7.73 (d, J=8.7Hz, 2H); 8.05 (d, J=8.7Hz, 1H); 8.14 (d, J=2.1Hz, 1H); 10.34 (br s, 1H); 10.55 (br s, 1H); ESI-MS m/z:485[M-H]
-.
Synthesizing of embodiment 6 compounds 4
Method is with embodiment 5, and different is the compound 3 that replaces embodiment 3 preparations with the compound 3 of embodiment 4 preparations, gets orange/yellow solid and is compound 4, and its chemical formula is suc as formula shown in (IVb):
Productive rate: 66%;
1H-NMR (300MHz, DMSO-d
6) δ (ppm): 2.84-2.90 (m, 4H); 3.24-3.29 (m, 2H); 3.87-3.93 (m, 4H); 4.20 (t, J=7.1Hz, 2H); 7.61 (d, J=9Hz, 2H); 7.72-7.76 (m, 4H); (7.96 dd, J=8.7,2.4Hz 1H); 8.50 (d, J=2.4Hz, 1H); 10.36 (br s, 1H); 10.49 (br s, 1H); ESI-MS m/z:519[M+Cl]
-.
Synthesizing of embodiment 7 compounds 4
Method is with embodiment 5, and different is to replace the 3-chlorpromazine chloride with the 2-chloroacetyl chloride, and getting orange/yellow solid is compound 4, and its chemical formula is suc as formula shown in (IVc):
Productive rate: 77%;
1H-NMR (300MHz, DMSO-d
6) δ (ppm): 3.24-3.28 (m, 2H); 4.19 (t, J=6.9Hz, 2H); 4.31 (s, 2H); 4.37 (s, 2H); 7.60-7.66 (m, 3H); 7.75 (d, J=8.7Hz, 2H); 7.94 (br s, 1H); 8.08 (d, J=8.7Hz, 1H); 8.23 (d, J=1.8Hz, 1H); 10.71 (br s, 1H); 11.03 (br s, 1H); ESI-MS m/z:491[M+Cl]
-.
Synthesizing of embodiment 8 compounds 4
Method is with embodiment 5, and different is the compound 3 that replaces embodiment 3 preparations with the compound 3 that embodiment 4 prepares, and replaces the 3-chlorpromazine chloride with the 2-chloroacetyl chloride, and getting orange/yellow solid is compound 4, and its chemical formula is suc as formula shown in (IVd):
Productive rate: 75%;
1H-NMR (300MHz, DMS0-d
6) δ (ppm): 3.24-3.27 (m, 2H); 4.20 (t, J=6.9Hz, 2H); 4.30 (s, 2H); 4.31 (s, 2H); 7.61 (d, J=8.7Hz, 2H); 7.73 (d, J=8.7Hz, 2H); 7.80 (d, J=9Hz, 1H); 7.88 (br s, 1H); 796 (dd, J=9,2.4Hz 1H); 8.47 (d, J=2.4Hz, 1H); 10.68 (br s, 1H); 10.83 (br s, 1H); ESI-MS m/z:491[M+Cl]
-.
9 pairs of fat amidos of embodiment replace the synthetic of Quinzolone derivatives
The compound 4 of embodiment 5 preparation of 0.0005mol is suspended in the 10ml ethanol with 50mg KI, past dropping 1.6ml is dissolved with 0.005mol pyrroles's ethanol, back flow reaction 2~3 hours, be cooled to 0 ℃, suction filtration, the crude product ethyl alcohol recrystallization obtains yellow solid powder compounds 5 promptly two fat amidos and replaces Quinzolone derivatives, and its chemical formula is suc as formula shown in (Ia):
Productive rate: 70%;
1H-NMR (300MHz, CDCl
3) δ (ppm): 1.95-1.98 (m, 8H); 2.59-2.64 (m, 4H); 2.64-2.80 (m, 8H); 2.90-2.94 (m, 4H); 3.27-3.32 (m, 2H); 4.29 (t, J=6.9Hz, 2H); 7.52 (d, J=8.7Hz, 2H); 7.59 (d, J=8.7Hz, 2H); 7.68 (dd, J=8.7,2.1Hz, 1H); 7.78 (d, J=2.1Hz, 1H); 7.80 (t, J=2.4Hz, 1H); 8.22 (d, J=8.7Hz, 1H); 11.45 (br s, 1H); 11.64 (br s, 1H); ESI-MS m/z:555[M+H]
+Ultimate analysis (hydrochloride): C
32H
38N
6O
33HCl3.5H
2O, theoretical value C, 52.86; H, 6.65; N, 11.56. measured value C, 52.83; H, 6.59; N, 11.60.
10 pairs of fat amidos of embodiment replace the synthetic of Quinzolone derivatives
Method is with embodiment 9, and different is the compound 4 that replaces embodiment 5 preparations with the compound 4 of embodiment 6 preparations, and product is that yellow solid powder compounds 5 promptly two fat amidos replace Quinzolone derivatives, and its chemical formula is suc as formula shown in (Ib):
Productive rate: 66%;
1H-NMR (300MHz, CDCl
3) δ (ppm): 1.91-1.92 (m, 8H); 2.53-2.59 (m, 4H); 2.65-2.75 (m, 8H); 2.84-2.89 (m, 4H); 3.24-3.30 (m, 2H); 4.27 (t, J=6.9Hz, 2H); 7.49 (d, J=9Hz, 2H); 7.55 (d, J=9Hz, 2H); (7.68 d, J=9Hz 1H); 7.74 (t, J=2.7Hz, 1H); 8.02 (d, J=2.4Hz, 1H); 8.20 (dd, J=9,2.4Hz, 1H); 11.49 (br s, 1H); 11.53 (br s, 1H); ESI-MS m/z:555[M+H]
+Ultimate analysis (hydrochloride): C
32H
38N
6O
33HCl1.5H
2O, theoretical value C, 55.61; H, 6.42; N, 12.16. measured value C, 55.83; H, 6.59; N, 11.96.
11 pairs of fat amidos of embodiment replace the synthetic of Quinzolone derivatives
Method is with embodiment 9, and different is to replace the pyrroles with piperidines, and product is a yellow solid powder compounds 5, and promptly two fat amidos replace Quinzolone derivatives, and its chemical formula is suc as formula shown in (Ic):
Productive rate: 68%;
1H-NMR (300MHz, CDCl
3) δ (ppm): 1.50-1.63 (m, 4H); 1.71-1.76 (m, 8H); 2.52-2.58 (m, 12H); 2.67-2.71 (m, 4H); 3.25-3.30 (m, 2H); 4.26 (t, J=7.2Hz, 2H); 7.51 (d, J=8.4Hz, 2H); 7.62 (d, J=8.7Hz, 2H); 7.64 (dd, J=8.7,1.8Hz, 1H); 7.79 (br s, 1H); 7.86 (d, J=1.8Hz, 1H); 8.20 (d, J=8.7Hz, 1H); 11.58 (br s, 1H); 11.70 (br s, 1H); ESI-MS m/z:583[M+H]
+Ultimate analysis (hydrochloride): C
34H
42N
6O
3.3HCl5H
2O, theoretical value C, 52.21; H, 7.09; N, 10.74. measured value C, C, 52.14; H, 6.95; N, 10.72.
12 pairs of fat amidos of embodiment replace the synthetic of Quinzolone derivatives
Method is with embodiment 9, different is the compound 4 that replaces embodiment 5 preparations with the compound 4 of embodiment 6 preparations, replace the pyrroles with piperidines, product is that yellow solid powder compounds 5 promptly two fat amidos replace Quinzolone derivatives, and its chemical formula is suc as formula shown in (Id):
Productive rate: 65%;
1H-NMR (300MHz, CDCl
3) δ (ppm): 1.60-1.61 (m, 4H); 1.74-1.79 (m, 8H); 2.54-2.60 (m, 12H); 2.69-2.74 (m, 4H); 3.28-3.33 (m, 2H); 4.30 (t, J=7.2Hz, 2H); 7.53 (d, J=8.7Hz, 2H); 7.64 (d, J=8.7Hz, 2H); (7.72 d, J=9Hz 1H); 7.77 (br s, 1H); 8.13 (d, J=2.4Hz, 1H); 8.26 (dd, J=9,2.4Hz, 1H); 11.59 (br s, 1H); 11.69 (br s, 1H); ESI-MS m/z:583[M+H]
+Ultimate analysis (hydrochloride): C
34H
42N
6O
33HCl.4H
2O, theoretical value C, 53.44; H, 6.99; N, 11.00. measured value C, 53.69; H, 7.13; N, 11.03.
Embodiment 13: two fat amidos replace the synthetic of Quinzolone derivatives
Method is with embodiment 9, and different is the compound 4 that replaces embodiment 5 preparations with the compound 4 of embodiment 7 preparations, and product is a yellow solid powder compounds 5, and promptly two fat amidos replace Quinzolone derivatives, and its chemical formula is suc as formula shown in (Ie):
Productive rate: 62%;
1H-NMR (300MHz, CDCl
3) δ (ppm): 1.87-1.93 (m, 8H); 2.72-2.78 (m, 8H); 3.28-3.34 (m, 2H); 3.34 (s, 2H); 3.36 (s, 2H); 4.30 (t, J=7.2Hz, 2H); 7.55 (d, J=8.7Hz, 2H); 7.69 (d, J=8.7Hz, 2H); 7.72 (dd, J=8.7,1.8Hz, 1H); 7.81 (t, J=2.4Hz, 1H); 7.93 (d, J=1.8Hz, 1H); 8.25 (d, J=8.7Hz, 1H); 9.28 (br s, 1H); 9.48 (br s, 1H); ESI-MSm/z:527[M+H]
+Ultimate analysis (hydrochloride): C
30H
34N
6O
34HCl4.5H
2O, theoretical value C, C, 47.82; H, 6.29; N, 11.15. measured value C, 47.66; H, 6.23; N, 11.09.
14 pairs of fat amidos of embodiment replace the synthetic of Quinzolone derivatives
Method is with embodiment 9, and different is the compound 4 that replaces embodiment 5 preparations with the compound 4 of embodiment 8 preparations, and product is that yellow solid powder compounds 5 promptly two fat amidos replace Quinzolone derivatives, and its chemical formula is suc as formula shown in (If):
Productive rate: 65%;
1H-NMR (300MHz, CDCl
3) δ (ppm): 1.87-1.93 (m, 8H); 2.71-2.76 (m, 8H); 3.29-3.35 (m, 6H); 4.32 (t, J=7.2Hz, 2H); 7.55 (d, J=8.4Hz, 2H); 7.69 (d, J=8.4Hz, 2H); (7.75 d, J=9Hz 1H); 7.79 (t, J=2.4Hz, 1H); 8.07 (d, J=2.4Hz, 1H); 8.44 (dd, J=9,2.4Hz, 1H); 9.25 (br s, 1H); 9.43 (br s, 1H); ESI-MS m/z:527[M+H]
+Ultimate analysis (hydrochloride): C
30H
34N
6O
3.3HCl4H
2O, theoretical value C, 50.89; H, 6.41; N, 11.87. measured value C, 50.95; H, 6.42; N, 11.89.
15 pairs of fat amidos of embodiment replace the synthetic of Quinzolone derivatives
Method is with embodiment 9, different is the compound 4 that replaces embodiment 5 preparations with the compound 4 of embodiment 7 preparations, replace the pyrroles with piperidines, product is that yellow solid powder compounds 5 promptly two fat amidos replace Quinzolone derivatives, and its chemical formula is suc as formula shown in (Ig):
Productive rate: 60%;
1H-NMR (300MHz, CDCl
3) δ (ppm): 1.47-1.58 (m, 4H); 1.64-1.74 (m, 8H); 2.57-2.63 (m, 8H); 3.13 (s, 2H); 3.14 (s, 2H); 3.27-3.33 (m, 2H); 4.29 (t, J=7.2Hz, 2H); 7.56 (d, J=8.7Hz, 2H); 7.68 (d, J=8.7Hz, 2H); 7.76 (dd, J=8.7,2.1Hz, 1H); 7.80 (t, J=2.4Hz, 1H); 7.87 (d, J=2.1Hz, 1H); 8.25 (d, J=8.7Hz, 1H); 9.46 (br s, 1H); 9.65 (br s, 1H); ESI-MS m/z:555[M+H]
+Ultimate analysis (hydrochloride): C
32H
38N
6O
34HCl4.5H
2O, theoretical value C, 49.17; H, 6.58; N, 10.75. measured value C, 49.12; H, 6.52; N, 10.76.
16 pairs of fat amidos of embodiment replace the synthetic of Quinzolone derivatives
Method is with embodiment 9, different is the compound 4 that replaces embodiment 5 preparations with the compound 4 of embodiment 8 preparations, replace the pyrroles with piperidines, product is that yellow solid powder compounds 5 promptly two fat amidos replace Quinzolone derivatives, and its chemical formula is suc as formula shown in (Ih):
Productive rate: 61%;
1H-NMR (300MHz, CDCl
3) δ (ppm): 1.48-1.57 (m, 4H); 1.65-1.73 (m, 8H); 2.54-2.62 (m, 8H); 3.12 (s, 2H); 3.13 (s, 2H); 3.29-3.35 (m, 2H); 4.32 (t, J=7.5Hz, 2H); 7.55 (d, J=8.7Hz, 2H); 7.68 (d, J=8.7Hz, 2H); (7.74 d, J=9Hz 1H); 7.79 (t, J=2.7Hz, 1H); 8.08 (d, J=2.4Hz, 1H); 8.41 (dd, J=9,2.4Hz, 1H); 9.44 (br s, 1H); 9.55 (brs, 1H); ESI-MS m/z:555[M+H]
+Ultimate analysis (hydrochloride): C
32H
38N
6O
33HCl4.5H
2O, theoretical value C, 51.58; H, 6.76; N, 11.28. measured value C, 51.85; H, 6.77; N, 11.32.
The Quinzolone derivatives that 17 pairs of fat amidos of embodiment replace is to the restraining effect of Telomerase
The Quinzolone derivatives that two fat amidos that embodiment 9~16 is prepared replace, adopt the TRAP method to carry out the cell-free system telomerase activity: from human breast cancer cell strain MCF-7, to extract total protein (including Telomerase), total protein extracting solution and medicament mixed to be measured are added in the TRAP reaction mixture, utilize fluorescence gel imager or fluorescence microplate reader to detect after the PCR reaction, calculate the inhibition telomerase activation by light absorption value and reach 50% o'clock compound concentration, with IC
50 TelExpression, the result is as shown in table 1:
Table 1 pair fat amido replaces Quinzolone derivatives to the active restraining effect (IC of Telomerase
50 Tel/ μ M)
The result shows that two fat amidos replace Quinzolone derivatives has obvious restraining effect external to Telomerase.Therefore to replace that Quinzolone derivatives can be used for preparing with the Telomerase be the cancer therapy drug of target spot for the of the present invention pair of fat amido.
The Quinzolone derivatives that 18 pairs of fat amidos of embodiment replace is to the restraining effect of growth of tumour cell
The Quinzolone derivatives that two fat amidos that embodiment 9~16 is prepared replace, with two kinds of tumor cell line: NCI-H460 (human lung adenocarcinoma cell line) and GLC-82 (human lung adenocarcinoma cell line), adopting mtt assay to carry out the cell in vitro poison measures: two fat amidos that the logarithmic phase cell adds different concns replace Quinzolone derivatives, act on after 48 hours, measure its absorbancy.Calculate the compound concentration that cell growth inhibiting reaches at 50% o'clock respectively, with IC
50Value representation, the result is as shown in table 2:
The Quinzolone derivatives that table 2 pair fat amido replaces is to the restraining effect (IC of tumor cell line growth
50/ μ M)
Two fat amidos replace Quinzolone derivatives | Embodiment 9 | Embodiment 10 | Embodiment 11 | Embodiment 12 | Embodiment 13 | Embodiment 14 | Embodiment 15 | Embodiment 16 |
NCI-H460 | 15 | 14 | 5 | 5 | 10 | 5 | 16 | 3 |
GLC-82 | 14 | 20 | 4 | 13 | 9 | 8 | 5 | 3 |
The result shows that two fat amidos replace Quinzolone derivatives and external these two kinds of tumor cell lines all had stronger restraining effect.Therefore of the present invention pair of fat amido replaces Quinzolone derivatives and can be used for preparing anticancer medicine.
The Quinzolone derivatives acute toxicity test that 19 pairs of fat amidos of embodiment replace
Select two fat amidos to replace Quinzolone derivatives (that present embodiment selects for use is embodiment 9, the two fatty amido replacement Quinzolone derivatives of preparation), carry out acute toxicity test.Get 18~22 gram mouse and divide six groups at random, every group of 10 mouse, replace Quinzolone derivatives 50mg/kg and handle with physiological saline, DMSO 2.5ml/kg, two fatty amido replacement Quinzolone derivatives 500mg/kg, two fatty amido replacement Quinzolone derivatives 200mg/kg, two fatty amido replacement Quinzolone derivatives 100mg/kg, two fatty amido respectively, observed 14 days, 45% death of the visible 500mg/kg group of result mouse, i.e. the two fatty amido replacement Quinzolone derivatives of embodiment 9 preparations is approximately 500mg/kg to the acute toxicity LD50 value of mouse.Therefore the acute toxicity of of the present invention pair of fat amido replacement Quinzolone derivatives is less, can be used for preparing cancer therapy drug.
Claims (8)
2. described pair of fat amido of claim 1 replaces the preparation method of Quinzolone derivatives, it is characterized in that comprising the steps:
(1)
Carry out ring closure reaction with pyrrolidone, obtain
3. preparation method according to claim 2, the molecular formula that it is characterized in that the substituted amine compound described in the step (4) is R
1-NH-R
2, R
1-NH
2Or R
2-NH
2, R wherein
1, R
2Be selected from H, C respectively
1-6Alkyl, C
3-6Cycloalkyl, piperidyl, morpholinyl, piperazinyl, Bi Evil quinoline base.
4. preparation method according to claim 3 is characterized in that in the step (1),
With the molar ratio of pyrrolidone be 2: 1; The ring closure reaction solvent is a toluene; The catalyzer of ring closure reaction is a phosphorus oxychloride; The temperature of reaction of ring closure reaction is 40 ℃~110 ℃, and the reaction times is 5~12 hours.
5. preparation method according to claim 3 is characterized in that in the step (2),
With
The molar ratio of reaction is 1: 8~10; The condensation reaction solvent is a diacetyl oxide; The reaction times of condensation reaction is 24~32 hours; The reduction reaction solvent is an ethanol; The reductive agent of reduction reaction is nine water cure sodium; The reduction reaction time is 4~8 hours.
8. described pair of fat amido of claim 1 replaces the application of Quinzolone derivatives in the preparation cancer therapy drug.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2008100270043A CN101250189B (en) | 2008-03-25 | 2008-03-25 | Bisfatty amido substituted quinazolone derivatives as well as preparation method and use thereof as anti-cancer drugs |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2008100270043A CN101250189B (en) | 2008-03-25 | 2008-03-25 | Bisfatty amido substituted quinazolone derivatives as well as preparation method and use thereof as anti-cancer drugs |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101250189A CN101250189A (en) | 2008-08-27 |
CN101250189B true CN101250189B (en) | 2010-06-16 |
Family
ID=39953807
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2008100270043A Expired - Fee Related CN101250189B (en) | 2008-03-25 | 2008-03-25 | Bisfatty amido substituted quinazolone derivatives as well as preparation method and use thereof as anti-cancer drugs |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN101250189B (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101857595B (en) * | 2010-05-21 | 2012-11-21 | 中山大学 | Quinnazolidone derivative, preparation method thereof and purpose of serving as anticarcinogen |
CN101967127B (en) * | 2010-09-28 | 2013-05-29 | 中山大学 | Quinazoline derivative and preparation method thereof and application of quinazoline derivative for preparing anticancer drugs |
CN102206222B (en) * | 2011-04-14 | 2013-04-10 | 中山大学 | 2-fatty-amino-substituted indole quinoline derivative and preparation method and application thereof in preparation of antitumor drugs |
CN102382064B (en) * | 2011-09-15 | 2014-01-15 | 中山大学 | Quinnazolidone derivative, preparation method for same and application thereof |
CN102702173B (en) * | 2012-06-26 | 2014-07-16 | 滕州市悟通香料有限责任公司 | Method for preparing sulfur ether intermediates of proton pump inhibitor |
CN106220631B (en) * | 2016-07-26 | 2019-02-05 | 中山大学 | A kind of 7 fluorine replace Isaindigotone derivative and preparation method thereof and are preparing the application in anticancer drug |
CN113773325A (en) * | 2021-09-26 | 2021-12-10 | 江苏医药职业学院 | Isoquinoline and vasicine ketone mixed alkaloid analogue and application thereof in anti-tumor |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1886384A (en) * | 2003-11-25 | 2006-12-27 | 希龙公司 | Quinazolinone compounds as anticancer agents |
-
2008
- 2008-03-25 CN CN2008100270043A patent/CN101250189B/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1886384A (en) * | 2003-11-25 | 2006-12-27 | 希龙公司 | Quinazolinone compounds as anticancer agents |
Also Published As
Publication number | Publication date |
---|---|
CN101250189A (en) | 2008-08-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101250189B (en) | Bisfatty amido substituted quinazolone derivatives as well as preparation method and use thereof as anti-cancer drugs | |
CN105461695B (en) | Pyrimidine or pyrrolotriazine derivatives and its production and use | |
CN101250187B (en) | Fatty amido substituted methylindole quinoline derivatives as well as preparation method and use thereof as anti-tumour drugs | |
CN100540551C (en) | Quinoline, its preparation method and medicinal use thereof | |
JP2013528164A (en) | Arylaminopurine derivatives, methods for their preparation and use as pharmaceuticals | |
CN104326979B (en) | 2-methyl-9-acridine (to methoxy benzamide base) thiocarbamide and its production and use | |
CN101050213A (en) | Fat amido substitutional berberine derviation, preparation method, and application of anticancer drugs | |
CN104292170A (en) | Quinazolinyl-aryl urea derivatives with antitumor function and application thereof | |
CN103833646A (en) | Fatty amino substituted quinazolinone derivative and preparation method and application thereof | |
CN101967127B (en) | Quinazoline derivative and preparation method thereof and application of quinazoline derivative for preparing anticancer drugs | |
CN101857595B (en) | Quinnazolidone derivative, preparation method thereof and purpose of serving as anticarcinogen | |
CN102206222B (en) | 2-fatty-amino-substituted indole quinoline derivative and preparation method and application thereof in preparation of antitumor drugs | |
CN111423438B (en) | Eudistomins Y derivatives with antitumor activity and preparation method and application thereof | |
CN103224500A (en) | Annular secondary amino substitution cryptolepine ramification and preparation method thereof and application of annular substitution cryptolepine ramification being used as anti-cancer drug | |
CN102875462B (en) | Anti-tumor 2-amino nicotinonitrile, application and preparation method thereof | |
CN103204808A (en) | Biquinoline derivative, preparation method thereof and application thereof in preparing anticancer medicament | |
CN109608371A (en) | O2Two alkoxide derivative of -4- (3- (4- sulfamic phenyl) urea) phenylazo, Preparation method and use | |
CN102633719B (en) | Anilino-substituted-methylbenzofuryl quinoline derivatives, and preparation method and application thereof | |
CN106397407B (en) | The preparation method of antitumor drug AZD9291 derivatives | |
CN111704634B (en) | Metal complex containing tridentate ligand and xanthine derivative ligand as well as preparation method and medical application of metal complex | |
CN102382064B (en) | Quinnazolidone derivative, preparation method for same and application thereof | |
CN107337609A (en) | A kind of dezocine crystal formation and preparation method thereof | |
CN104341407A (en) | Quinazoline compounds, preparation method and applications thereof | |
CN102491972B (en) | Carbazole derivative, preparation method thereof, and application of carbazole derivative serving as anticancer drug | |
CN104130200A (en) | 2-substituted phenyl-4-arylamidoquinazoline derivative, preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100616 Termination date: 20180325 |
|
CF01 | Termination of patent right due to non-payment of annual fee |