CN100434425C - 4-quinazolone derivative and its use in anti-tumor medicine - Google Patents
4-quinazolone derivative and its use in anti-tumor medicine Download PDFInfo
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- CN100434425C CN100434425C CNB2005100536185A CN200510053618A CN100434425C CN 100434425 C CN100434425 C CN 100434425C CN B2005100536185 A CNB2005100536185 A CN B2005100536185A CN 200510053618 A CN200510053618 A CN 200510053618A CN 100434425 C CN100434425 C CN 100434425C
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Abstract
The present invention relates to a 4-quinazolone derivative with a dithiocarbamate side chain, medicinal salts thereof and medicinal composition with the 4-quinazolone derivative with a dithiocarbamate side chain as an active component, wherein the 4-quinazolone derivative with a dithiocarbamate side chain is disclosed in a general formula (I). The compound disclosed as the general formula (I) can be used as antitumor medicine.
Description
Technical field
The present invention relates to have 4-Quinazol derivative and their application in antitumor drug of dithiocarbamate side chain.
Background technology
Quianzolinones has wide biological activity, as tranquilizing soporific (Kacker, I.K., Zaheer, S.H.J.Indian Chem.Soc., 1951,28,344; Gujral, M.L.et al.Indian J.Med.Res., 1955,43,637), anti-microbial activity (Kung, P.P.et al., J.Med.Chem., 1999,42,4705), hypertension (Hess, H.J.et al.J.Med.Chem., 1968,11,130), anticonvulsion (Mannschreck, A.et al.Eur.J.Med.Chem., 1984,19,381), anti-inflammatory activity (Chao, Q.et al, J.Med.Chem., 1999,42,3860), the folacin that particularly contains the quinazolinone structure demonstrates effective antitumour activity (Bavetsias V, Marriott J H, Melin C, et al., J.Med.Chem., 2000,43 (10), 1910; Curtin, N.J., Hughes, A.N.Lancet Oncol., 2001,2 (5), 298), wherein ZD-1694 (Raltitrexed, Tomudex) from 1997 after Britain listing, at more than 40 national registrations, become line medicine (Marsham, P.R., a Hughes of treatment colorectal cancer in late period, L.R., Jackman, A.L.et al.J.Med.Chem., 1991,34 (5), 1594; Cunningham, D., Zalcberg, J., Maroun, J.et al., Eur.J.Cancer, 2002,38 (4), 478).
Summary of the invention
The purpose of this invention is to provide the 4-Quinazol derivative that a class has the dithiocarbamate side chain, and this compounds in antitumor drug as the purposes of activeconstituents.Compound of the present invention is inhibited to the growth of human tumor cells.
The present invention promptly has the 4-Quinazol derivative of dithiocarbamate side chain shown in general formula (I):
Wherein:
R
1Be selected from H, C
1-10The straight or branched alkyl, C
2-6Alkenyl or alkynyl, have one or more C that are selected from hydroxyl, amino, halogen atom
1-3Alkyl, C
3-6Cycloalkyl, aralkyl, replace or the phenyl of various replacements (connect the individual substituent phenyl of 1-3 as encircling, described substituting group is not selected from OCH
3, CF
3, NO
2, halogen etc.), aromatic heterocyclic radical, halogen atom, amino;
R
1Preferably from H, C
1-4The straight or branched alkyl, vinyl, allyl group, propargyl, methylol, aminomethyl, trifluoromethyl, benzyl, phenyl, thienyl, furyl, p-methoxy-phenyl, trifluoromethyl, nitrophenyl, the phenyl that halogen such as F, Cl, Br replace, chlorine atom, bromine atoms, amino;
R
2And R
3One be selected from H independently of one another, C
1-10The straight or branched alkyl, have the C of dialkyl amido
1-6The straight or branched alkyl, C
3-10Cycloalkyl, replace or the benzyl of various replacements (connect the individual substituent benzyl of 1-3 as encircling, described substituting group is not selected from CH
3, OCH
3, CF
3, NO
2, halogen etc.), contain 1-3 N, the C that the heterocyclic radical of O or S (as furans, thiophene, pyridine etc.) replaces
1-3Alkyl, wherein R
2And R
3At least one is not a hydrogen; Perhaps-NR
2R
3Be to contain 1-3 N, the heterocyclic radical that does not replace or replace of O or S;
R
2And R
3Independently of one another preferably from H, C
1-4The straight or branched alkyl, have the C of dialkyl amido
1-4Alkyl, pentamethylene base, cyclohexyl, adamantyl, the benzyl that benzyl, halogen replace, methyl substituted benzyl, the benzyl that trifluoromethyl replaces, the benzyl that methoxyl group replaces, the benzyl of carboxyl substituted, furfuryl, thenyl, picolyl, wherein R
2And R
3At least one is not a hydrogen;
Perhaps-NR
2R
3Preferably certainly
Wherein, R
4And R
5Be H or C
1-6Alkyl; R
6Be H or C
1-6Alkyl, replace or the phenyl of various replacements (connect the individual substituent phenyl of 1-3 as encircling, described substituting group is not selected from CH
3, OCH
3, CF
3, NO
2, halogen etc.); R
7Be hydroxyl, cyano group, carboxyl, ester group, amide group; R
8Be H or C
1-10Alkyl, the phenyl that does not replace or replace, (connect individual substituent phenyl of 1-3 or benzyl as encircling, described substituting group is selected from CH to the benzyl that does not replace or replace
3, OCH
3, CF
3, halogen etc.).
Below be the preparation method of The compounds of this invention, wherein initial compounds 2-amino-5-tolyl acid can be purchased.
(1) 2-amino-5-tolyl acid and acyl chloride reaction, the 2-that obtains amide group-5-tolyl acid and diacetyl oxide effect generate 2-replacement-6-Jia base benzoxazine-4-ketone; Perhaps, directly obtain 2-replacement-6-Jia base benzoxazine-4-ketone, i.e. formula (II) compound with 2-amino-5-tolyl acid and suitable anhydride reaction:
(2) hot altogether 2-replacement-6-methyl-4-quinazolinone, i.e. formula (III) compound that generate of 2-replacement-6-Jia base benzoxazine-4-ketone and methane amide; Wherein 2,6-dimethyl-4-quinazolinone can by 2-amino-5-tolyl acid and thioacetamide altogether thermal response directly obtain:
(3) formula (III) compound and N-bromosuccinimide react in the presence of benzoyl peroxide, obtain 2-replacement-6-brooethyl-4-quinazolinone, i.e. formula (IV) compound:
(4) formula (IV) compound and amine (HNR
2R
3) and dithiocarbonic anhydride (CS
2) in the presence of potassiumphosphate, at N, reaction obtains formula (I) compound in the dinethylformamide:
R wherein
1, R
2And R
3As defined above.
The salt of compound and salt form thereof, particularly HX (X the represents halogen atom) form of formula (I) has anti-tumor activity, can be used as antitumor drug or is used for antineoplastic pharmaceutical compositions as antitumor activity component.
Embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
The preparation of embodiment 1 diethylamino dithio formic acid (3,4-dihydro-2-methyl-4-oxygen quinazoline-6-yl) methyl ester (compound 1)
The first step: the mixture of heating 2-amino-5-tolyl acid 6.5g (43mmol) and thioacetamide 6.5g (87mmol), keep 135-150 ℃ of reaction 2h, the gained crude product gets 2 with the Glacial acetic acid recrystallization, 6-dimethyl-4-quinazolinone (5.5g, 73%), m.p.249.2-250.6 ℃;
1H NMR (200MHz, CD
3OD): δ 2.57 (s, 3H, CH
3), 2.76 (s, 3H, CH
3), 7.63 (d, 1H, J=8.4Hz, C
7-H), 7.89 (dd, 1H, J=8.4and 1.6Hz, C
8-H)), 8.14 (d, 1H, J=1.6Hz, C
5-H); ESI-MS:m/z175.2 (MH
+); Ultimate analysis: C
10H
10N
2O, calculated value (%): C 68.95, and H 5.79, and N 16.08; Measured value (%): C 68.64, and H 5.73, and N 15.99.
Second step: with 2,6-dimethyl-4-quinazolinone 2.3g (13.2mmol), N-bromosuccinimide 2.6g (14.4mmol) and benzoyl peroxide 0.05g (0.2mmol) are dissolved in 200mL CHCl
3In, under the irradiation of 100W incandescent light, slowly be heated to 60-62 ℃, stirring reaction 3h.Be cooled to room temperature, the white solid that the filter collection is separated out is used CHCl
3Wash 2 times, dry back gets 2-methyl-6-brooethyl-4-quinazolinone (2.6g, 77%) with methyl alcohol-re-crystallizing in ethyl acetate, m.p.>330 ℃;
1H NMR (200MHz, DMSO-d
6): δ 2.36 (s, 3H, C
2-CH
3), 4.86 (s, 2H, CH
2Br), 7.56 (d, 1H, J=8.4Hz, C
7-H), 7.82 (dd, 1H, J=8.4and 2.1Hz, C
8-H)), 8.15 (d, 1H, J=2.1Hz, C
5-H); FAB-MS:m/z 255 (MH
+); Ultimate analysis: C
10H
9BrN
2O, calculated value (%): C 47.46, and H 3.58, and N 11.07; Measured value (%): C 47.34, and H 3.47, and N 10.94.
The 3rd step: with diethylamine 0.11g (1.5mmol), potassiumphosphate 0.32g (1.5mmol) and N, dinethylformamide 15ml adds in the reaction flask, stir and add dithiocarbonic anhydride 0.57g (7.5mmol) down, stirring at room 30min, add 2-methyl-6-brooethyl-4-quinazolinone 0.25g (1mmol), continue stirring at room 1h.In reaction solution impouring 100ml water, with dichloromethane extraction 3 times, united extraction liquid is washed 1 time, anhydrous sodium sulfate drying, remove and desolvate, and resistates silica gel column chromatography purifying (elutriant: methylene dichloride: methyl alcohol=95: 5, vol/vol), get diethylamino dithio formic acid (3,4-dihydro-2-methyl-4-oxygen quinazoline-6-yl) methyl ester (0.27g, 84%), m.p.210-212 ℃;
1H NMR (200MHz, CDCl
3): δ 1.29 (t, 6H, 2CH
3), 2.60 (s, 3H, CH
3), 3.75 (q, 2H, NCH
2), 4.05 (q, 2H, NCH
2), 4.70 (s, 2H, CH
2S), 7.64 (d, 1H, J=8.4Hz, quinazolinone 8-H), 7.83 (dd, 1H, J=8.4and 2.1Hz, quinazolinone 7-H), 8.26 (d, 1H, J=2.1Hz, quinazolinone 5-H); ESI-MS:m/z 322.1 (MH
+); Ultimate analysis: C
15H
19N
3OS
2, calculated value (%): C 56.04, and H 5.96, and N 13.07; Measured value (%): C 56.08, and H 5.89, and N 13.11.
The preparation of embodiment 2 (3-(dimethylamino) propyl group) aminodithioformic acid (3,4-dihydro-2-methyl-4-oxygen quinazoline-6-yl) methyl ester (compound 2)
Prepare according to embodiment 1 identical method, just use 3-(dimethylamino) propylamine to replace diethylamine in the 3rd step.M.P.143-146 ℃;
1H NMR (200MHz, CDCl
3): δ 1.81 (t, 2H, NCH
2), 2.30 (s, 6H, N (CH
3)
2), 2.57 (m, 5H, C
2-CH
3, CH
2CH
2CH
2), 3.82 (t, 2H, NCH
2), 4.64 (s, 2H, CH
2S), 7.60 (d, 1H, J=8.4Hz, quinazolinone 8-H), 7.83 (dd, 1H, J=8.4and 2.1Hz, quinazolinone 7-H), 8.23 (d, 1H, J=2.1Hz, quinazolinone 5-H); ESI-MS:m/z 351.3 (MH
+); FAB-HRMS:C
16H
22N
4OS
2, calculated value: m/z 351.1313 (MH
+), measured value: m/z 351.1306 (MH
+).
The preparation of embodiment 3 dicyclohexyl aminodithioformic acids (3,4-dihydro-2-methyl-4-oxygen quinazoline-6-yl) methyl ester (compound 3)
Prepare according to embodiment 1 identical method, just use dicyclohexylamine to replace diethylamine in the 3rd step.M.p.228-230 ℃;
1H NMR (200MHz, CDCl
3): δ 1.1-1.7 (m, 12H, cyclohexylCH
2* 6), 1.7-2.0 (m, 8H, cyclohexyl CH
2* 4), 2.93 (m, 2H, NCH * 2), 2.60 (s, 3H, CH
3), 4.69 (s, 2H, CH
2S), 7.64 (d, 1H, J=8.4Hz, quinazolinone 8-H), 7.83 (dd, 1H, J=8.4and 2.1Hz, quinazolinone 7-H), 8.27 (d, 1H, J=2.1Hz, quinazolinone 5-H); ESI-MS:m/z 428.4 (M-H)
-Ultimate analysis: C
23H
31N
3OS
21/3H
2O, calculated value (%): C63.45, H 7.28, and N 9.66; Measured value (%): C 63.26, and H 7.58, and N 9.76.
The preparation of embodiment 4 benzylamino dithio formic acid (3,4-dihydro-2-methyl-4-oxygen quinazoline-6-yl) methyl ester (compound 4)
Prepare according to embodiment 1 identical method, just use benzyl amine to replace diethylamine in the 3rd step.M.p.183-185 ℃;
1H NMR (200MHz, DMSO-d
6): δ 2.34 (s, 3H, CH
3), 4.68 (s, 2H, CH
2S), 4.86 (s, 2H, CH
2Ph), 7.29 (m, 5H, Ar-H), 7.52 (d, 1H, J=8.4Hz, quinazolinone 8-H), 7.76 (dd, 1H, J=8.4 and 2.1Hz, quinazolinone 7-H), 8.08 (d, 1H, J=2.1Hz, quinazolinone 5-H), 10.52 (t, 1H, S
2CNH), 12.2 (br s, 1H, NH); ESI-MS:m/z 356.1 (MH
+); Ultimate analysis: C
18H
17N
3OS
2, calculated value (%): C 60.82, and H 4.82, and N 11.82; Measured value (%): C 60.96, and H 4.85, and N 11.92.
The preparation of embodiment 5 (furans-2-yl) methylamino dithio formic acid (3,4-dihydro-2-methyl-4-oxygen quinazoline-6-yl) methyl ester (compound 5)
Prepare according to embodiment 1 identical method, just use (furans-2-yl) methylamine to replace diethylamine in the 3rd step.M.p.189-192 ℃;
1H NMR (200MHz, DMSO-d
6): δ 2.34 (s, 3H, CH
3), 4.66 (s, 2H, CH
2S), 4.83 (s, 2H, NHCH
2), 6.35 (d, 1H, J=2.7Hz, furan-H), 6.41 (d, 1H, J=1.8Hz, furan-H), 7.51 (d, 1H, J=8.4Hz, quinazolinone 8-H), 7.61 (s, 1H, furan-H), (7.75 dd, 1H, J=8.4and 2.1Hz, quinazolinone 7-H), (8.06 d, 1H, J=2.1Hz, quinazolinone 5-H); ESI-MS:m/z 368.0 (MNa
+); Ultimate analysis: C
16H
15N
3O
2S
2, calculated value (%): C 55.63, and H 4.38, and N 12.16; Measured value (%): C 55.24, H4.58, and N 11.87.
The preparation of embodiment 61-(((3,4-dihydro-2-methyl-4-oxygen quinazoline-6-yl) methylthio group) thiocarbonyl)-4-Phenylpiperidine-4-ethyl formate (compound 6)
Prepare according to embodiment 1 identical method, just use 4-Phenylpiperidine-4-carboxylic acid, ethyl ester to replace diethylamine in the 3rd step.M.p.186-188 ℃;
1H NMR (200MHz, CDCl
3): δ 1.19 (t, 3H, CH
2CH
3), 2.04 (br s, 2H, CH
2), 2.58 (s, 3H, C
2-CH
3), 2.63 (t, 2H, CH
2), 3.49 (t, 2H, CH
2), 4.17 (q, 2H, CH
2CH
3), 4.45 (m, 1H, CH
2), 4.70 (s, 2H, CH
2S), 5.33 (m, 1H, CH
2), 7.33 (m, 5H, Ph-H), 7.62 (d, 1H, J=8.4Hz, quinazolinone 8-H), 7.81 (dd, 1H, J=8.4and 2.0Hz, quinazolinone 7-H), 8.22 (d, 1H, J=2.0Hz, quinazolinone 5-H), 12.05 (br s, 1H, NH); ESI-MS:m/z 482.3 (MH
+); Ultimate analysis: C
25H
27N
3O
3S
2, calculated value (%): C 62.34, and H 5.65, and N 8.72; Measured value (%): C 62.51, H5.67, and N 8.62.
Embodiment 72, the preparation of 6-thebaine-4-dithio formic acid (3,4-dihydro-2-methyl-4-oxygen quinazoline-6-yl) methyl ester (compound 7)
Prepare according to embodiment 1 identical method, just use 2 in the 3rd step, the 6-thebaine replaces diethylamine.M.p.279-281 ℃;
1H NMR (200MHz, CDCl
3): δ 1.22,1.25 (2s, 6H, 2CH
3), 2.49 (s, 3H, C
2-CH
3), 2.81,3.65,4.10 (3br, 6H, N (CH
2)
2, 2OCH), 4.73 (s, 2H, CH
2S), 7.63 (d, 1H, J=8.4Hz, quinazolinone 8-H), 7.81 (dd, 1H, J=8.4and 2.1Hz, quinazolinone 7-H), 8.26 (d, 1H, J=2.1Hz, quinazolinone 5-H); ESI-MS:m/z386.3 (MNa
+); FAB-HRMS:C
17H
21N
3O
2S
2, calculated value: m/z 363.1075 (M
+), measured value: m/z 363.1069 (MH
+).
The preparation of embodiment 84-benzyl diethylenediamine-1-dithio formic acid (3,4-dihydro-2-methyl-4-oxygen quinazoline-6-yl) methyl ester (compound 8)
Prepare according to embodiment 1 identical method, just use the 1-benzyl diethylenediamine to replace diethylamine in the 3rd step.M.p.217-219 ℃;
1H NMR (200MHz, CDCl
3): δ 2.58 (m, 7H, CH
3And N (CH
2)
2), 3.56 (s, 2H, CH
2Ph), 3.94 (br s, 2H, NCH
2), 4.36 (br s, 2H, NCH
2), 4.72 (s, 2H, CH
2S), 7.32 (m, 5H, Ar-H), and 7.62 (d, 1H, J=8.4Hz, quinazolinone 8-H), 7.82 (dd, 1H, J=8.4and 2.1Hz, quinazolinone 7-H), 8.26 (d, 1H, J=2.1Hz, quinazolinone5-H); ESI-MS:m/z 425.1 (MH
+); FAB-HRMS:C
22H
24N
4OS
2, calculated value: m/z425.1470 (MH
+), measured value: m/z 425.1462 (MH
+).
The preparation of embodiment 94-(4-fluorophenyl) piperazine-1-dithio formic acid (3,4-dihydro-2-methyl-4-oxygen quinazoline-6-yl) methyl ester (compound 9)
Prepare according to embodiment 1 identical method, just use 1-(4-fluorophenyl) piperazine to replace diethylamine in the 3rd step.M.p.246-248 ℃;
1HNMR (200MHz, CDCl
3): δ 2.56 (s, 3H, CH
3), 3.2 (t, 4H, N (CH
2)
2), 4.13 (br s, 2H, NCH
2), 4.42 (br s, 2H, NCH
2), 4.74 (s, 2H, CH
2S), 6.94 (m, 4H, Ph-H), 7.63 (d, 1H, J=8.5Hz, quinazolinone 8-H), 7.82 (dd, 1H, J=8.5and 2.1Hz, quinazolinone 7-H), 8.26 (d, 1H, J=2.1Hz, quinazolinone 5-H); ESI-MS:m/z 429.3 (MH
+); Ultimate analysis: C
21H
21FN
4OS
2, calculated value (%): C 58.86, H4.94, and N 13.07; Measured value (%): C 58.84, and H 4.99, and N 12.93.
The preparation of embodiment 10 (3,4,5-trimethoxy benzyl) aminodithioformic acid (3,4-dihydro-2-methyl-4-oxygen quinazoline-6-yl) methyl ester (compound 10)
Prepare according to embodiment 1 identical method, just use 3,4 in the 3rd step, 5-trimethoxy benzylamine replaces diethylamine.M.p.:173.3-173.8 ℃;
1H NMR (300MHz, DMSO-d
6): δ 2.34 (s, 3H, C
2-CH
3), 3.63 (s, 3H, OCH
3), 3.71 (s, 6H, 2OCH
3), 4.68 (s, 2H, CH
2S), 4.78 (s, 2H, CH
2Ph), 6.62 (s, 2H, Ph-H), and 7.51 (d, 1H, J=8.3Hz, quinazolinone 8-H), 7.76 (dd, 1H, J=8.3,2.0Hz, quinazolinone 7-H), 8.08 (d, 1H, J=2.0Hz, quinazolinone5-H), 10.45 (t, 1H, NHCH
2), 12.21 (br s, 1H, NH); ESI-MS:m/z 446.3 (MH
+); Ultimate analysis: C
21H
23N
3O
4S
2, calculated value (%): C 56.61, and H 5.20, and N 9.43; Measured value (%): C56.28, H 5.28, and N 9.15.
The preparation of embodiment 11 (2, the 4-dichloro benzyl) aminodithioformic acid (3,4-dihydro-2-methyl-4-oxygen quinazoline-6-yl) methyl ester (compound 11)
Prepare according to embodiment 1 identical method, just use 2 in the 3rd step, the 4-dichloro-benzylamine replaces diethylamine.M.p.:206-208 ℃;
1H NMR (200MHz, DMSO-d
6): δ 2.35 (s, 3H, C
2-CH
3), 4.68 (s, 2H, CH
2S), 4.84 (s, 2H, CH
2Ph), 7.27 (d, 1H, J=8.3Hz, Ph 6-H), (7.43 dd, 1H, J=8.3,1.9Hz, Ph 5-H), (7.53 d, 1H, J=8.4Hz, quinazolinone 8-H), 7.64 (d, 1H, J=1.9Hz, Ph 3-H), 7.75 (dd, 1H, J=8.4,1.8Hz, quinazolinone 7-H), 8.08 (d, 1H, J=1.8Hz, quinazolinone 5-H), 10.53 (t, 1H, NHCH
2), 12.23 (s, 1H, NH); ESI-MS:m/z 424.2 (MH
+); Ultimate analysis: C
18H
15Cl
2N
3OS
2, calculated value (%): C 50.94, H3.56, and N 9.90; Measured value (%): C 50.77, and H 3.62, and N 9.78.
The preparation of embodiment 12 (pyridine-2-yl) methylamino dithio formic acid (3,4-dihydro-2-methyl-4-oxygen quinazoline-6-yl) methyl ester (compound 12)
Prepare according to embodiment 1 identical method, just use (pyridine-2-yl) methylamine to replace diethylamine in the 3rd step.M.p.:214-215 ℃;
1H NMR (300MHz, DMSO-d
6): δ 2.34 (s, 3H, C
2-CH
3), 4.66 (s, 2H, CH
2S), 4.77 (s, 2H, CH
2Pyr), and 7.22-7.32 (m, 2H, Pyr-H), (7.52 d, 1H, J=8.6Hz, quinazolinone 8-H), (7.72-7.81 m, 2H, Pyr-H, quinazolinone 7-H), (8.08 d, 1H, J=2.0Hz, quinazolinone 5-H), 8.52 (m, 1H, Pyr-H), 10.58 (t, 1H, NHCH
2), 12.20 (s, 1H, NH); ESI-MS:m/z 357.2 (MH
+); Ultimate analysis: C
17H
16N
4OS
21/4H
2O, calculated value (%): C 56.58, and H 4.58, and N 15.53; Measured value (%): C 56.64, and H 4.54, and N 15.23.
The anti tumor activity in vitro test (MTT colorimetry) of embodiment 13 compounds 1~12
People's myelogenous leukemia K562 cell is the cell of suspension growth, calf serum with 10% and 0.2%NaHCO
3The RPMI-1640 nutrient solution, at 37 ℃, 5%CO
2Cultivate under the condition.All with aseptic ultrapure water preparation, with 0.22 μ m membrane filtration degerming, calf serum uses after the 30min deactivation in 56 ℃ each composition after the substratum dissolving.
MTT is made into 5mg/mL concentration with 1 * PBS solution, and with the millipore filter degerming of 0.22 μ m, packing, 4 ℃ keep in Dark Place, and is effective in two weeks.
Get the K562 cell of exponential phase of growth, be inoculated in 96 orifice plates with the density of 2 * 105/mL, in 37 ℃, 5%CO
2Incubator in cultivate 4h after, add all cpds solution of different concns respectively, every kind of sample is established three multiple holes, establishes negative control (only containing 1% DMSO) and positive control (cis-platinums of 50 μ g/mL) simultaneously.Behind the effect 24h, add MTT solution (10 μ L/ hole), centrifugal 5min behind the continuation cultivation 4h inhales and removes supernatant liquor, adds the DMSO in 100 μ L/ holes, cultivate about 10min for 37 ℃, and it is complete with the about 1min of micro oscillator vibration crystallization to be dissolved, and measures the OD value in the 490nm place with microplate reader, is calculated as follows cell proliferation inhibition rate (Inhibition Rate, IR%), obtain half-inhibition concentration (IC then
50Value), test-results sees Table 1.
IR%=(blank OD-sample OD)/blank OD * 100%
Table 1: the restraining effect of 1~12 pair of K562 cell in-vitro growth of compound
Compound (compound among the embodiment) | IC 50(μM) |
Compound 1 | 4.4 |
Compound 2 | 25.6 |
Compound 3 | 7.6 |
Compound 4 | 4.0 |
Compound 5 | 2.1 |
Compound 6 | 8.7 |
Compound 7 | 3.7 |
Compound 8 | 7.4 |
Compound 9 | 0.5 |
Compound 10 | 19 |
Compound 11 | 34.5 |
Compound 12 | 57.7 |
Claims (5)
1. the compound shown in general formula (I):
Wherein:
R
1Be H, C
1-10The straight or branched alkyl;
R
2And R
3Be H independently of one another, C
1-10The straight or branched alkyl, have the C of dialkyl amido
1-6The straight or branched alkyl, C
3-10Cycloalkyl, do not replace or 1~3 CH
3, OCH
3, CF
3, NO
2, the benzyl that replaces of halogen atom, contain the C that furans, thiophene, pyridine replace
1-3Alkyl, wherein R
2And R
3At least one is not a hydrogen; Perhaps-NR
2R
3Be
Wherein, R
4And R
5Be H or C
1-6Alkyl, R
6Be H or C
1-6Alkyl, unsubstituted or 1~3 CH
3, OCH
3, CF
3, NO
2, the phenyl that replaces of halogen atom, R
7Be hydroxyl, cyano group, carboxyl, ester group, amide group, R
8Be H or C
1-10Alkyl, do not replace or 1~3 CH
3, OCH
3, CF
3, the phenyl that replaces of halogen atom, do not replace or 1~3 CH
3, OCH
3, CF
3, the benzyl that replaces of halogen atom.
2. compound according to claim 1 is characterized in that R
1Be H, C
1-4The straight or branched alkyl.
3. compound according to claim 1 is characterized in that R
2And R
3Be H independently of one another, C
1-4The straight or branched alkyl, have the C of dialkyl amido
1-4Alkyl, pentamethylene base, cyclohexyl, adamantyl, the benzyl that benzyl, halogen replace, methyl substituted benzyl, the benzyl that trifluoromethyl replaces, the benzyl that methoxyl group replaces, furfuryl, thenyl, picolyl, wherein R
2And R
3At least one is not a hydrogen.
5. as the purposes of the described arbitrary compound of claim 1~4 as the activeconstituents in preparation antitumor drug or the conduct preparation antineoplastic pharmaceutical compositions.
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CN101759654B (en) * | 2010-01-20 | 2011-12-28 | 首都师范大学 | 4-quinazolinone-6-methylamino dithiocarbamate as well as medical composition and application thereof |
CN102391191B (en) * | 2011-09-01 | 2014-03-26 | 首都师范大学 | Piperazine di-thiocarboxylic acid ester derivative of 2,4-di-aminoquinazoline, as well as preparation method and anti-tumor application of the derivative |
CN103755647B (en) * | 2014-01-24 | 2015-12-09 | 首都师范大学 | C2 bit derivant of 4 (3H)-quinazolinones and its production and use |
CN104098587B (en) * | 2014-07-16 | 2016-10-05 | 首都师范大学 | 2,4-diaminothiophen also [2,3-d] pyrimidine derivatives and its production and use |
CN104803927B (en) * | 2015-03-31 | 2017-11-07 | 首都师范大学 | Chalcone analog of the base containing 2 methyl, 4 oxoquinazolin 6 and its production and use |
CN106146487B (en) * | 2015-04-27 | 2019-05-10 | 北京大学 | Pyridylmethyl dithiocarbonic acid hetero-aromatic ring alkyl esters compound and its preparation method and application |
CN106432208B (en) * | 2015-08-10 | 2019-12-13 | 北京大学 | amino dithioformic acid (sulfamoyl) ethyl ester compound and preparation method and application thereof |
CN107226789B (en) * | 2017-05-09 | 2019-11-08 | 北京大学 | Dithiocarbamates compound, preparation method and purposes in the preparation of antitumor drugs |
CN113880806B (en) * | 2021-09-29 | 2022-09-13 | 深圳大学 | 2-amino-4-oxo-quinazoline dithiocarbamate derivative, and pharmaceutical composition and application thereof |
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---|---|---|---|---|
CN1058208A (en) * | 1990-06-19 | 1992-01-29 | 惠尔康基金会集团公司 | Medical compounds |
WO1997006805A1 (en) * | 1995-08-15 | 1997-02-27 | Davidson, Clifford, M. | Quinazolinone-containing pharmaceutical compositions for prevention of neovascularization and for treating human malignancies |
WO2000066560A1 (en) * | 1999-05-04 | 2000-11-09 | American Home Products Corporation | Quinazolinone and benzoxazine derivatives as progesterone receptor modulators |
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2005
- 2005-03-09 CN CNB2005100536185A patent/CN100434425C/en not_active Expired - Fee Related
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CN1058208A (en) * | 1990-06-19 | 1992-01-29 | 惠尔康基金会集团公司 | Medical compounds |
WO1997006805A1 (en) * | 1995-08-15 | 1997-02-27 | Davidson, Clifford, M. | Quinazolinone-containing pharmaceutical compositions for prevention of neovascularization and for treating human malignancies |
WO2000066560A1 (en) * | 1999-05-04 | 2000-11-09 | American Home Products Corporation | Quinazolinone and benzoxazine derivatives as progesterone receptor modulators |
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