CN101921271B - Pyridine [2,3-d] pyrimidone compounds and application thereof to pharmacy - Google Patents
Pyridine [2,3-d] pyrimidone compounds and application thereof to pharmacy Download PDFInfo
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Abstract
The invention relates to 3-substituted pyridine [2,3-d] pyrimidone compounds, belonging to the field of medicaments, wherein R1, R2, R3 and X are defined in the specification. The invention also relates to a preparation method of the compounds and application of the compounds in the preparation of drugs for resisting tumors.
Description
Technical field
The invention belongs to pharmaceutical field, relate to pyrido [2, the 3-d] pyrimidinones of a class 3-position replacement, the invention still further relates to preparation method and the application in the preparation antitumor drug thereof of this compound.
Background technology
Quinolones as the antimicrobial drug history of existing three more than ten years, is mainly by anti-bacteria DNA topoisomerase, i.e. gyrase and bring into play anti-microbial effect.But the people such as nearest Wentland discovery, 3-Quinolonecar boxylic acid derivatives WIN57294 also can interact with mammiferous Top II.Find its EC in the DNA break test that utilizes Hela cell Top II to carry out
50Reach 7.6 μ M.And also discovery of research, some non-carboxylic acid derivative in 3-position also have similar anti-tumor activity, as the EC of 3-(2,6-dihydroxy benzyl) derivative (WIN64593)
50Value is 96 μ M.In addition, the 7-position of quinolinone replaces with other pyridines, 4-methyl isophthalic acid-piperazinyl or pyrroles, or uses NH
2Or F replaces 5-position hydrogen activity and still keeps, 8-position fluorine or methoxy substitution can strengthen anti-tumor activity (referring to Chinese Pharmaceutical Journal, 1997,32,4529; Acta Pharmaceutica Sinica, 1998,33,121).
In patent documentation CN 03132296.4, we have prepared 3 compounds that replaced by benzoglyoxaline, benzoxazole and benzothiazole of quinolinone, have showed stronger anti-tumor activity in the anti tumor activity in vitro test.But whether the position replacement has corresponding feature to pyrido [2,3-d] pyrimidine 6-, report is arranged not yet.
Summary of the invention
The invention discloses pyrido [2, the 3-d] pyrimidinones (I) of a class 3-position replacement:
Wherein, R
1Represent H, C
1～C
10Alkyl or by halogen, nitro, amino, hydroxyl, C
1～C
10Alkoxyl group, carboxyl or the C that replaces of itrile group
1～C
10Alkyl;
R
2Represent H, halogen, nitro, amino, itrile group, hydroxyl, C
1～C
10Alkoxyl group, C
1～C
10Alkyl or by the C of halogen, nitro, amino, hydroxyl or carboxyl substituted
1～C
10Alkyl;
R
3Represent H, halogen, hydroxyl, nitro, amino, substituted-amino, C
1～C
10Alkyl, C
1～C
10Alkoxyl group, five yuan or hexa-atomic aryl or five yuan or the hexa-atomic aryl that is replaced by halogen, nitro, amino, methyl or methoxy, described aryl is to contain 1 or 2 heterocyclic radical that is selected from N, O or S; Wherein substituted-amino is R
4NH or R
4R
5N, wherein R
4Or R
5Be C
1～C
6Alkyl, or R
4, R
5Connect into ring-type or connect into ring-type by 1～3 heteroatoms.
X represents O, S or NH.
R
1Preferably represent H, C
1-C
4Alkyl or the C that replaces of halogen
1-C
4Alkyl.
R
2Preferably represent H, halogen, nitro, amino, C
1～C
4Alkoxyl group, C
1～C
4Alkyl.
R
3Preferably represent H, amino, dimethylamino, diethylamino, piperazinyl or the piperazinyl that is replaced by methyl, ethyl or ethanoyl.
The available following method preparation of compound of the present invention (I):
R wherein
1, R
2, R
3, X definition the same.
Work as R
2Be NO
2Or NH
2The time, its preparation method comprises the steps:
R in general formula (I)
2Be NO
2Or NH
2The time, its preparation method can be represented by reaction formula 2:
Namely with R in general formula I
2The compound of=H is raw material, directly carries out nitratedly, gets R in general formula I
2=NO
2Compound; With nitroreduction, get R in general formula I
2=NH
2Compound.
Pharmacological testing proves, Compound I of the present invention has stronger anti-tumor activity, can be used for preparing antitumour drug, and the preparation method of this compound provided by the invention is simple, effectively.
The cytotoxic activity data of the compounds of this invention:
This mensuration adopts blue (MTT) method of bromination tetrazole routinely, namely use the trysinization tumour cell, to contain the RPMI1640 nutrient solution preparation cell suspension of 10% calf serum, concentration is 10000 cells/ml, every hole inoculation 100 μ l (containing 1000 cells/well) in 96 well culture plates.If different pharmaceutical concentration is established three parallel holes for every group.Put to cultivate after 4 days in 37 ℃, 5%CO2 incubator and discard nutrient solution, every hole adds 100 μ l 0.5%MTT solution (RPMI 1640 preparations).37 ℃ are incubated 4 hours, abandon supernatant, and every hole adds DMSO 150 μ l dissolving Formazan particles, and vibration detects (reference wavelength 450nm, detection wavelength 570nm), the inhibiting rate of calculating medicine cell growth with microplate reader.With the drug level logarithmic value, inhibiting rate is done linear regression, get straight-line equation, therefrom obtain medicine to the half-inhibition concentration (IC of cancer cells
50).
Reagent source:
MTT: bromination tetrazole blue (Thiazolyl Blue Tetrazolum Bromide), the import of Sigma company; RPMI 1640 substratum: GIBCO company product; Pancreatin (Trypsin): GIBCO company product; DMSO (dimethyl sulfoxide (DMSO)): the Beijing Chemical Plant produces; Calf serum: military region animal doctor's centre of prevention and cure provides.
General formula (I)
Above-mentioned testing data shows: the compounds of this invention has strong cytotoxicity to human lung carcinoma cell (A549), human promyelocytic leukemia cell (HL-60), the low differentiation of people gastric adenocarcinoma cells (BGC-823), human liver cancer cell (SMMC-7721).Wherein, the cytotoxic activity of majority of compounds and positive control drug are suitable.Because the screening of antineoplastic compound is that cytotoxic activity with compound embodies routinely, so the compounds of this invention has stronger anti-tumor activity, can mix with pharmaceutical carrier the preparation antitumor drug.
The present invention also provides a kind of pharmaceutical composition, wherein contains compound of Formula I and the pharmaceutically acceptable carrier for the treatment of significant quantity.Described pharmaceutical composition can be dosage form conventional on the technology of pharmaceutics such as conventional tablet or capsule, slow releasing tablet or capsule, controlled release tablet or capsule, oral liquid, injection.
Usually, when compound of the present invention was used for the treatment of, the human dosage range was 2mg～2000mg/ days.Also can be according to difference and the disease severity of formulation, using dosage exceeds this scope.
Embodiment
Embodiment 1
8-ethyl-5,8-dihydro-5-oxygen-2-(piperazine-1-yl)-6-2-(benzimidazolyl-) pyrido [2,3-d] pyrimidine (LW1)
With pipemidic acid (5.00g; 17mmol); O-Phenylene Diamine (2.07g, 17mmol) is ground, and adds in the 100ml three-necked bottle; add PPA (30ml); be warming up to 130-140 ℃ under nitrogen protection, insulation 15min makes reaction be homogeneous phase, is warming up to 170 ℃ of reaction 4h; thin layer plate is monitored to raw material disappearance, stopped reaction.Be cooled to 100 ℃, in impouring 500ml trash ice, separate out a large amount of solids under the reaction solution vigorous stirring, be neutralized to pH=8 with NaOH, suction filtration, drying gets brown color solid 2.61g.Productive rate 40.9%.305～306 ℃ of fusing points.
EI-MS(m/z)：375，345，333，319，306，86；
IR：3423，2979，28611642，1610，1473，1270，1036，809，775cm
-1。
1HNMR(DMSO-d6)δ：1.26(t，J＝7.0Hz，3H，CH
2-CH
3)，2.73(br，4H，2×N-CH
2)，3.88(br，4H，2×N-CH
2)，4.41(q，J＝7.0Hz，2H，CH
3-CH
2)，7.16(s，2H，Ar-H)，7.58(d，J＝7.49Hz，2H，Ar-H)，9.07(s，1H，Ar-H)，9.2(s，1H，Ar-H)。
Embodiment 2
8-ethyl-5,8-dihydro-5-oxygen-2-(piperazine-1-yl)-6-[2-(6-nitrobenzimidazole base)] pyrido [2,3-d] pyrimidine (LW 2)
Lw1 (1.00g, 2.7mmol) is dissolved in the 7ml vitriol oil, and cryosel is bathed and is chilled to 0 ℃, slowly drip concentrated nitric acid (0.28ml, 4mmol), temperature remains on 0 ℃ of left and right, finish, stirring at room 10h is warming up to 40-45 ℃ of reaction 1h, thin layer plate is monitored to the raw material disappearance, and reaction solution is inclined to the 150ml frozen water, separates out solid, transfer to pH=8 with NaOH, suction filtration, vacuum-drying, column chromatography gets the 0.66g yellow solid.Productive rate 39.5%.Fusing point: 280～282 ℃.
EI-MS(m/z)：420，404，378，352，80。
IR：3448，3240，2926，2848，1618，1526，1447，1408，1383，1317，1259，991，830，809cm
-1。
1HNMR(DMSO-d6)δ：1.37(t，J＝6.42Hz，3H，CH2-CH
3)，2.78(br，4H，2×N-CH
2)，3.84(br，4H，2×N-CH
2)，4.34(q，J＝6.42Hz，2H，CH3-CH
2)，7.16(d，J＝8.73Hz，1H，Ar-H)，7.74(d，J＝8.28Hz，2H，Ar-H)，9.04(s，1H，Ar-H)，9.17(s，1H，Ar-H)。
Embodiment 3
8-ethyl-5,8-dihydro-5-oxygen-2-(piperazine-1-yl)-6-[2-(6-aminobenzimidazole base)] pyrido [2,3-d] pyrimidine (LW 3)
Lw2 (0.6g, 14mmol) is dissolved in appropriate acetic acid (approximately 9ml), adds Pb/C (0.12g), pass into hydrogen, room temperature reaction 12h, stopped reaction.Suction filtration, filtrate transfers to pH=8 with sodium hydroxide, separates out solid, suction filtration, drying, column chromatography gets brown color solid 0.17g, productive rate 30.5%.258～260 ℃ of fusing points.
EI-MS(m/z)：390，375，360，321，85；
IR：3448，2843，2100，1618，1528，1448，1356，1320，1262，1118，995，877，810，638cm
-1。
1HNMR(DMSO-d6)δ：1.39(t，J＝6.1Hz，3H，CH
2-CH
3)，2.78(br，4H，2×N-CH
2)，3.89(br，4H，2×N-CH
2)，4.35(q，J＝6.1Hz，2H，CH
3-CH
2)，7.44(d，J＝8.73Hz，1H，Ar-H)，7.77(d，J＝8.4Hz，1H，Ar-H)，8.55(s，1H，Ar-H)，9.05(s，1H，Ar-H)，9.17(s，1H，Ar-H)。
Embodiment 4
8-ethyl-5,8-dihydro-5-oxygen-2-(piperazine-1-yl)-6-2-(benzoxazolyl) pyrido [2,3-d] pyrimidine (LW 4)
With pipemidic acid (15.2g, 0.05mol), Ortho-Aminophenol (5.45g; 0.05mol) be ground, add in the 250ml three-necked bottle, add PPA (150ml); be warming up to 130-140 ℃ under nitrogen protection, insulation 15min makes reaction be homogeneous phase, is warming up to 170 ℃ of reaction 4h; be cooled to 100 ℃, in impouring 500ml trash ice under the reaction solution vigorous stirring, separate out a large amount of solids; be neutralized to pH=8 with NaOH, suction filtration, drying; recrystallization gets 1.75g pink solid a, productive rate 9.7%.Fusing point: 287～289 ℃.
EI-MS(m/z)：376，334，308，86。
IR：3438，2985，2926，2460，2194，1619，1571，1548，1511，1477，1449，1362，1300，1269，1138，1109，993，844，809，771，762。
1HNMR(DMSO-d6)δ：1.23(t，J＝7.02Hz，3H，CH
2-CH
3)，2.86(br，4H，2×N-CH
2)，3.89(br，4H，2×N-CH
2)，4.36(q，J＝7.02Hz，2H，CH
3-CH
2)，7.37(t，J＝5.64Hz，2H，Ar-H)，7.73(d，J＝2.34Hz，2H，Ar-H)，8.91(s，1H，Ar-H)，9.1(s，1H，Ar-H)。
Embodiment 5
8-ethyl-5,8-dihydro-5-oxygen-2-(piperazine-1-yl)-6-[2-(6-Xiao base benzoxazolyl)] pyrido [2,3-d] pyrimidine (LW 5)
Lw4 (3.35g, 0.01mol) is dissolved in the appropriate vitriol oil, and cryosel is bathed and is cooled to 0 ℃, slowly drip concentrated nitric acid (0.80ml, 12mmol), temperature of reaction remains on 0 ℃ of left and right, finish, stirring at room 10h is warming up to 40-45 ℃ of reaction 1h, reaction solution is inclined to the 500ml frozen water, separate out solid, NaOH transfers to pH=8, suction filtration, vacuum-drying, recrystallization get the 2.3g yellow solid, productive rate 54.8%.Fusing point: 236～237 ℃.
EI-MS(m/z)：421，379，353，86。
IR：3448，3296，3151，2926，2812，1615，1547，1508，1434，1339，1265，1093，912，873，829，808，734。
1HNMR(DMSO-d6)δ：1.36(t，J＝7.62Hz，3H，CH2-CH
3)，2.76(br，4H，×N-CH
2，3.82(br，4H，2×N-CH
2)，4.31(q，J＝7.62Hz，2H，CH3-CH
2)，7.84(d，J＝8.67Hz，1H，Ar-H)，8.22(t，J＝7.86Hz，2H，Ar-H)，8.94(s，1H，Ar-H)，9.02(s，1H，Ar-H)。
Embodiment 6
8-ethyl-5,8-dihydro-5-oxygen-2-(piperazine-1-yl)-6-[2-(the amino benzoxazole azoles of 6-base)] pyrido [2,3-d] pyrimidine (LW 6)
With lw5 (0.35g, 0.0008mol), be dissolved in appropriate acetic acid (approximately 5ml), add Pb/C (0.10g), pass into hydrogen, room temperature reaction 12h, stopped reaction, suction filtration, filtrate transfers to pH=8 with sodium hydroxide, separates out solid, suction filtration, drying, column chromatography get yellow solid 0.14g, and productive rate is 44.8%.221～222 ℃ of fusing points.
EI-MS(m/z)：391，377，355，281，86。
IR：3432，2963，2937，2843，2607，2442，1638，1571，1474，1449，1260，1095，847，807，713。
1HNMR(DMSO-d6)δ：1.4(t，J＝6.57Hz，3H，CH
2-CH
3)，2.83(br，4H，2×N-CH
2)，3.88(br，4H，2×N-CH
2)，4.36(q，J＝6.57Hz，2H，CH
3-CH
2，6.67(t，J＝8.28Hz，1H，Ar-H)，6.85(s，1H，Ar-H)，7.4(d，J＝8.43Hz，1H，Ar-H)，8.91(s，1H，Ar-H)，9.1(s，1H，Ar-H)。
Embodiment 7
8-ethyl-5,8-dihydro-5-oxygen-2-(piperazine-1-yl)-6-2-(benzothiazolyl) pyrido [2,3-d] pyrimidine (LW 7)
With pipemidic acid (15.2g, 0.05mol), o-amino thiophenol (5.4ml; 0.05mol) be ground, add in the 250ml three-necked bottle, add PPA (150ml); be warming up to 130-140 ℃ under nitrogen protection, insulation 15min makes reaction be homogeneous phase, is warming up to 170 ℃ of reaction 4h; be cooled to 100 ℃, in impouring 1000ml trash ice under the reaction solution vigorous stirring, separate out a large amount of solids; be neutralized to pH=8 with NaOH, suction filtration, drying; recrystallization gets 3.55g khaki color solid, productive rate 18%.Fusing point: 248～255 ℃.
EI-MS(m/z)：392，364，324，135，85，73。
IR：3438，2975，2926，2787，2710，2608，1612，1572，1485，1370，1150，976，937，768，522。
1HNMR(DMSO-d6)δ：1.39(t，J＝6.84Hz，3H，CH
2-CH
3)，2.97(br，4H，2×N-CH
2)，3.99(br，4H，2×N-CH
2)，4.43(q，J＝6.84Hz，2H，CH
3-CH
2)，7.37(t，J＝7.35Hz，1H，Ar-H)，7.473(t，J＝7.62Hz，1H，Ar-H)，7.93(dd，J
1＝7.8Hz，J
2＝7.68Hz，2H，Ar-H)，9.16(d，J＝6.24，2H，Ar-H)。
Embodiment 8
8-ethyl-5,8-dihydro-5-oxygen-2-(piperazine-1-yl)-6-[2-(6-nitrobenzene thiazole base)] pyrido [2,3-d] pyrimidine (LW 8).
Lw7 (2.55g, 64mmol) is dissolved in the appropriate vitriol oil, and cryosel is bathed and is cooled to 0 ℃, slowly drip concentrated nitric acid (5.40ml, 81mmol), temperature of reaction remains on 0 ℃ of left and right, finish, stirring at room 10h is warming up to 40-45 ℃ of reaction 1h, reaction solution is inclined to the 500ml frozen water, separate out solid, transfer to pH=8 with NaOH, suction filtration, vacuum-drying, recrystallization gets brown color solid 0.95g,, productive rate 33.7%.Fusing point: 238～241 ℃.
EI-MS(m/z)：437，395，381，369，96，85。
IR：3448，2930，2844，2718，2587，1616，1577，1479，1367，1130，809，755。
1HNMR(DMSO-d6)δ：1.39(t，J＝6.99Hz，3H，CH2-CH
3)，3.25(br，4H，2×N-CH
2)，4.12(br，4H，2×N-CH
2)，4.4(q，J＝6.99Hz，2H，CH3-CH
2)，7.51(t，J＝8.67Hz，1H，Ar-H)，7.93(d，J＝7.86Hz，1H，Ar-H)，8.54(d，J＝6.4Hz，1H，Ar-H)，9.02(dd，J1＝1.98Hz，J2＝13.95Hz，2H，Ar-H)。
Embodiment 9
8-ethyl-5,8-dihydro-5-oxygen-2-(piperazine-1-yl)-6-[2-(6-aminobenzothiazole base)] pyrido [2,3-d] pyrimidine (LW 9)
Lw8 (0.65g, 0.0016mol) adds in the HCl of 10ml 1M, be heated with stirring to 80 ℃, gradation adds the iron powder of salt acid treatment, adds post-heating to boiling and keeping 2 hours, until without till the nitro thing, the heat filter is neutralized to PH=8 with NaOH, separates out solid, suction filtration, drying, column chromatography get yellow solid 0.2g, and productive rate is 30.5%.Fusing point: 230～233 ℃.
EI-MS(m/z)：407，385，338，252，86。
IR：3448，3229，3155，2924，2853，1612，1565，1444，1256，1138，808，760，723，619。
1HNMR(DMSO-d6)δ：1.39(t，J＝6.57Hz，3H，CH
2-CH
3)，2.83(br，4H，2×N-CH
2)，3.88(br，4H，2×N-CH
2)，4.36(q，J＝6.57Hz，2H，CH
3-CH
2)，6.78(d，J＝8.28Hz，1H，Ar-H)，7.1(s，1H，Ar-H)，7.6(d，J＝8.43，1H，Ar-H)，8.95(s，1H，Ar-H)，9.15(s，1H，Ar-H)。
Embodiment 10
8-ethyl-5,8-dihydro-5-oxygen-2-(piperazine-1-yl)-6-[2-(6-fluorobenzene and imidazolyl)] pyrido [2,3-d] pyrimidine (LW 10)
With pipemidic acid (15.20g, 0.05mol), 4-fluorine O-Phenylene Diamine (7.00g; 0.05mol) be ground, add in the 250ml three-necked bottle, add PPA (150ml); be warming up to 130-140 ℃ under nitrogen protection, insulation 15min makes reaction solution be homogeneous phase, is warming up to 170 ℃ of reaction 4h; be cooled to 100 ℃, in impouring 500ml trash ice under the reaction solution vigorous stirring, separate out solid; be neutralized to pH=8 with NaOH, suction filtration, drying; get 6.37g brownish black solid, productive rate 32.4%.Fusing point: 245～250 ℃.
EI-MS(m/z)：393，365，351，337，207，85，73。
IR：3423，2973，2454，2100，1639，1609，1574，1527，1419，1253，1136，975，959，852，808，717。
1HNMR(DMSO-d6)δ：1.23(t，J＝6.51Hz，3H，CH
2-CH
3)，2.78(br，4H，2×N-CH
2)，3.84(br，4H，2×N-CH
2)，4.34(q，J＝7.14Hz，2H，CH
3-CH
2)，6.98(t，J＝2.28Hz，1H，Ar-H)，7.3(d，J＝3.4Hz，1H，Ar-H)，7.55(d，J＝4.3Hz，1H，Ar-H)，9.02(s，1H，Ar-H)，9.17(s，1H，Ar-H)。
Embodiment 11
8-ethyl-5,8-dihydro-5-oxygen-2-(piperazine-1-yl)-6-[2-(6-chloro benzimidazole base)] pyrido [2,3-d] pyrimidine (LW 11)
With pipemidic acid (15.20g, 0.05mol), 4-chlorine O-Phenylene Diamine (7.85g; 0.05mol) be ground, add in the 250ml three-necked bottle, add PPA (150ml); be warming up to 130-140 ℃ under nitrogen protection, insulation 15min makes reaction be homogeneous phase, is warming up to 170 ℃ of reaction 4h; be cooled to 100 ℃, in impouring 500ml trash ice under the reaction solution vigorous stirring, separate out solid; be neutralized to pH=8 with NaOH, suction filtration, drying; get the 7.95g yellow solid, productive rate 28%.Fusing point: 126～128 ℃.
EI-MS(m/z)：409，394，379，340，85，56。
IR：3441，2861，2584，2466，1638，1610，1575，1526，1420，1256，1138，997，977，808，759.，716。
1HNMR(DMSO-d6)δ：1.36(t，J＝6.78Hz，3H，CH
2-CH
3)，2.78(br，4H，2×N-CH
2)，3.83(br，4H，2×N-CH
2)，4.32(q，J＝6.63Hz，2H，CH
3-CH
2)，7.14(t，J＝1.53Hz，1H，Ar-H)，7.55(s，1H，Ar-H)，7.62(t，J＝8.76Hz，1H，Ar-H)，9.00(s，1H，Ar-H)，9.15(s，1H，Ar-H)。
Embodiment 12
8-ethyl-5,8-dihydro-5-oxygen-2-(piperazine-1-yl)-6-[2-(6-bromobenzene and imidazolyl)] pyrido [2,3-d] pyrimidine (LW 12)
With pipemidic acid (15.20g, 0.05mol), 4-bromine O-Phenylene Diamine (10.05g; 0.05mol) be ground, to the 250ml three-necked bottle, add PPA (150ml); be warming up to 130-140 ℃ under nitrogen protection, insulation 15min makes reaction solution be homogeneous phase, is warming up to 170 ℃ of reaction 4h; be cooled to 100 ℃, in the trash ice with impouring 500ml under the reaction solution vigorous stirring, separate out a large amount of solids; be neutralized to pH=8 with NaOH, suction filtration, drying; get orange/yellow solid 7.95g, productive rate 35%.Fusing point: 163～166 ℃.
EI-MS(m/z)：453，437，425，411，397，375，80。
IR：3423，3321，3280，2937，2843，2731，2483，2123，1637，1610，1572，1525，1415，1262，1138，994，975，931，916，808，741，715。
1HNMR(DMSO-d6)δ：1.39(t，J＝6.78Hz，3H，CH
2-CH
3)，2.79(br，4H，2×N-CH
2)，3.83(br，4H，2×N-CH
2)，4.33(q，J＝6.63Hz，2H，CH
3-CH
2)，7.14(t，J＝1.53Hz，1H，Ar-H)，7.61(s，2H，Ar-H)，8.9(t，J＝8.76，1H，Ar-H)，9.14(d，J＝6.42Hz，1H，Ar-H)。
Embodiment 13
8-ethyl-5,8-dihydro-5-oxygen-2-(piperazine-1-yl)-6-[2-(6-tolimidazole base)] pyrido [2,3-d] pyrimidine (LW 13)
With pipemidic acid (5.00g, 17mmol), 4-methyl-o-phenylenediamine (2.07g, 17mmol) is ground, and adds in the 100ml three-necked bottle, adds PPA (30ml).Be warming up to 130-140 ℃ under nitrogen protection; insulation 15min makes reaction be homogeneous phase; be warming up to 170 ℃ of reaction 4h, be cooled to 100 ℃, in impouring 500ml trash ice under the reaction solution vigorous stirring; separate out a large amount of solids; be neutralized to pH=8 with NaOH, suction filtration, drying; recrystallization gets brown color solid 1.7g, productive rate 25.7%.250～251 ℃ of fusing points.
EI-MS(m/z)：389，374，333，292，85。
IR：3415，2975，2861，1638，1609，1570，1527，1420，1255，1133，974，885，931，809。
1HNMR(CDCl
3)δ：1.89(t，J＝6.78Hz，3H，CH
2-CH
3)，2.94(br，4H，2×N-CH
2)，3.85(br，4H，2×N-CH
2)，4.29(q，J＝6.78Hz，2H，CH
3-CH
2)，7.02(t，J＝1.53Hz，1H，Ar-H)，7.42(s，2H，Ar-H)，8.9(d，J＝11.94Hz，1H，Ar-H)，9.34(s，1H，Ar-H)。
Embodiment 14
8-ethyl-5,8-dihydro-5-oxygen-2-(piperazine-1-yl)-6-[2-(6-methoxyl group benzo imidazolyl)] pyrido [2,3-d] pyrimidine (LW 14)
With pipemidic acid (5.00g, 17mmol), 4-methoxyl group O-Phenylene Diamine (2.07g, 17mmol) is ground, and adds in the 100ml three-necked bottle, adds PPA (30ml).Be warming up to 130-140 ℃ under nitrogen protection; insulation 15min makes reaction be homogeneous phase; be warming up to 170 ℃ of reaction 4h, be cooled to 100 ℃, in impouring 500ml trash ice under the reaction solution vigorous stirring; separate out a large amount of solids; be neutralized to pH=8 with NaOH, suction filtration, drying; recrystallization gets brown color solid 1.7g, productive rate 25.7%.250～251 ℃ of fusing points.
Embodiment 15
8-ethyl-5,8 dihydros-5-oxygen-2-(4-methylpiperazine-1-yl)-6-(2-benzimidazolyl-)-pyridine [2,3-d] pyrimidine (LW 15)
with 8-ethyl-2-(4-methylpiperazine-1-yl)-5-oxygen-5, 8 dihydropyridines [2, 3-d] pyrimidine-6-carboxylic acid (15.15g, 0.05mol), O-Phenylene Diamine (10.05g, 0.05mol) be ground, to the 250ml three-necked bottle, add PPA (150ml), be warming up to 130-140 ℃ under nitrogen protection, insulation 15min makes reaction solution be homogeneous phase, be warming up to 170 ℃ of reaction 4h, be cooled to 100 ℃, in trash ice with impouring 500ml under the reaction solution vigorous stirring, separate out a large amount of solids, be neutralized to pH=8 with NaOH, suction filtration, dry, get orange/yellow solid 7.15g, productive rate 31.5%.Fusing point: 168～170 ℃.
Embodiment 16
8-cyclopropyl-5,8 dihydros-5-oxygen-2-(piperazine-1-yl)-6-(2-benzimidazolyl-)-pyridine [2,3-d] pyrimidine (LW16)
with 8-cyclopropyl-2-(piperazine-1-yl)-5-oxygen-5, 8 dihydropyridines [2, 3-d] pyrimidine-6-carboxylic acid (15.8g, 0.05mol), O-Phenylene Diamine (10.05g, 0.05mol) be ground, to the 250ml three-necked bottle, add PPA (150ml), be warming up to 130-140 ℃ under nitrogen protection, insulation 15min makes reaction solution be homogeneous phase, be warming up to 170 ℃ of reaction 4h, be cooled to 100 ℃, in trash ice with impouring 500ml under the reaction solution vigorous stirring, separate out a large amount of solids, be neutralized to pH=8 with NaOH, suction filtration, dry, get orange/yellow solid 15.3g, productive rate 77.0%.Fusing point: 177～179 ℃.
Embodiment 17
8-cyclopropyl-5,8 dihydros-5-oxygen-2-(3,5-lupetazin-1-yl)-6-(2-benzimidazolyl-)-pyridine [2,3-d] pyrimidine (LW 17)
with 8-cyclopropyl-2-(3, 5-lupetazin-1-yl)-5-oxygen-5, 8 dihydropyridines [2, 3-d] pyrimidine-6-carboxylic acid (17.15g, 0.05mol), O-Phenylene Diamine (10.05g, 0.05mol) be ground, to the 250ml three-necked bottle, add PPA (150ml), be warming up to 130-140 ℃ under nitrogen protection, insulation 15min makes reaction solution be homogeneous phase, be warming up to 170 ℃ of reaction 4h, be cooled to 100 ℃, in trash ice with impouring 500ml under the reaction solution vigorous stirring, separate out a large amount of solids, be neutralized to pH=8 with NaOH, suction filtration, dry, get orange/yellow solid 6.64g, productive rate 34.0%.Fusing point: 201～203 ℃.
Embodiment 18
8-ethyl-5,8 dihydros-5-oxygen-2-(3-methylpiperazine-1-yl)-6-(2-benzimidazolyl-)-pyridine [2,3-d] pyrimidine (LW 18)
with 8-ethyl-2-(3-methylpiperazine-1-yl)-5-oxygen-5, 8 dihydropyridines [2, 3-d] pyrimidine-6-carboxylic acid (15.15g, 0.05mol), O-Phenylene Diamine (10.05g, 0.05mol) be ground, to the 250ml three-necked bottle, add PPA (150ml), be warming up to 130-140 ℃ under nitrogen protection, insulation 15min makes reaction solution be homogeneous phase, be warming up to 170 ℃ of reaction 4h, be cooled to 100 ℃, in trash ice with impouring 500ml under the reaction solution vigorous stirring, separate out a large amount of solids, be neutralized to pH=8 with NaOH, suction filtration, dry, get orange/yellow solid .6.23g, productive rate 32.0%.Fusing point: 185～186 ℃.
Embodiment 19
Get embodiment 1 gained compound 0.5g, add the conventional auxiliary material of tablet, make tablet by the tablet common process.
Embodiment 20
Get embodiment 1 gained compound 0.5g, add the conventional auxiliary material of granule, press the agent of granule common process granulation.
Claims (6)
1. lead to Pyridopyrimidine derivatives or its pharmacy acceptable salt of formula I:
Wherein, R
1Represent H, C
1～C
10Alkyl or by halogen, nitro, amino, hydroxyl, C
1～C
10Alkoxyl group, carboxyl or the C that replaces of itrile group
1～C
10Alkyl;
R
2Represent H, halogen, nitro, amino, itrile group, hydroxyl, C
1～C
10Alkoxyl group, C
1～C
10Alkyl or by the C of halogen, nitro, amino, hydroxyl or carboxyl substituted
1～C
10Alkyl;
R
3Represent H, halogen, hydroxyl, nitro, amino, dimethylamino, diethylamino, piperazinyl or methylpiperazine base;
X represents O, S or NH.
2. the Pyridopyrimidine derivatives of claim 1 or its pharmacy acceptable salt, wherein R
1Represent H, C
1-C
4Alkyl or the C that replaces of halogen
1-C
4Alkyl.
3. the Pyridopyrimidine derivatives of claim 1 or its pharmacy acceptable salt, wherein R
2Represent H, halogen, nitro, amino, C
1～C
4Alkoxyl group, C
1～C
4Alkyl.
4. the preparation method of the Pyridopyrimidine derivatives of any one in claims 1 to 3 comprises:
R wherein
1, R
2, R
3, X definition with claim 1.
5. pharmaceutical composition wherein contains Pyridopyrimidine derivatives or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
In claims 1 to 3 the Pyridopyrimidine derivatives of any one for the preparation of the purposes of medicine for the treatment of tumour.
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