CN100488960C - 2-substituted quinolone compound and use in pharmacy - Google Patents
2-substituted quinolone compound and use in pharmacy Download PDFInfo
- Publication number
- CN100488960C CN100488960C CNB2006100387429A CN200610038742A CN100488960C CN 100488960 C CN100488960 C CN 100488960C CN B2006100387429 A CNB2006100387429 A CN B2006100387429A CN 200610038742 A CN200610038742 A CN 200610038742A CN 100488960 C CN100488960 C CN 100488960C
- Authority
- CN
- China
- Prior art keywords
- compound
- quinoline
- ketone
- chain
- amino
- 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
A 2-bit substituted quinonone compound and its use in pharmacy are disclosed. It has antineoplastic activity and can be used for antineoplastic medicine.
Description
Technical field
The invention belongs to pharmacy field, relate to the carbostyril compound that a kind of new 2-position replaces, the invention still further relates to the application of this compound in the preparation antitumor drug.
Background technology
In recent years, the bibliographical information carbostyril compound has better antitumor activity, has multiple action target spot.According to another bibliographical information, benzoglyoxaline, benzoxazole and benzothiazole compound may have topoisomerase I and suppress active.But do not disclose quinolone 2-position by the compound that benzoglyoxaline, benzoxazole and benzothiazole replace, whether the compound that does not also have these quinolones 2-position to be replaced by benzoglyoxaline, benzoxazole and benzothiazole has the report of anti-tumor activity.
Summary of the invention
The objective of the invention is provides a kind of new quinolone 2-position with anti-tumor activity by the compound of benzoglyoxaline, benzoxazole and benzothiazole replacement at above-mentioned technical problem.
Another object of the present invention provides the application of above-claimed cpd in the preparation antitumour drug.
For addressing the above problem, provide following technical solution:
Following general formula (I) compound
Wherein, R
1Represent H, alkyl, aryl, heterocyclic radical, aryl, substituted hydrocarbon radical, substituted arene base, substituted heterocyclic radical, substituted aryl;
R
2And R
5Identical or different, represent H, halogen, nitro, amino, itrile group, hydroxyl, alkoxyl group, alkyl, aryl, heterocyclic radical, aryl, substituted hydrocarbon radical, substituted arene base, substituted heterocyclic radical, substituted aryl independently of one another;
R
6And R
7Identical or different, represent the ternary～eight yuan heterocycle of nitrogen atom of ternary～eight yuan heterocycle, the replacement of H, halogen, hydroxyl, alkyl, alkoxyl group, aralkoxy, heterocycle alkoxyl group, aryl, fragrant heterocycle, nitro, amino, nitrogen atom independently of one another;
R
8Alkyl, nitro, amino, itrile group, hydroxyl, alkoxyl group, aralkoxy, the heterocycle alkoxyl group of representing H, halogen, alkyl, halogen to replace;
X represents O, S, NH.
Described general formula (I) compound, wherein: R
1, R
2, R
5, R
6, R
7Or R
8The aryl or aralkyl of representative or the aryl in the aralkoxy are benzene, biphenyl or naphthalene, perhaps are F, Cl, Br, I, C
1～10Alkyl, C
1～10Alkoxyl group, nitro or amino mono-substituted benzene, biphenyl or naphthalene.
Described general formula (I) compound, wherein: R
1, R
2, R
5, R
6, R
7Or R
8The alkyl of representative or the alkyl in the aryl refer to have the alkyl of the straight or branched of 1-10 carbon atoms, or the thiazolinyl of the straight or branched of 2-10 carbon atoms, or the cycloalkyl of 3-10 carbon atoms; Alkyl in alkoxyl group or aralkoxy or the heterocycle alkoxyl group refers to have the alkyl of the straight or branched of 1-10 carbon atoms.Wherein alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, heptyl, octyl group, nonyl, decyl; Thiazolinyl is vinyl, propenyl, allyl group, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonene base, decene base; Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl.
Described general formula (I) compound, wherein: R
1, R
2, R
5, R
6, R
7Or R
8The heterocyclic radical of representative refers to contain one or more heteroatomic saturated heterocyclic or aromatic heterocycle optional from oxygen, nitrogen, sulphur atom.
Described general formula (I) compound, wherein: R
1, R
2, R
5, R
6, R
7Or R
8The halogen of representative is F, Cl, Br or I.
Described general formula (I) compound, wherein: R
6, R
7Ternary～eight yuan the heterocycle of the nitrogen atom of the replacement of representative is F, Cl, Br, I, C
1～10Alkyl, C
1～10Acyl group, C
1～10Alkoxyl group, C
1～10Ternary～eight yuan the heterocycle of alkylamino, nitro, the amino nitrogen atom that replaces.
Described general formula (I) compound, wherein: R
1, R
2, R
5Middle alkyl, aryl, heterocyclic radical, the aryl that replaces, its substituting group is halogen, nitro, amino, hydroxyl, ether, carboxyl, ester group and amido.
Described general formula (I) compound, wherein: R
1, R
2, R
5, R
6, R
7The aryl of representative is a phenyl ring, perhaps is F, Cl, Br, I, C
1～10Alkyl, C
1～10Alkoxyl group, nitro, amino benzene, biphenyl or the naphthalene that replaces; The virtue heterocycle is to contain 1～3 heteroatomic aromatic heterocycle, perhaps is F, Cl, Br, I, C
1～10Alkyl, C
1～10Alkoxyl group, nitro, amino replace contain 1～3 heteroatomic aromaticity heterocycle.
Described general formula (I) compound, wherein: amino is NH
2, R
9NH, R
10R
11N; R wherein
9, R
10Or R
11For right is wanted 3 described alkyl, perhaps R
10R
11N is the ternary～eight yuan heterocycle of nitrogen atom.
Described general formula (I) compound, wherein:
R
1Expression H, C
1～C
4Branched-chain or straight-chain alkyl or cyclic alkane;
R
2And R
5Identical or different, represent H, halogen independently of one another;
R
6And R
7Identical or different, represent H, halogen, hydroxyl, C independently of one another
1～C
4Branched-chain or straight-chain alkyl, amino or C
1～C
4Replace amino of branched-chain or straight-chain alkyl or contain five yuan or hexa-member heterocycle of 1-2 nitrogen-atoms;
R
8Expression H, halogen, the side chain of C1～C4 or the alkyl of straight chain;
X represents O, S, NH.
Described general formula (I) compound, wherein:
R
1Expression H, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl;
R
2And R
5Identical or different, represent H, Cl, F independently of one another;
R
6And R
7Identical or different, represent H, Cl, F, hydroxyl, methyl, second third, propyl group, sec.-propyl, amino independently of one another, or dimethylamino, diethylamino, piperazinyl;
R
8Expression H, Cl, F, methyl, second third, propyl group, sec.-propyl.
The application of above-claimed cpd in the preparation antitumor drug.
The present invention is a starting raw material with the aniline of various replacements, according to a conventional method with diethyl oxaloacetate condensation, cyclization, hydrolysis prepares corresponding quinolone-2-formic acid, then with the O-Phenylene Diamine of O-Phenylene Diamine, Ortho-Aminophenol, o-amino thiophenol, replacement, the Ortho-Aminophenol of replacement or the o-amino thiophenol reaction of replacement, prepared the compound that a series of new quinolone 2-positions are replaced by benzoglyoxaline, benzoxazole and benzothiazole, these compounds have better antitumor activity.
The preparation method of general formula (I) compound may further comprise the steps:
A. aniline of Qu Daiing (II) and diethyl oxaloacetate (III) condensation, cyclization, process R
1Br (IV) replaces or does not replace the quinolone that hydrolysis must replace-2-formic acid (V);
B. with the quinolone-2-formic acid (V) and O-Phenylene Diamine, Ortho-Aminophenol, o-amino thiophenol, the O-Phenylene Diamine of replacement, the Ortho-Aminophenol of replacement or o-amino thiophenol (VI) condensation in polyphosphoric acid of replacement that replace; Get general formula (I) compound;
(annotate: the R among Compound I I, IV, V, the VI
1, R
2, R
5, R
6, R
7With R
8The substituting group of representative is identical with the above-mentioned qualification in Compound I).
Wherein, amino general formula (I ＇) compound that replaces obtains corresponding nitro-compound reduction; General formula (I) compound that hydroxyl replaces is that the compound demethylation that corresponding methoxyl group replaces is obtained.
The preparation method of the carbostyril compound that the general formula that the present invention relates to (I) 2-position replaces can be represented by synthetic synoptic diagram 1～2:
A. the aniline of various replacements and diethyl oxaloacetate condensation, cyclization, replacement, the hydrolysis quinolone-2-formic acid that must replace (seeing synthetic synoptic diagram 1) then;
B. the o-amino thiophenol of the Ortho-Aminophenol of the O-Phenylene Diamine of quinolone-2-formic acid that gained is replaced and O-Phenylene Diamine, Ortho-Aminophenol, o-amino thiophenol, replacement, replacement or replacement in polyphosphoric acid in 160-190 ℃ of condensations (see and synthesize synoptic diagram 2);
C. (the column chromatography condition is: Haiyang Chemical Plant, Qingdao produces column chromatography silica gel, 100 orders with the silica gel column chromatography separation with the condensation reaction products therefrom; Developping agent: the mixed solvent of vinyl acetic monomer and sherwood oil), get target compound.
Synthetic synoptic diagram 1:
Beneficial effect of the present invention:
At present, the screening of antineoplastic compound is that cytotoxic activity with compound embodies routinely.
Experimental data (seeing embodiment 30 for details) shows: compound of the present invention is that (A2780) and human liver cancer cell 7402 are that (Be17402) has stronger cytotoxicity to human oral epidermoid carcinoma cell (KB), Proliferation of Human Ovarian Cell 2780.
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.
Embodiment 1
The preparation of diethyl oxaloacetate
Add dehydrated alcohol (50ml) in the 500ml three-necked bottle that reflux exchanger, drying tube are housed, (10g, 0.435mol), the slow slightly post-heating of question response is back to sodium and disappears sodium.Change reflux into water distilling apparatus, decompression steams ethanol to doing, and removes vacuum after being cooled to room temperature.Add anhydrous diethyl ether (80ml) and stir into pasty state, be chilled to below-5 ℃, (58.23ml is 0.427mol) with ethyl acetate (39.3ml, mixed solution 0.401mol) in slowly dripping oxalic acid diethyl ester below-5 ℃.Continue to stir 1 hour, be warming up to 38～40 ℃ then, refluxed 1 hour, placement is spent the night.Low temperature is neutralized to pH1-2 with 10% sulfuric acid down, and divide and get ether layer, washed several times with water, saturated solution of sodium bicarbonate is given a baby a bath on the third day after its birth inferior, then with saturated common salt washing, anhydrous Na
2SO
4Dry.Filter, 70～88 ℃/9.5mmHg cut is collected in underpressure distillation behind the filtrate recovery ether, gets colourless liquid 11.2g, yield 14.8%.
Embodiment 2
1,4H-quinoline-4-ketone-2-ethyl formate
(14g, 0.15mol), (29g, 0.154mol), benzene (20ml) is added in the reaction flask diethyl oxaloacetate aniline, under the nitrogen protection, refluxes 3 hours.Reclaim benzene, silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets yellow liquid.The gained yellow liquid is mixed with phenyl ether (60ml), be heated to backflow, be incubated 1 hour.Faint yellow solid is separated out in cooling, filters, and sherwood oil is washed, and drying gets the 11.7g product, yield 35.9%, mp 209-211 ℃.
Embodiment 3
1,4H-quinoline-4-ketone-2-formic acid
Gained 1 among the embodiment 2, and (11.5g, 0.053mol) (4.24g, 0.016mol), the mixture of water (57ml) refluxed 2 hours 4H-quinoline-4-ketone-2-ethyl formate with sodium hydroxide.Cooling is filtered, washing, and drying gets the 9.1g pale powder, yield 90.8%, 279 ℃ of mp.
Embodiment 4
2-(2-benzimidazolyl-)-4 (1H)-quinolinones (1)
1, and 4H-quinoline-4-ketone-2-formic acid (1.89g, 0.01mol), O-Phenylene Diamine (1.08g, 0.01mol), PPA (25ml), temperature of reaction is 170 ℃.Silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets gray solid 0.9g, yield 34.5%, 338 ℃ of mp (dec.).Ultimate analysis: Found C 73.24% H 4.67% N 16.07%requires C 73.56% H 4.31% N 16.10%; IR (cm
-1): 3431,3173,3059,2993,2932,2814,1631,1596,1587,1552,1506,1485,1425,1320,1296,1238,1141,1007,848,841,761,743; HR-ESIMS (M+1): Found 262.0995 C
16H
12N
3O Requires 262.0975;
1HNMR (δ, ppm, DMSO-d6): 6.97 (s, 1H), 7.30 (m, 3H), 7.63 (m, 2H), 7.80 (d, 1H), 8.06 (d, 1H), 8.13 (d, 1H), 12.24 (s, 1H, NH), 13.37 (s, 1H, NH).
Embodiment 5
6-fluoro-7-chloro-1,4H-quinoline-4-ketone-2-ethyl formate
(12g, 0.082mol), (17.6g, 0.094mol), benzene (40ml) is added in the reaction flask diethyl oxaloacetate 3-fluoro-4-chloroaniline, under the nitrogen protection, refluxes 1 hour.Reclaim benzene, silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets yellow liquid 19g.(30ml) is heated to backflow with phenyl ether, adds the gained yellow liquid then, is incubated 1.5 hours.Faint yellow solid is separated out in cooling, filters, and sherwood oil is washed, and drying gets the 10g product, yield 61.8%, mp 249-251 ℃.IR(cm
-1)：3449，3203，3139，3097，3051，2991，2945，2909，1734，1625，1608，1572，1520，1473，1375，1278，1265，1242，1249，1211，1025，999，906，857，778；
1HNMR(δ，ppm，DMSO-d6)：1.36(m，3H，CH
3)，4.41(m，2H，CH
2)，6.60(br.，0.5H)，6.67(br.，0.5H)，7.67(t，0.5H)，7.83(d，0.5H)，7.94(q，0.5H)，8.13(d，0.5H)，11.95(br.)。
Embodiment 6
6-fluoro-7-chloro-1,4H-quinoline-4-ketone-2-formic acid
The preparation method is with embodiment 3,6-fluoro-7-chloro-1,4H-quinoline-4-ketone-2-ethyl formate (0.053mol) and sodium hydroxide (0.016mol), the mixture back flow reaction of water (57ml), yield 94%, mp279-281 ℃.IR(cm
-1)：3401，3190，3102，3200-2600，1754，1732，1620，1600，1470，1256，1202，1103，898，797，723；
1HNMR(δ，ppm，DMSO-d6)：6.56(s，0.5H)，6.62(s，0.5H)，7.63(t，0.5H)，7.82(d，0.5H)，7.94(q，0.5H)，8.12(d，0.5H)，11.98(br.)。
Embodiment 7
6-fluoro-7-chloro-2-(2-benzimidazolyl-)-4 (1H)-quinolinones (2)
6-fluoro-7-chloro-1, and 4H-quinoline-4-ketone-2-formic acid (2.42g, 0.01mol), O-Phenylene Diamine (1.08g, 0.01mol), PPA (30ml), temperature of reaction is 175 ℃, other are operated with embodiment 3.Silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets pale solid 0.7g, yield 22.3%, mp374 ℃ (dec.).IR(cm
-1)：3296，3259，3173，3112，3037，3006，2916，2821，1646，1611，1600，1546，1498，1479，1399，1259，1007，911，872，842，779，746，732；HR-ESIMS(M+1)：Found?314.0506Cl
6H
10N
3OFCl?Requires?314.0491；
1HNMR(δ，ppm，DMSO-d6)：6.92(s，1H)，7.36(m，1H)，7.64(d，1H)，7.74(d，1H)，7.90(d，1H)，7.95(s，1H)，8.31(d，1H)，12.47(NH)，13.49(NH)。
Embodiment 8
6-(N, N dimethylamine base)-1,4H-quinoline-4-ketone-2-ethyl formate
(8g, 0.059mol), other operate with embodiment 2 4-(N, N dimethylamine base) aniline.Get the pale brown look solid of 5.8g, yield 37.8%, mp207-209 ℃.IR((cm
-1))：3204，3131，3068，2980，2939，2893，2805，1727，1622，1594，1551，1504，1444，1382，1269，1239，1215，1172，1084，1022，964，856，784；HR-ESIMS(M+1)：Found?261.1242?C
14H
17N
2O
3?Requires?261.1234；
1HNMR(δ，ppm，DMSO-d6)：1.27(t，3H，CH
3)，2.95(s，6H，CH
3 *2)，4.39(q，2H，CH
2)，6.60(br，1H，3-H)，7.13(d，1H，5-H)，7.36-7.4(dd，1H，7-H)，7.87(d，1H，8-H)，11.94(br，1H，NH)。
Embodiment 9
6-(N, N dimethylamine base)-1,4H-quinoline-4-ketone-2-formic acid
6-(N, N dimethylamine base)-1,4H-quinoline-4-ketone-2-ethyl formate (0.053mol) and sodium hydroxide (0.016mol), the mixture of water (57ml) is pressed embodiment 3 same procedure, back flow reaction, yield 92.9%, mp281-283 ℃.IR(cm
-1)：3402，3206，3092，2932，2882，2481，2600～3400，1622，1610，1580，1573，1514，1444，1380，1323，1234，1177，1125，1093，966，886，799，755；HR-ESIMS(M+1)：Found?233.0910C
12H
13N
2O
3?Requires?233.0921；
1HNMR(δ，ppm，DMSO-d6)：2.99(s，6H，CH
3 *2)，6.66(s，IH，3-H)，7.14(d，1H，5-H，J2.7)，7.38-7.41(dd，1H，7-H)，7.89(d，1H，8-H)。
Embodiment 10
6-(N, N dimethylamine base)-2-(2-benzimidazolyl-)-4 (1H)-quinolinones (3)
The preparation method is with embodiment 4.6-(N, N dimethylamine base)-1, and 4H-quinoline-4-ketone-2-formic acid (1.00g, 0.0043mol), O-Phenylene Diamine (0.465g, 0.0043mol), PPA (10ml), temperature of reaction is 182 ℃.Silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets gray solid 0.08g, yield 8%, mp335 ℃.IR((cm
-1))：3289，3257，3173，3111，3008，2989，2861，1623，1616，1588，1546，1494，1444，1389，1302，1283，1246，1225，916，824，798，737，565；HR-ESIMS(M+1)：Found?305.1400?C
18H
17N
4ORequires?305.1397；
1HNMR(δ，ppm，DMSO-d6)：3.01(s，6H，CH
3 *2)；7.18(s，1H，3-H)；7.30(br)，7.38(br)，7.68(br)6H)，7.94(d，8-H)。
Embodiment 11
1-ethyl-6-(N, N dimethylamine base)-1,4H-quinoline-4-ketone-2-ethyl formate
6-(N, N dimethylamine base)-1, and 4H-quinoline-4-ketone-2-ethyl formate (3.67g, 0.014mol), DMF (22ml), K
2CO
3(3.8g), be heated to about 70 ℃, (3.79g 0.02mol), is warming up to 110 ℃ after adding slowly to drip the monobromethane that is dissolved in an amount of DMF, be incubated 2.5 hours, add monobromethane 1g, continue reaction 1.5 hours, filter, drying gets the 3g yellow solid, yield 73.8%, mp196-197 ℃.IR((cm
-1))：3084，2981，2936，2905，2865，2811，1704，1613，1579，1561，1508，1440，1382，1345，1255，1233，1225，1113，1028，963，879，827，787；HR-ESIMS(M+1)：Found?289.1541?C
16H
21N
2O
3?Requires?289.1547；
1HNMR(δ，ppm，DMSO-d6)：1.37(t，3H，CH
3)，1.49(t，3H，CH
3)，3.08(s，6H，CH
3 *2)，4.34(m，4H，CH
2 *2)，6.99(d，1H，5-H)，7.39(s，1H，3-H)，7.48(dd，1H，7-H)，7.90(d，1H，8-H)。
Embodiment 12
1-ethyl-6-(N, N dimethylamine base)-1,4H-quinoline-4-ketone-2-formic acid
1-ethyl-6-(N, N dimethylamine base)-1,4H-quinoline-4-ketone-2-ethyl formate (0.053mol) and sodium hydroxide (0.016mol), the mixture of water (57ml) is pressed embodiment 3 same procedure, back flow reaction, yield 99%, mp 242-243 ℃ of .IR ((cm
-1)): 3500～3600,3420,3026,2980,2979,2943,1659,1611,1582,1515,1445,1374,1342,1305,1246,1181,1105,1019,972,822,799,754; HR-ESIMS (M+1): Found261.1220 C
14H
17N
2O
3Requires 261.1234;
1HNMR (δ, ppm, DMSO-d6): 1.49 (t, 3H, CH
3), 3.07 (s, 6H, CH
3 *2), 4.36 (q, 2H, CH
2), 6.99 (d, 1H, 5-H), 7.42 (s, 1H, 3-H), 7.50 (dd, 1H, 7-H), 7.96 (d, 1H, 8-H).
Embodiment 13
1-ethyl-6-(N, N dimethylamine base)-2-(2-benzimidazolyl-)-4 (1H)-quinolinones (4)
1-ethyl-6-(N, N dimethylamine base)-1, and 4H-quinoline-4-ketone-2-formic acid (0.6g, 0.0023mol), O-Phenylene Diamine (0.25g, 0.0023mol), PPA (9ml), temperature of reaction is 188 ℃, embodiment 4 is pressed in other operations.Silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets yellow solid 0.06g, yield 7.8%, mp287 ℃ (dec.); IR (cm
-1): 3287,3162,3004,2925,2886,2803,1615,1589,1544,1495,1444,1395,1283,1228,1157,915,828,804,741; HR-ESIMS (M+1): Found 333.1689C
20H
21N
4O Requires 333.1710;
1HNMR (δ, ppm, DMSO-d6): 1.26 (t, 3H, CH
3), 3.01 (s, 6H, CH
3 *2), 3.35 (q, 2H, CH
2 *2), 6.95 (s, 1H, 3-H), 7.18 (dd, 1H, 7-H), 7.40 (m, 2H, 5 ', 6 '-H), 7.67 (m, 2H, CH
2 *2), 7.81 (d, 1H, 8-H), 7.95 (d, 1H, 5-H).
Embodiment 14
2-(2-benzoxazolyl)-4 (1H)-quinolinones (5)
1, and 4H-quinoline-4-ketone-2-formic acid (1.89g, 0.01mol), o-aminophenol (1.09g, 0.01mol), PPA (25ml) presses embodiment 4, and temperature of reaction is 188 ℃.Silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets gray solid 0.9g, yield 34.4%, mp335-338 ℃.IR(cm
-1)：3392，3234，3154，3000，2966，2904，2791，1634，1597，1568，1514，1469，1440，1239，1138，1093，965，855，760，744；HR-ESIMS(M+1)：Found?263.0825?C
16H
11N
2O
2?Requires?263.0815；
1HNMR(δ，ppm，DMSO-d6)：6.93(s，1H)，7.43(1H)，7.55(m，2H)，7.76(1H)，7.94(2H)，8.02(1H)，8.16(1H)，12.57(1H，NH).
Embodiment 15
The 6-methyl isophthalic acid, 4H-quinoline-4-ketone-2-ethyl formate
(37.5g, 0.35mol), other operations are with pressing embodiment 2 for the 4-monomethylaniline.Get the 17.8g gray solid, yield 22%, mp213 ℃.
Embodiment 16
The 6-methyl isophthalic acid, 4H-quinoline-4-ketone-2-formic acid
The 6-methyl isophthalic acid, 4H-quinoline-4-ketone-2-ethyl formate (0.053mol) and sodium hydroxide (0.016mol), the mixture of water (57ml) is pressed embodiment 3 same procedure, back flow reaction.Yield 73.7%, mp279 ℃.
Embodiment 17
6-methyl-2-(2-benzoxazolyl)-4 (1H)-quinolinones (6)
The preparation method is with embodiment 4.The 6-methyl isophthalic acid, and 4H-quinoline-4-ketone-2-formic acid (2.03g, 0.01mol), o-aminophenol (1.09g, 0.01mol), PPA (30ml), temperature of reaction is 190 ℃.Silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets faint yellow look solid 0.06g, yield 2.2%, 301 ℃ of mp (dec.).Ultimate analysis: Found C 73.90% H 4.49% N 9.99%requires C 74.02% H 4.31% N 10.10%; IR (cm
-1): 3146,3119,3071,3059,2971,2916,1639,1598,1566,1508,1450,1247,1198,1084,965,848,816,740,726; HR-ESIMS (M+1): Found 277.0982 C
17H
13N
2O
2Requires 277.0972;
1HNMR (δ, ppm, DMSO-d6): 6.85 (s, 1H), 7.51～7.64 (m, 3H), 7.89～7.99 (m, 4H), 12.50 (NH).
Embodiment 18
6-(N, N dimethylamine base)-2-(2-benzoxazolyl)-4 (1H)-quinolinones (7)
The preparation method is with embodiment 4.6-(N, N dimethylamine base)-1, and 4H-quinoline-4-ketone-2-formic acid (1.00g, 0.0043mol), o-aminophenol (0.47g, 0.0043mol), PPA (10ml), temperature of reaction is 194 ℃.Silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets yellow solid 0.09g, yield 6.8%, mp289 ℃ (dec.).IR(cm
-1)：3241，3224，3136，3060，2959，2921，2851，1626，1599，1556，1545，1504，1450，1384，1343，1245，1082，964，841，812，739；HR-ESIMS(M+1)：Found?306.1231C
18H
16N
3O
2?Requires?306.1237；
1HNMR(δ，ppm，DMSO-d6)：1.22(t，3H，CH
3)，3.04(s，6H，CH
3 *2)，3.35(q，2H，CH
2)，6.79(br.，1H，3-H)，7.52(m，4H，5’，6’，7，8-H)，7.89(m，2H，4’，7’-H)，7.93(d，1H，5-H)，11.50(br.)，12.47(br.)。
Embodiment 19
1-ethyl-6-(N, N dimethylamine base)-2-(2-benzoxazolyl)-4 (1H)-quinolinones (8)
The preparation method is with embodiment 4.1-ethyl-6-(N, N dimethylamine base)-1, and 4H-quinoline-4-ketone-2-formic acid (0.5g, 0.0019mol), o-aminophenol (0.21g, 0.0019mol), PPA (8ml), temperature of reaction is 194 ℃.Silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets yellow solid 0.07g, yield 11.06%, 267 ℃ of mp (dec.); IR (cm
-1): 3140,3070,2963,2898,2799,1624,1595,1552,1504,1449,1382,1343,1308,1244,1175,1084,964,842,814,744; HR-ESIMS (M+1): Found 334.1555C
20H
20N
3O
2Requires 334.1550;
1HNMR (δ, ppm, DMSO-d6): 1.28 (t, 3H, CH
3), 3.04 (s, 6H, CH
3 *2), 3.42 (q, 2H, CH
2), 7.07 (s, 1H, 3-H), 7.54 (m, 4H, 5 ', 6 ', 7,8-H), 7.89 (m, 2H, 4 ', 7 '-H), 7.94 (d, 1H, 5-H).
Embodiment 20
2-(2-[4-morpholinodithio base)-4 (1H)-quinolinones (9)
The preparation method is with embodiment 4.1, and 4H-quinoline-4-ketone-2-formic acid (1.89g, 0.01mol), o-amino thiophenol (1.25g, 0.01mol), PPA (25ml), temperature of reaction is 192 ℃.Silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets faint yellow solid 1.2g, yield 43.2%, mp263-267 ℃.IR(cm
-1)：3222，3192，3152，3094，3057，2962，2902，1624，1605，1589，1564，1516，1469，1313，1251，1199，1135，1052，934，842，759，726；HR-ESIMS(M+1)：Found?279.0606?C
16H
11N
2OS?Requires?279.0587；
1HNMR(δ，ppm，DMSO-d6)：7.40(3H)，7.74(1H)，7.86(1H)，8.02(1H)，8.17(2H)，8.22(1H)，12.2(NH)。
Embodiment 21
6-methoxyl group-1,4H-quinoline-4-ketone-2-ethyl formate
(52.9g, 0.43mol), other operate with embodiment 2 the 4-anisidine.Get the 20g faint yellow solid, yield 16.9%, mp223 ℃.
Embodiment 22
6-methoxyl group-1,4H-quinoline-4-ketone-2-formic acid
6-methoxyl group-1,4H-quinoline-4-ketone-2-ethyl formate (0.053mol) and sodium hydroxide (0.016mol), the mixture of water (57ml) is pressed embodiment 3 same procedure, back flow reaction.Yield 73.7%, mp294 ℃.
Embodiment 23
6-hydroxyl-2-(2-[4-morpholinodithio base)-4 (1H)-quinolinones (10)
6-methoxyl group-1, and 4H-quinoline-4-ketone-2-formic acid (2.06g, 0.0094mol), o-amino thiophenol (1.17g, 0.0094mol), PPA (25ml), temperature of reaction is 190 ℃, presses embodiment 4 reactions.Silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets faint yellow solid 0.06g, yield 2.1%, mp 331-335 ℃.Ultimate analysis: Found C64.99% H 3.72% N 9.39% requires C 65.28% H 3.46% N 9.51%; IR (cm
-1): 3427,3301,3100,2975,2797,1605,1583,1553,1535,1499,1480,1447,1376,1245,1237,1192,1048,919,830,756; HR-ESIMS (M+1): Found 295.0557 C
16H
11N
2O
2S Requires 295.0536;
1HNMR (δ, ppm, DMSO-d6): 7.33 (d, 1H, 7 ＇-H), 7.40 (d, 1H, 5-H), 7.48～7.60 (m, 2H, 7
T, 4 ＇-H), 7.74 (br, 1H, 3-H), 7.88 (d, 1H, 8-H), 8.14 (m, 2H, 5 ＇, 6 ＇-H), 10.18 (br, OH), 11.62 (br, NH).
Embodiment 24
6-chloro-1,4H-quinoline-4-ketone-2-ethyl formate
(54.8g, 0.43mol), other operate with embodiment 2 the 4-chloroaniline.Get the 36.8g faint yellow solid, yield 34%, 241 ℃ of mp.
Embodiment 25
6-chloro-1,4H-quinoline-4-ketone-2-formic acid
6-chloro-1,4H-quinoline-4-ketone-2-ethyl formate (0.053mol) and sodium hydroxide (0.016mol), the mixture of water (57ml) is pressed embodiment 3 same procedure, back flow reaction.Yield 42.1%, mp285 ℃.
Embodiment 26
6-chloro-2-(2-[4-morpholinodithio base)-4 (1H)-quinolinones (11)
6-chloro-1, and 4H-quinoline-4-ketone-2-formic acid (1.12g, 0.005mol), o-amino thiophenol (0.625g, 0.005mol), PPA (15ml), temperature of reaction is 190 ℃, presses embodiment 4 reactions.Silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets faint yellow solid 0.11g, yield 43.2%, mp256 ℃ (dec.).IR(cm
-1)：3438，3187，3121，3063，2945，2885，1629，1592，1567，1502，1486，1467，1384，1292，1190，839，823，753，722，541；HR-ESIMS(M+1)：Found?313.0190?C
16H
10N
2OSCL?Requires313.0197；
1HNMR(δ，ppm，DMSO-d6)：7.48～7.63(m，2H)，7.78(d，1H)，7.81(d，1H)，8.04(d，1H)，8.14(m，1H)，8.23(m，2H)，12.44(NH)。
Embodiment 27
6-(N, N dimethylamine base)-2-(2-[4-morpholinodithio base)-4 (1H)-quinolinones (12)
6-(N, N dimethylamine base)-1, and 4H-quinoline-4-ketone-2-formic acid (0.7g, 0.003mol), o-amino thiophenol (0.38g, 0.003mol), PPA (9ml), temperature of reaction is 192 ℃, presses embodiment 4 reactions.Silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets yellow solid 0.07g, yield 7.3%, 253 ℃ of mp (dec.).IR(cm
-1)：3424，3208，3130，3063，2959，2897，2798，1623，1600，1586，1546，1504，1383，1311，1191，936，836，811，757，730；HR-ESIMS(M+1)：Found?322.0994?C
18H
16N
3OSRequires?322.1009。
Embodiment 28
2-[2-(6-chloro benzimidazole base)-4 (1H)-quinolinones (13)
1, and 4H-quinoline-4-ketone-2-formic acid (1.89g, 0.01mol), 4-chloro-1, the 2-phenylenediamine (1.43g, 0.01mol), PPA (25ml), temperature of reaction is 180 ℃, presses embodiment 4 reactions.Silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets Vandyke brown solid 1.45g, yield 49.1%, 254 ℃ of mp (dec.).IR(cm
-1)：3259，3061，2997，2890，2777，2654，1632，1604，1558，1505，1428，1349，1297，1246，1139，1056，1000，840，796，779，753，733；HR-ESIMS(M+1)：Found?296.0565?C
16H
11N
3OClRequires?296.0585；
1HNMR(δ，ppm，DMSO-d6)：7.06(1H)，7.36(2H)，7.71(1H)，7.74(2H)，8.05(1H)，8.12(1H)，12.44(NH)。
Embodiment 29
1-ethyl-6-(N, N dimethylamine base)-2-[2-(6-chloro benzimidazole base)-4 (1H)-quinolinones (14)
1-ethyl-6-(N, N dimethylamine base)-1, and 4H-quinoline-4-ketone-2-formic acid (0.6g, 0.0023mol), 4-chloro-1, the 2-phenylenediamine (0.33g, 0.0023mol), PPA (10ml), temperature of reaction is 188 ℃, presses embodiment 4 reactions.Silica gel column chromatography is a developping agent with ethyl acetate and sherwood oil mixed solvent, gets tawny solid 0.07g, yield 8.3%, mp304 ℃ (dec.); IR (cm
-1): 3287,3168,3005,2933,2885,2807,1614,1589,1542,1495,1397,1283,1157,1059,920,828,805,740; HR-ESIMS (M+1): Found 368.0561 C
20H
19ClN
4O Requires368.0585;
1HNMR (δ, ppm, DMSO-d6): 1.22 (t, 3H, CH
3), 3.01 (s, 6H, CH
3 *2), 3.39 (q, 2H, CH
2), 7.18 (dd, 1H, 7-H), 7.39 (m, 2H, 3,5 '-H), 7.68 (m, 2H, 4 ', 7 '-H), 7.83 (d, 1H, 5-H), 7.94 (d, 1H, 8-H).
Embodiment 30
The cytotoxic activity data of target compound among the embodiment.
This mensuration adopts bromination tetrazole indigo plant (MTT) method routinely, promptly use the trysinization tumour cell, to contain the RPMI RPMI-1640 preparation cell suspension of 10% calf serum, concentration is 10000 cells/ml, and 100 μ l (containing 1000 cells/well) are inoculated in every hole in 96 well culture plates.If different pharmaceutical concentration is established three parallel holes for every group.Put 37 ℃, 5% CO
2Cultivate after 4 days in the 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 particle, and vibration detects (reference wavelength 450nm, detection wavelength 570nm) with microplate reader, calculates the inhibiting rate of medicine cell growth.With the drug level logarithmic value inhibiting rate is done linear regression, get straight-line equation, therefrom obtain the half-inhibition concentration (IC of medicine cancer cells
50).
Reagent source:
MTT: bromination tetrazole indigo plant (Thiazolyl Blue Tetrazolum Bromide), the import of Sigma company;
RPMI 1640 substratum (GIBCO company)
Pancreatin (Trypsin) (GIBCO company)
ND: undetermined
Above-mentioned experimental data shows: The compounds of this invention is that (A2780) and human liver cancer cell 7402 are that (Be17402) has strong cytotoxicity to human oral epidermoid carcinoma cell (KB), Proliferation of Human Ovarian Cell 2780.Wherein, compound 4 and 14 cytotoxic activity are suitable with the positive control drug 10-hydroxycamptothecine.Because the screening of antineoplastic compound is that cytotoxic activity with compound embodies routinely,, can mix the preparation antitumor drug so The compounds of this invention has anti-tumor activity with pharmaceutical carrier.
Claims (3)
1, following general formula (I) compound
Wherein, R
1Expression H, C
1～C
4Branched-chain or straight-chain alkyl or cyclic alkane;
R
2And R
5Identical or different, represent H, halogen independently of one another;
R
6And R
7Identical or different, represent H, halogen, hydroxyl, C independently of one another
1～C
4Branched-chain or straight-chain alkyl, amino or C
1～C
4Replace amino of branched-chain or straight-chain alkyl or contain five yuan or hexa-member heterocycle of 1-2 nitrogen-atoms;
R
8Expression H, halogen, the side chain of C1～C4 or the alkyl of straight chain;
X represents O, S, NH.
2, according to the described general formula of claim 1 (I) compound, it is characterized in that:
Wherein, R
1Expression H, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl;
R
2And R
5Identical or different, represent H, Cl, F independently of one another;
R
6And R
7Identical or different, represent H, Cl, F, hydroxyl, methyl, second third, propyl group, sec.-propyl, amino independently of one another, or dimethylamino, diethylamino, piperazinyl;
R
8Expression H, Cl, F, methyl, second third, propyl group, sec.-propyl.
3, claim 1 or the 2 described compounds application in the medicine of preparation treatment tumour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100387429A CN100488960C (en) | 2006-03-09 | 2006-03-09 | 2-substituted quinolone compound and use in pharmacy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100387429A CN100488960C (en) | 2006-03-09 | 2006-03-09 | 2-substituted quinolone compound and use in pharmacy |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1817880A CN1817880A (en) | 2006-08-16 |
| CN100488960C true CN100488960C (en) | 2009-05-20 |
Family
ID=36918106
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100387429A Expired - Fee Related CN100488960C (en) | 2006-03-09 | 2006-03-09 | 2-substituted quinolone compound and use in pharmacy |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100488960C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675200B (en) * | 2012-05-16 | 2014-04-09 | 中国药科大学 | 2-phenyl-4-carbostyril compounds with antineoplastic activity, and preparation method and usage thereof |
| CN108516973A (en) * | 2018-03-30 | 2018-09-11 | 广西师范大学 | 3- benzothiazoles -1- (3- dimethylaminos) propyl quinoline -4- ketone derivatives and its preparation method and application |
| CN110974968B (en) * | 2019-12-11 | 2021-03-26 | 中山万远新药研发有限公司 | Quinolone compound-containing composition and application thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5571822A (en) * | 1994-09-30 | 1996-11-05 | The University Of North Carolina At Chapel Hill | Antitumor compounds |
| US6479512B1 (en) * | 1999-10-19 | 2002-11-12 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
| CN1473827A (en) * | 2003-08-11 | 2004-02-11 | 中国药科大学 | 3-position substituted quinolone derivativers and its use in pharmacy |
| CN1476435A (en) * | 2000-09-25 | 2004-02-18 | 北卡罗来纳查佩尔山大学 | Fluorinated quinolones as antimitotic and antitumor agents |
| CN1659165A (en) * | 2002-04-05 | 2005-08-24 | 希龙公司 | Quinolinone derivatives |
| US20050209247A1 (en) * | 2003-11-07 | 2005-09-22 | Chiron Corporation | Pharmaceutically acceptable salts of quinolinone compounds having improved pharmaceutical properties |
-
2006
- 2006-03-09 CN CNB2006100387429A patent/CN100488960C/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5571822A (en) * | 1994-09-30 | 1996-11-05 | The University Of North Carolina At Chapel Hill | Antitumor compounds |
| US6479512B1 (en) * | 1999-10-19 | 2002-11-12 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
| CN1476435A (en) * | 2000-09-25 | 2004-02-18 | 北卡罗来纳查佩尔山大学 | Fluorinated quinolones as antimitotic and antitumor agents |
| CN1659165A (en) * | 2002-04-05 | 2005-08-24 | 希龙公司 | Quinolinone derivatives |
| CN1473827A (en) * | 2003-08-11 | 2004-02-11 | 中国药科大学 | 3-position substituted quinolone derivativers and its use in pharmacy |
| US20050209247A1 (en) * | 2003-11-07 | 2005-09-22 | Chiron Corporation | Pharmaceutically acceptable salts of quinolinone compounds having improved pharmaceutical properties |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1817880A (en) | 2006-08-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6782756B2 (en) | Formulations of compounds useful for treating KIT-related diseases and intermediate compounds | |
| CN102105462B (en) | Amidophenoxyindazoles useful as inhibitors of C-MET | |
| JP5789259B2 (en) | Nitrogen-containing aromatic heterocyclic derivatives | |
| CN107406453B (en) | A kind of crystal form and preparation method thereof of BTK kinase inhibitor | |
| AU2023270195A1 (en) | 2,3-dihydroquinazolin compounds as NAV1.8 inhibitors | |
| ZA200607518B (en) | Pyrimidine derivatives for use as vanilloid receptor ligands and their use in the treatment of pain | |
| CN104854090A (en) | Heteroaryl derivatives and uses thereof | |
| CN101781269A (en) | 4-tertiary butyl-2-(nitrobenzyl imino) thiazole derivative as well as preparation method and application thereof | |
| CN100488960C (en) | 2-substituted quinolone compound and use in pharmacy | |
| CN112225748B (en) | Small molecule compound with FLT3 kinase inhibitory activity and application thereof | |
| WO2010020810A1 (en) | 2-(imidaz0lylamin0)-pyridine derivatives and their use as jak kinase inhibitors | |
| CA3174865A1 (en) | Quinazoline compound and preparation method, application, and pharmaceutical composition thereof | |
| EP2794569A1 (en) | Heterocyclic urea compounds | |
| WO2008135786A1 (en) | Amino-thiazolyl- pyrimidine derivatives and their use for the treatment of cancer | |
| CN103880822B (en) | Containing 2,4,6-trisubstituted pyrimidine compounds of 1,2,3-triazole, preparation method and application thereof | |
| CN107311937A (en) | The licochalcone A dihydro amino-metadiazine compound and its synthetic method of one class tool antitumor activity | |
| CN111518104B (en) | 1,2, 4-triazolo [1,5-a ] pyrimidine compound containing thiourea pyrimidine and preparation method and application thereof | |
| CN112457260B (en) | N-heterocyclic aryl quinazoline-4-amine compound and preparation method thereof | |
| AU6280199A (en) | 2-piperazino alkylamino benzoazole derivatives: dopamine receptor subtype specific ligands | |
| CN101870696B (en) | N-aryl piperazine derivative having double activity of dopamine D2 and 5-HT2a | |
| CN106432208B (en) | amino dithioformic acid (sulfamoyl) ethyl ester compound and preparation method and application thereof | |
| CN1325494C (en) | 3-substituted nalidixic acid analog compound and its preparation method and uses in pharmacy | |
| CN106939002B (en) | A kind of crystal form and preparation method thereof of BTK kinase inhibitor | |
| CN105481778A (en) | Pyrimidine derivative, preparation method and applications thereof | |
| CN105237512A (en) | 6-substituted-1-((1-substituted phenyl-1,2,3-triazole-4-yl)methyl)-4-carbonylquinoline-3-carboxylic acid or pharmaceutical salt, preparation and application |
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 | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090520 Termination date: 20130309 |