CN101012224A - Quinoline derivative, preparation method and medical use thereof - Google Patents

Quinoline derivative, preparation method and medical use thereof Download PDF

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CN101012224A
CN101012224A CN 200710019900 CN200710019900A CN101012224A CN 101012224 A CN101012224 A CN 101012224A CN 200710019900 CN200710019900 CN 200710019900 CN 200710019900 A CN200710019900 A CN 200710019900A CN 101012224 A CN101012224 A CN 101012224A
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quinoline
amino
halogen
methyl
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CN100540551C (en
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尤启冬
曹鑫
刘晓蓉
李志裕
陆小云
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The invention discloses a making method of compound I and drug composition and application to treat tumour, which is 3-nitrile quinoline derivant (I) as dual-inhibitor protein kinase of tyrosine and nitric oxide synthase, wherein G1, G2, G3, G4, X, Z and n are defined as instruction.

Description

Quinoline, its preparation method and medicinal use thereof
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a class tyrosine protein kinase and nitric oxide synthetase double inhibitor 3-itrile group quinoline, the invention also discloses its preparation method, contain its pharmaceutical composition, and be used for the treatment of the purposes of tumor disease.
Background technology
Tyrosine protein kinase (protein tyrosine kinase, PTK) for a kind of can catalysis ATP or GTP on γ-phosphoric acid transfer to protein kinase family on the receptor tyrosine residue of protein substrate from donor, in (for example mitotic division of many cell regulate processes, cytodifferentiation, grow, the formation of tumour, vascularization, apoptosis, cell forms and sticks, cell cycle regulating, the cell adjusting and controlling growth, T cell and B cell-stimulating, the reaction of extracellular stimulus, the conduction of neurotransmitter signal, platelet activation, transcriptional control, the absorption of glucose) plays an important role in.Yet in some cases, the result as sudden change or transition expression is lacked of proper care by the PTKs Mediated Signal Transduction.Cause growth of tumor and this disease of cancer takes place thereby the result of this situation is a uncontrolled cellular proliferation.In addition, in mammalian body, nitric oxide synthetase (NOS) also plays an important role to the generation and the autoimmunity of tumour.NOS mainly contains two class isozyme: primary type (Constitutive NOS, cNOS) and induce type (inducible NOS, iNOS), the former mainly is present in endotheliocyte and neurocyte, main information transfer function of exercising cell, the latter mainly is present in scavenger cell and some other cell, carries out immunologic function.Therefore, be pursuant to the difference of the growing amount of NO, NO has dual function for tumour cell.On the one hand, the NO that continues suitable concn (pmol or fmol level) produces, and helps tumor growth, and under the synergy of angiogenesis factor, stimulates new vessel to generate, and then promotes growth of tumor and diffusion; On the other hand, produce the NO of high density (nmol level) when having a liking for cell-stimulating in that immunity of organism is huge, mainly play cytotoxicity, suppress and kill and wound normal cell, or the trigger cell cycle is out of control, promotes tumour to take place.So optionally suppress the iNOS of mammalian cell, can reduce NO level in the tumour cell, do not influencing or seldom influencing under the situation of the content of NO in other tissue or the cell, tumor growth and diffusion there are certain restraining effect.
Summary of the invention
The invention discloses a class 3-itrile group quinoline, they have the double inhibition function, can suppress simultaneously to express and too much activated PTKs and iNOS, and treatment is potential treatment cancer drugs by these 2 not normal tumours that cause of aspects regulation and control.
3-itrile group quinoline general structure of the present invention (I) is as follows:
Figure A20071001990000051
Wherein
Wherein Z represents O, S or NR, and R represents the alkyl of hydrogen or 1 to 3 carbon atom;
X represents 5 yuan or 6 yuan of aromatic rings, described aromatic ring contains 1 to 3 heteroatoms that independently is selected from N, O and S, and aromatic ring can be replaced by 1 to 4 following substituting group: alkyl, halogenated methyl, hydroxyl, trifluoromethyl, trifluoromethoxy, itrile group, nitro, carboxyl, benzoyl, amino, alkoxyl group, phenoxy group or the sulfydryl of halogen, 1 to 3 carbon atom; Or X represents the bicyclic heteroaryl ring of 8 to 10 atoms, described heteroaryl ring contains 1 to 4 heteroatoms that independently is selected from N, O and S, and they can be replaced by 1 to 4 following substituting group: alkyl, halogenated methyl, hydroxyl, trifluoromethyl, trifluoromethoxy, itrile group, nitro, carboxyl or the benzoyl of halogen, 1 to 3 carbon atom;
G 1Or G 4Independently represent hydrogen or halogen separately;
G 2Or G 3Independently represent separately alkyl, methylol, the halogenated methyl of hydrogen, halogen, 1 to 6 carbon atom, 1 to 6 carbon atom alkoxyl group, hydroxyl, trifluoromethyl, trifluoromethoxy, itrile group, nitro, carboxyl, amino, hydroxylamino, phenoxy group, phenyl, benzyl, N-alkyl-carbamoyl, phenyl amino, benzylamino,
Figure A20071001990000052
Wherein Y represents O, NR or S, and R represents hydrogen or 1 to 3 carbon atom; The R1 representative contains the saturated heterocyclic of 4 to 7 atoms, described heterocycle contains 1 to 3 heteroatoms that independently is selected from N, O or S, can there be 1 to 4 substituting group to replace on this heterocycle, described substituting group be selected from methyl, ethyl, third class, halogen, hydroxyl, methylol, hydroxyethyl, aminomethyl, dimethylamino, aminoethyl, methylamino-, ethylamino or diethylin, m is 0 to 4 integer;
N represents 0,1 or 2.
G 2Preferred represent methylidene, methoxyl group, oxyethyl group, dimethylamino, diethylin, halogen or first sulfydryl.
G 3Preferred representative
Figure A20071001990000053
Y represents O, NH or S; The R1 representative contains the saturated heterocyclic of 5 to 6 atoms, described heterocycle contains 1 to 3 heteroatoms that independently is selected from N, O and S, can also have 1 to 4 substituting group to replace on this heterocycle, described substituting group be selected from methyl, ethyl, third class, halogen, hydroxyl, methylol, hydroxyethyl, aminomethyl, dimethylamino, aminoethyl, methylamino-, ethylamino or diethylin; M represents 0 to 3 integer.
X preferably represents 5 yuan or 6 yuan of aromatic rings, and described aromatic ring contains 1 to 3 heteroatoms that independently is selected from N, O and S.
X also preferably represents the heteroaryl ring of the dicyclo that does not contain or contain 1 substituent 8 to 10 atom; described heteroaryl ring contains 1 to 4 heteroatoms that independently is selected from N, O or S, and described substituting group is alkyl, halogenated methyl, hydroxyl, trifluoromethyl, trifluoromethoxy, itrile group, nitro, carboxyl or the benzoyl of halogen, 1 to 3 carbon atom.
X further preferably represents phenyl ring, (2-pyridine) base, (2-[4-morpholinodithio) base, (2-benzoglyoxaline) base, (2-[4-morpholinodithio) base that replaces or (2-benzoglyoxaline) base that replaces, and wherein substituting group is selected from halogen, methyl, trifluoromethyl, trifluoromethoxy, methoxyl group, oxyethyl group, amino, nitro or hydroxyl.
Z preferably represents NH.
N is preferably 0.
G 1The preferred hydrogen of representing.
The preferred compound of the present invention's part is as follows:
6-methyl-4-(replacing benzothiazole-2-amino)-7-(alkoxyl group-3-substituted piperidine)-3-itrile group quinoline;
6-methyl-4-(replacing benzothiazole-2-amino)-7-(alkoxyl group-3-substituted-piperazinyl)-3-itrile group quinoline;
6-methyl-4-(replacing benzothiazole-2-amino)-7-(alkoxyl group-3-piperazine)-3-itrile group quinoline;
6-methyl-4-(replacing benzothiazole-2-amino)-7-(alkoxyl group-3-morpholine)-3-itrile group quinoline;
6-methyl-4-(replacing benzothiazole-2-amino)-7-(alkoxyl group-3-pyrroles)-3-itrile group quinoline;
6-methoxyl group-4-(replacing benzothiazole-2-amino)-7-(alkoxyl group-3-substituted piperidine)-3-itrile group quinoline;
6-methoxyl group-4-(replacing benzothiazole-2-amino)-7-(alkoxyl group-3-substituted-piperazinyl)-3-itrile group quinoline;
6-methoxyl group-4-(replacing benzothiazole-2-amino)-7-(alkoxyl group-3-morpholine)-3-itrile group quinoline;
6-methoxyl group-4-(replacing benzothiazole-2-amino)-7-(alkoxyl group-3-pyrroles)-3-itrile group quinoline;
6-methyl-4-(replacing benzothiazole-2-amino)-7-(alkylamino radical-3-substituted piperidine)-3-itrile group quinoline;
6-methyl-4-(replacing benzothiazole-2-amino)-7-(alkylamino radical-3-substituted-piperazinyl)-3-itrile group quinoline;
6-methyl-4-(replacing benzothiazole-2-amino)-7-(alkylamino radical-3-piperazine)-3-itrile group quinoline;
6-methyl-4-(replacing benzothiazole-2-amino)-7-(alkylamino radical-3-morpholine)-3-itrile group quinoline;
6-methyl-4-(replacing benzothiazole-2-amino)-7-(alkylamino radical-3-pyrroles)-3-itrile group quinoline;
6-methoxyl group-4-(replacing benzothiazole-2-amino)-7-(alkylamino radical-3-substituted piperidine)-3-itrile group quinoline;
6-methoxyl group-4-(replacing benzothiazole-2-amino)-7-(alkylamino radical-3-substituted-piperazinyl)-3-itrile group quinoline;
6-methoxyl group-4-(replacing benzothiazole-2-amino)-7-(alkylamino radical-3-morpholine)-3-itrile group quinoline;
6-methoxyl group-4-(replacing benzothiazole-2-amino)-7-(alkylamino radical-3-pyrroles)-3-itrile group quinoline;
6-methyl-4-(substituted benzimidazole-2-amino)-7-(alkoxyl group-3-substituted piperidine)-3-itrile group quinoline;
6-methyl-4-(substituted benzimidazole-2-amino)-7-(alkoxyl group-3-substituted-piperazinyl)-3-itrile group quinoline;
6-methyl-4-(substituted benzimidazole-2-amino)-7-(alkoxyl group-3-piperazine)-3-itrile group quinoline;
6-methyl-4-(substituted benzimidazole-2-amino)-7-(alkoxyl group-3-morpholine)-3-itrile group quinoline;
6-methyl-4-(substituted benzimidazole-2-amino)-7-(alkoxyl group-3-pyrroles)-3-itrile group quinoline;
6-methoxyl group-4-(substituted benzimidazole-2-amino)-7-(alkoxyl group-3-substituted piperidine)-3-itrile group quinoline;
6-methoxyl group-4-(substituted benzimidazole-2-amino)-7-(alkoxyl group-3-substituted-piperazinyl)-3-itrile group quinoline;
6-methoxyl group-4-(substituted benzimidazole-2-amino)-7-(alkoxyl group-3-morpholine)-3-itrile group quinoline;
6-methoxyl group-4-(substituted benzimidazole-2-amino)-7-(alkoxyl group-3-pyrroles)-3-itrile group quinoline;
6-methyl-4-(substituted benzimidazole-2-amino)-7-(alkylamino radical-3-substituted piperidine)-3-itrile group quinoline;
6-methyl-4-(substituted benzimidazole-2-amino)-7-(alkylamino radical-3-substituted-piperazinyl)-3-itrile group quinoline;
6-methyl-4-(substituted benzimidazole-2-amino)-7-(alkylamino radical-3-piperazine)-3-itrile group quinoline;
6-methyl-4-(substituted benzimidazole-2-amino)-7-(alkylamino radical-3-morpholine)-3-itrile group quinoline;
6-methyl-4-(substituted benzimidazole-2-amino)-7-(alkylamino radical-3-pyrroles)-3-itrile group quinoline;
6-methoxyl group-4-(substituted benzimidazole-2-amino)-7-(alkylamino radical-3-substituted piperidine)-3-itrile group quinoline;
6-methoxyl group-4-(substituted benzimidazole-2-amino)-7-(alkylamino radical-3-substituted-piperazinyl)-3-itrile group quinoline;
6-methoxyl group-4-(substituted benzimidazole-2-amino)-7-(alkylamino radical-3-morpholine)-3-itrile group quinoline;
6-methoxyl group-4-(substituted benzimidazole-2-amino)-7-(alkylamino radical-3-pyrroles)-3-itrile group quinoline;
6-methyl-4-substituted-amino pyridine-7-(alkoxyl group-3-substituted piperidine)-3-itrile group quinoline;
6-methyl-4-substituted-amino pyridine-7-(alkoxyl group-3-substituted-piperazinyl)-3-itrile group quinoline;
6-methyl-4-substituted-amino pyridine-7-(alkoxyl group-3-piperazine)-3-itrile group quinoline;
6-methyl-4-substituted-amino pyridine-7-(alkoxyl group-3-morpholine)-3-itrile group quinoline;
6-methyl-4-substituted-amino pyridine-7-(alkoxyl group-3-pyrroles)-3-itrile group quinoline;
6-methoxyl group-4-substituted-amino pyridine-7-(alkoxyl group-3-substituted piperidine)-3-itrile group quinoline;
6-methoxyl group-4-substituted-amino pyridine-7-(alkoxyl group-3-substituted-piperazinyl)-3-itrile group quinoline;
6-methoxyl group-4-substituted-amino pyridine-7-(alkoxyl group-3-morpholine)-3-itrile group quinoline;
6-methoxyl group-4-substituted-amino pyridine-7-(alkoxyl group-3-pyrroles)-3-itrile group quinoline;
6-methyl-4-substituted-amino pyridine-7-(alkylamino radical-3-substituted piperidine)-3-itrile group quinoline;
6-methyl-4-substituted-amino pyridine-7-(alkylamino radical-3-substituted-piperazinyl)-3-itrile group quinoline;
6-methyl-4-substituted-amino pyridine-7-(alkylamino radical-3-piperazine)-3-itrile group quinoline;
6-methyl-4-substituted-amino pyridine-7-(alkylamino radical-3-morpholine)-3-itrile group quinoline;
6-methyl-4-substituted-amino pyridine-7-(alkylamino radical-3-pyrroles)-3-itrile group quinoline;
6-methoxyl group-4-substituted-amino pyridine-7-(alkylamino radical-3-substituted piperidine)-3-itrile group quinoline;
6-methoxyl group-4-substituted-amino pyridine-7-(alkylamino radical-3-substituted-piperazinyl)-3-itrile group quinoline;
6-methoxyl group-4-substituted-amino pyridine-7-(alkylamino radical-3-morpholine)-3-itrile group quinoline;
6-methoxyl group-4-substituted-amino pyridine-7-(alkylamino radical-3-pyrroles)-3-itrile group quinoline.
The compounds of this invention can contain one or more unsymmetrical carbon; In this case, The compounds of this invention comprises its various single diastereomers, raceme and single R and S enantiomer.
The compounds of this invention can with pharmacy acceptable salt in conjunction with salify.This paper adopts the form of selecting suitable salt according to institute's salt-forming compound physics and chemical stability, water absorbability and solvability well known to those skilled in the art.Pharmaceutically acceptable salt can be used organic or inorganic alkali form.For example with basic metal or alkaline-earth metal (as sodium, potassium, calcium or magnesium) or organic bases and N-tetraalkylammonium salt (as the N-TBuA) salify.For the formula with basic group (I) compound, then can be by organic or inorganic acid salify.For example can be by hydrochloric acid, sulfuric acid, sulfuric acid, phosphoric acid, formic acid, acetate, propionic acid, lactic acid, citric acid, tartrate, succsinic acid, fumaric acid, toxilic acid, tussol, oxysuccinic acid, camphorsulfonic acid and similar known acceptable acid formation salt.
The The compounds of this invention compound also can adopt makes ester, carbamate and other prodrug forms, and when with this form administration, it changes the activity form onset in vivo into.
The invention also discloses a kind of medicinal compositions, wherein contain The compounds of this invention or its pharmaceutical salts and the pharmaceutically acceptable carrier of significant quantity.
Except that these purposes, described herein part of compounds can be used as the intermediate for preparing other compounds of the present invention.
According to different substituting groups, compound of the present invention can prepare with following method:
Method 1:
Figure A20071001990000091
Method 3:
Figure A20071001990000101
Wherein Z, X, n, G 1, G 2, G 3, G 4, Y, m and R 1Meaning is as indicated above.
Compound of the present invention is estimated with several standard pharmacology inspection procedures, and the result shows that The compounds of this invention has remarkable activity and can be used as antitumour drug as PTKs and no inhibitor.Can be used for the treatment of or suppress on those nosetiology to small part by PTKs and the caused disease of NOS functional disorder.Based on shown activity in the described standard pharmacology testing procedures evaluation, The compounds of this invention thereby can be used for antitumor field, the scope of application comprises mammary cancer, kidney, bladder cancer, oral carcinoma, laryngocarcinoma, the esophageal carcinoma, cancer of the stomach, colorectal carcinoma, ovarian cancer, uterus carcinoma, lung cancer, carcinoma of the pancreas, prostate cancer, liver cancer, skin carcinoma and leukemia etc.
Be the pharmacology test and the data of part of compounds of the present invention below:
One, anti-tumour cell proliferative sulphonyl rhodamine B (SRB) test
SR (Sulforhodamine) is a kind of fluorescence dye, can combine with the basic aminoacids of cell protein after trichoroacetic acid(TCA) is fixing and develop the color, manifest a kind of bright pink, its absorbance measurement, the numerical value of the cell protein content of a sensitivity can be provided, showing cell with this and suppress situation, is a kind of in recent years method of newer screening cancer therapy drug.
SRB test concrete operations are as follows: get lung cell A549 (Lung, A549), stomach cancer cell AGS (Stomach, AGS), colon cancer cell (HT-29 Colon, HT-29) and prostate cancer cell PC-3 (Prostate, PC-3), add 10% fresh calf serum with the RPMI1640 substratum and place 37 ℃ of temperature, CO 2The cell culture incubator of content 5% is hatched; (Liver HepG2), adds 10% fresh calf serum with the MEM substratum and places 37 ℃ of temperature, CO to get liver cancer cell HepG2 2The cell culture incubator of content 5% is hatched; According to 10000 cells/well 5 kinds of cancer cells being inoculated in 96 orifice plates respectively then hatched in cell culture incubator 24 hours.Different pharmaceutical concentration and blank are set, establish 3 parallel multiple holes for every group.T 0The moment and 48 hours are detected the cell dyeing situation according to the standard schedule of dyeing reading with the long microplate reader of all-wave respectively, and then draw compound for the effect of cancer proliferation cell inhibiting.
Test-results sees Table 1
Table 1 The compounds of this invention is to the restraining effect of various tumour cells.
Compound number Growth of tumour cell rate % (10 μ M)
Lung，A549 Stomach，AGS Liver，HepG2 Colon，HT-29 Prostate，PC-3
CPU-Y001 59.14 35.34 28.86 64.55 54.35
CPU-Y002 86.04 47.75 71.75 66.85 63.26
CPU-Y004 89.61 80.77 111.41 120.99 88.71
CPU-Y005 97.40 100.21 101.07 112.97 90.19
CPU-Y006 115.97 83.89 87.10 119.54 90.19
CPU-Y007 110.88 99.58 119.91 111.86 83.51
CPU-Y008 95.98 97.89 117.14 109.63 84.06
CPU-Y009 108.08 92.87 110.03 111.19 83.43
CPU-Y010 95.39 31.01 37.10 92.70 67.68
CPU-Y011 108.77 97.04 95.65 116.53 77.15
CPU-Y012 78.04 77.08 71.13 85.06 56.70
CPU-Y015 99.88 106.67 115.46 84.00 101.16
CPU-Y016 94.25 106.79 124.44 107.62 99.07
CPU-Y017 72.44 80.62 82.23 80.36 78.94
CPU-Y019 104.77 108.53 116.06 109.73 94.90
CPU-Y020 109.00 110.15 116.00 108.94 79.88
CPU-Y021 79.55 78.90 79.64 70.00 78.31
CPU-Y022 83.75 83.09 87.37 78.90 67.34
CPU-Y041 86.77 72.11 83.04 64.11 77.35
CPU-Y042 101.92 72.03 86.27 81.01 73.66
CPU-Y013 51.49 26.20 51.13 75.53 30.87
CPU-Y043 9.32 3.80 9.20 -2.84 7.81
Wherein CPU-Y013 and CPU-Y043 are respectively the compd E KB-569 and the SKI-606 of Wyeth exploitation, are the activity positive control drugs preferably of open report.From above-mentioned data as can be seen, compound of the present invention has certain antitumous effect, and some compound has the activity that is better than reference substance for certain cancer.
The structure of listed compound code name correspondence is as follows in the table 1:
CPU-Y001 CPU-Y002
Figure A20071001990000121
Figure A20071001990000131
Two, the inhibition activity test of compound pair cell nitric oxide synthetase
Measure the inhibition activity that institute's synthetic compound generates NO by NO growing amount in the mensuration mouse macrophage.
Nitric oxide synthetase detection kit (Nitric oxide synthase assay kit) is adopted in this test, this test kit provides under physiological condition by the method for fluoroscopic examination viable cell intracellular nitric oxide synthase activity, does not need the radio isotope that uses traditional method required.Test kit adopt can permeates cell membranes nitrogen protoxide fluorescent detection probe DAF-FMDA (3-amino-4-aminomethyl-2 ', 7 '-difluorescein, diacetate), detect the nitrogen protoxide amount that intracellular nitric oxide synthetase can catalysis produces providing under the condition of competent substrate, thereby detect the activity of nitric oxide synthetase.
Testing used cell is the mouse ANA-1 scavenger cell higher to the iNOS expression amount, process of the test is as follows: earlier cell inoculation is carried out monolayer culture in culturing bottle, nutrient solution is the RPMI1640 nutrient solution [ (calf serum)=10%] that contains calf serum, 37 ℃, and air  (CO 2Cultivate under)=5% condition.Then with cell inoculation in 96 well culture plates, treat that cell grows up to continuous individual layer after, every hole adds reaction buffer and LPS (final concentration 20 μ mol/L).In incubator, hatch 24 backs by requirement of experiment grouping administration, add blank group and control group.Treat behind the drug effect 30min centrifugally, inhale and remove supernatant liquor, after PBS cleans 2 times, with the long fluorescence microplate reader mensuration of Varioskan all-wave detection reaction result.Excitation wavelength is 495nm, and emission wavelength is 515nm.Carrying out the relative vigor of iNOS enzyme by survey fluorescence numerical value calculates.The relative vigor of iNOS enzyme=(RFU Stimulate-RFU ( Stimulate+ Inhibitor))/(RFU Stimulate-RFU Blank), RFU, relative fluorescence unit is the relative intensity of fluorescence that practical measurement obtains.Use LOGIT method computerized compound IC by the relative vigor of iNOS enzyme 50Numerical value.Test-results sees Table 2
Table 2 The compounds of this invention is to the IC of iNOS 50
Compound number iNOS IC 50/μM Compound number iNOS IC 50/μM
CPU-Y001 30.7 CPU-Y015 139
CPU-Y002 156 CPU-Y016 21.4
CPU-Y004 98 CPU-Y017 28.7
CPU-Y005 412 CPU-Y019 181
CPU-Y006 44.8 CPU-Y020 65.6
CPU-Y007 50.9 CPU-Y021 26.7
CPU-Y008 12.7 CPU-Y022 2.18
CPU-Y009 16.3 CPU-Y041 18.6
CPU-Y010 313 CPU-Y042 15.5
CPU-Y011 58.9 CPU-Y003’ 18
CPU-Y012 7.14 CPU-Y013’ 42
Wherein CPU-Y003 ' and CPU-Y013 ' are respectively thiazolamine and L-Canavanine, are the activity positive control drugs preferably of open report.This patent institute inclusion compound reaches the active amt level of existing positive drug report as can be seen, and some compound has the activity more than 10 times that is better than reference substance.The structural formula of listed compound code name correspondence is the same in the table 2.
The compounds of this invention can be used as prodrug and plays a role in vivo.By chemical reaction or metabolic result, The compounds of this invention can be transformed into the compound that can be used for treating tumour.
The compounds of this invention can be made preparation for administration separately or with one or more pharmaceutically acceptable carrier combinations.For example, solvent, thinner etc. can be used the oral dosage form administration, but as tablet, capsule dispersed powders, granule etc.Can contain for example activeconstituents of 0.05% to 90% weight with carrier combinations in these medicinal preparationss, the activeconstituents of weight between more common about 15% to 60%.The compounds of this invention dosage can be 0.001～100mg/kg/ days, also can depart from this dosage range according to the difference of disease degree or the difference of formulation.
For tumor treatment, can be with The compounds of this invention and other antitumorigenic substances or radiotherapy combined utilization.These other materials or radiotherapy can give simultaneously or at different time with The compounds of this invention.These combination therapys can produce synergy and can improve action effect.For example, can be with The compounds of this invention and following medication combined use: mitotic inhibitor (as taxol or vinealeucoblastine(VLB)), alkylating agent (as endoxan or cis-platinum), antimetabolite (as 5 FU 5 fluorouracil or hydroxyurea), DNA intercalating agent (as Zorubicin), topoisomerase enzyme inhibitor (as camptothecine).
Embodiment
Embodiment 1
3-isopropoxy-4-methyl oil of mirbane (1)
3-hydroxy-4-methyl oil of mirbane 60g (0.39mol) and salt of wormwood 100g (0.72mol) are joined in the 500ml three-necked bottle, be dissolved in acetone 300ml, mechanical stirring slowly drips 2-N-PROPYLE BROMIDE 50ml (0.50mol), and 40 ℃ were reacted 6 hours.With in the reaction solution impouring 1000ml water, use chloroform extraction 3 times then, concentrated extract, vacuum-drying gets pale brown look liquid product 72.2g, productive rate 95%.Molecular formula: C10H13NO3, molecular weight: 195.22
MS(EI)m/z195。
Embodiment 2
3-isopropoxy-4-monomethylaniline (2)
Iron powder 41g (0.73mol), water 200ml, acetic acid 50ml and ethanol 50ml are added respectively in the 500ml three-necked bottle, stir and be heated to 30 ℃ of reaction 20min, slowly drip 3-isopropoxy-4-methyl oil of mirbane 60g (0.31mol) then, 50 ℃ were reacted 2 hours, suction filtration, merging filtrate is used chloroform extraction 3 times, concentrated extract, vacuum-drying get brown oily liquids 45g.Productive rate 89%.Molecular formula: C10H15NO, molecular weight: 165.24.
MS(EI)m/z165。
Embodiment 3
(Z)-2-itrile group-3-(3-isopropoxy-4-methylbenzene-amino)-ethyl propenoate (3)
3-isopropoxy-4-monomethylaniline 45g (0.27mol), (Z)-3-oxyethyl group-2-itrile group-ethyl propenoate 51g (0.30mol) and toluene 160ml are added in the 250ml three-necked bottle, heated and stirred, back flow reaction 4 hours, be cooled to room temperature, separate out a large amount of white solids, suction filtration, reclaim toluene in the filtrate, the filter cake ethyl alcohol recrystallization gets product 72g, productive rate 93%.Molecular formula: C16H20N2O3, molecular weight: 288.35.Mp：138℃.
MS(EI)m/z288。
1H-NMR(AV-500，δ，DMSO-d 6)：1.21-1.28(m，9H)；2.08(s，3H)；4.14-4.26(t，2H)；4.55-4.57(m，1H)；6.81-6.89(m，2H)；7.01-7.02(d，1H)；8.26-8.39(t，1H)；10.58-10.68(d，1H)
Embodiment 4
7-isopropoxy-6-methyl-4-oxo-1,4-dihydro-3-itrile group quinoline (4)
(Z)-2-itrile group-3-(3-isopropoxy-4-toluidine) ethyl propenoate 60g (0.21mol) and whiteruss 300ml are joined in the 500ml three-necked bottle N 2Protection, 240 ℃ were reacted 4 hours, and being cooled to room temperature has the brown solid to separate out suction filtration; filter cake is washed till canescence with sherwood oil, uses re-crystallizing in ethyl acetate then, the dry beige solid 20.4g that gets; productive rate 40%, molecular formula: C14H14N2O2, molecular weight: 242.28.Mp：＞300℃。
MS(EI)m/z242。
1H-NMR(AV-500，δ，DMSO-d 6)：1.21-1.22(s，6H)；2.10(s，3H)；4.55-4.57(m，1H)；7.06(s，1H)；7.48(s，1H)；8.58(s，1H)
Embodiment 5
4-chloro-7-isopropoxy-6-methyl-3-itrile group quinoline (5)
With 7-isopropoxy-6-methyl isophthalic acid, 4-dihydro-4-oxo-3-itrile group quinoline 12.1g (0.05mol) and phosphorus oxychloride 40ml add in the single neck bottle of 100ml, heating reflux reaction 4 hours, the pressure reducing and steaming phosphorus oxychloride is transferred PH to 7 with the unsaturated carbonate potassium solution, chloroform extraction, silica gel column chromatography gets white cotton-shaped solid 8.8g, productive rate 68%, molecular formula: C14H13C1N2O, molecular weight: 260.73.Mp：142℃。
MS(EI)m/z260。
1H-NMR(AV-500，δ，DMSO-d 6)：1.38-1.40(s，6H)；2.38(s，3H)；7.51(s，1H)；8.05-8.06(d，1H)；9.02(s，1H)
Embodiment 6
4-(6-methylbenzothiazole-2-amino)-7-isopropoxy-6-methyl-3-itrile group quinoline (6)
2-aminobenzothiazole 2g (0.012mol) is added in the single neck bottle of 100ml, be dissolved in dry DMF 20ml, add NaH0.5g, after room temperature activates half an hour, with 4-chloro-7-isopropoxy-6-methyl-3-itrile group quinoline 2.4g (0.01mol) slowly splashes in the reaction flask, dropwise and be heated to backflow, reacted 6 hours, have faint yellow solid to separate out, the cooling suction filtration, the filter cake ethyl alcohol recrystallization, dry product 2.33g, the productive rate 60% of getting.Molecular formula: C22H20N4OS, molecular weight: 388.49.Mp：187℃(dec)。
MS(EI)m/z388。
1H-NMR(AV-500，δ，DMSO-d 6)：1.41-1.42(s，6H)；2.36(s，3H)；2.43(s，3H)；4.85-4.89(m，1H)；7.18(s，1H)；7.31-7.38(dd，1H)；7.95(s，1H)；8.40(s，1H)；8.93(s，1H)；9.32-9.35(d，1H)；9.58(s，1H)
Embodiment 7
4-(6-methylbenzothiazole-2-amino)-7-hydroxyl-6-methyl-3-itrile group quinoline (7)
4-(6-methylbenzothiazole-2-amino)-7-isopropoxy-6-methyl-3-itrile group quinoline 0.78g (0.002mol), aluminum chloride 0.53g (0.004mol) and methylene dichloride 30ml are added in the single neck bottle of 50ml, 0-5 ℃ was reacted 1 hour, and had yellow solid to separate out.Suction filtration respectively cleans filter cake 3 times with 0.1N hydrochloric acid and water, dry yellow product 0.52g, the productive rate 75% of getting.Molecular formula: C19H14N4OS, molecular weight: 346.41.Mp：251℃。
MS(EI)m/z346。
1H-NMR(AV-500，δ，DMSO-d 6)：2.30(s，3H)；2.46(s，3H)；7.30(s，1H)；7.35-7.37(dd，1H)；7.99(s，1H)；8.42(s，1H)；8.96(s，1H)；9.33(s，1H)；9.60(s，1H)
Embodiment 8
4-(6-methylbenzothiazole-2-amino)-7-(3-chlorine propoxy--)-6-methyl-3-itrile group quinoline (8)
4-(6-methylbenzothiazole-2-amino)-7-hydroxyl-6-methyl-3-itrile group quinoline 0.51g (1.5mmol) and salt of wormwood 0.30g (2.1mmol) are added in the 50ml three-necked bottle, be dissolved in DMF30ml, add 1-bromo-3-chloropropane 0.1ml (1.6mmol) then, 60 ℃ were reacted 3 hours, and in reaction solution impouring 50ml water, had cotton-shaped solid to separate out, suction filtration, the filter cake recrystallizing methanol gets faint yellow solid 0.39g, productive rate 60%.Molecular formula: C22H19ClN4OS, molecular weight: 422.94.Mp：248℃(dec)。
MS(EI)m/z422。
1H-NMR(AV-500，δ，DMSO-d 6)：2.27-2.29(m，2H)；2.31(s，3H)；2.44(s，3H)；3.80-3.84(t，2H)；4.34-4.38(t，2H)；7.30(s，1H)；7.36-7.37(dd，1H)；7.99(s，1H)；8.43(s，1H)；8.99(s，1H)；9.35(s，1H)
Embodiment 9
6-methyl-4-(6-methylbenzothiazole-2-amino)-7-(propoxy--3-piperidines)-3-itrile group quinoline (9, CPU-Y010)
4-(6-methylbenzothiazole-2-amino)-7-(propoxy--3-chlorine)-6-methyl-3-itrile group quinoline 0.127g (0.3mmol) and salt of wormwood 0.10g (0.7mmol) are joined in the 25ml three-necked bottle, be dissolved in DMF15ml, add piperidines 0.1ml (0.1mmol) then, 80 ℃ were reacted 4 hours.In reaction solution impouring 50ml water, there is faint yellow solid to separate out, the dry crude product 0.12g that gets of suction filtration.Column chromatography gets pure product 0.10g, productive rate 70.8%.Molecular formula: C27H29N5OS, molecular weight: 471.63.Mp：270℃。
MS(EI)m/z471。
1H-NMR(AV-500，δ，DMSO-d 6)：1.18(m，8H)；1.82(s，3H)；2.34-2.45(m，2H)；3.02-3.25(m，5H)；3.47-3.51(m，2H)；4.29-4.33(t，3H)；7.46-7.50(d，1H)；7.57(s，1H)；7.93(s，1H)；8.56(s，1H)；8.78-8.81(d，1H)；9.51(s，1H)
Embodiment 10
6-methyl-4-(6-methylbenzothiazole-2-amino)-7-(propoxy--3-(4-methylpiperazine) base)-3-itrile group quinoline (10, CPU-Y008)
With embodiment 9 methods, piperidines is replaced to methylpiperazine, other preparation method is identical, promptly.
Molecular formula: C27H30N6OS, molecular weight: 486.64.Mp：272℃。
MS(EI)m/z486。
1H-NMR(AV-500，δ，D 2O)：1.99(s，3H)；2.27(m，5H)；3.06(s，3H)；3.43(m，2H)；3.73-3.85(m，10H)；6.70(s，1H)；7.10-7.12(d，1H)；7.36(s，1H)；7.64(s，1H)；7.90-7.92(d，1H)；8.93(s，1H)
Embodiment 11
6-methyl-4-(6-methylbenzothiazole-2-amino)-7-(propoxy--morpholinyl)-3-itrile group quinoline (11, CPU-Y012)
With embodiment 9 methods, piperidines is replaced to morpholine, other preparation method is identical, promptly.
Molecular formula: C26H27N5O2S, molecular weight: 473.60.Mp：279℃。
MS(EI)m/z473。
1H-NMR(AV-500，δ，D 2O)：1.44(m，2H)；2.63(m，7H)；3.44(s，3H)；3.64(m，2H)；3.77(m，2H)；4.02(m，4H)；7.05(m，2H)；7.73(s，1H)；8.04(s，1H)；8.44(m，1H)；9.43(s，1H)
Embodiment 12
2,3,4-trifluoromethyl aniline (12)
Iron powder 40g (0.72mol), water 200ml, acetic acid 50ml and ethanol 50ml are added respectively in the 500ml three-necked bottle, stir and be heated to 30 ℃ of reaction 20min, slowly drip 2,3 then, 4-trifluoronitrobenzene 50g (0.28mol), 60 ℃ were reacted 3 hours, suction filtration, merging filtrate is used chloroform extraction 3 times, concentrated extract, vacuum-drying get yellow oily liquid 35g.Productive rate 86%.Molecular formula: C6H4F3N, molecular weight: 147.10.
MS(EI)m/z147。
Embodiment 13
(Z)-2-cyano group-3-(2,3,4-trifluoro-benzene amido)-ethyl propenoate (13)
With 2,3,4-trifluoromethyl aniline 35g (0.24mol), (Z)-3-oxyethyl group-2-cyano group-ethyl propenoate 40g (0.24mol) and toluene 100ml add in the 250ml three-necked bottle, heated and stirred, back flow reaction 6 hours, be cooled to room temperature, separate out white solid, suction filtration, reclaim toluene in the filtrate, the filter cake ethyl alcohol recrystallization gets product 52g, productive rate 80%.Molecular formula: C12H9F3N2O2, molecular weight: 270.21.
MS(EI)m/z270。
Embodiment 14
6,7,8-three fluoro-4-oxos-1,4-dihydro-3-cyano quinolines (14)
(Z)-2-cyano group-3-(2,3,4-trifluoro-benzene amido)-ethyl propenoate 20g (0.074mol) and whiteruss 700ml are joined in the 1000ml three-necked bottle N 2Protection, 280 ℃ were reacted 6 hours, and being cooled to room temperature has the brown solid to separate out suction filtration; filter cake is washed till canescence with sherwood oil, uses re-crystallizing in ethyl acetate then, the dry beige solid 10g that gets; productive rate 60%, molecular formula: C10H3F3N2O, molecular weight: 224.14.Mp：＞300℃。
MS(EI)m/z224。
Embodiment 15
4-chloro-6,7,8-three fluoro-3-cyano quinolines (15)
With 6,7,8-three fluoro-4-oxos-1,4-dihydro-3-cyano quinolines 5g (0.022mol) and phosphorus oxychloride 40ml add in the single neck bottle of 100ml, heating reflux reaction 4 hours, the pressure reducing and steaming phosphorus oxychloride is transferred PH to 7 with the unsaturated carbonate potassium solution, chloroform extraction, silica gel column chromatography gets product 4.0g, productive rate 75%, molecular formula: C10H2F31N2, molecular weight: 242.59.。
MS(EI)m/z242。
Embodiment 16
4-(pyridine-2-amido)-6,7, and 8-three fluoro-3-cyano quinolines (16, CPU-Y007)
2-aminopyridine 0.10g (1.1mmol) is added in the single neck bottle of 50ml, be dissolved in dry DMF 10ml, add NaH 0.050g, after room temperature activates half an hour, with 4-chloro-6,7,8-three fluoro-3-cyano quinolines 0.24g (1mmol) slowly splash in the reaction flask, dropwise and be heated to backflow, reacted 6 hours, have faint yellow solid to separate out, the cooling suction filtration, the filter cake ethyl alcohol recrystallization, dry product 0.23g, the productive rate 77% of getting.Molecular formula: C15H7F3N4, molecular weight: 300.25.Mp：187℃(dec)。
MS(EI)m/z300。
1H-NMR(AV-300，δ，DMSO-d 6)：7.12-7.17(t，1H)，7.48-7.51(d，1H)，7.88-7.93(m，1H)，8.33-8.36(m，1H)，9.21-9.23(d，1H)，9.59(s，1H)，10.04(s，1H)
Embodiment 17
(Z)-2-cyano group-3-(3-chloro-4-fluoroanilino)-ethyl propenoate (17)
3-chloro-4-fluoroaniline 35g (0.24mol), (Z)-3-oxyethyl group-2-cyano group-ethyl propenoate 40g (0.24mol) and toluene 100ml are added in the 250ml three-necked bottle, heated and stirred, back flow reaction 6 hours, be cooled to room temperature, separate out white solid, suction filtration, reclaim toluene in the filtrate, the filter cake ethyl alcohol recrystallization gets product 60g, productive rate 93%.Molecular formula: C12H10C1FN2O2, molecular weight: 268.68.
MS(EI)m/z268。
Embodiment 18
6-fluoro-7 chloro-4-oxos-1,4-dihydro-3-cyano quinolines (18)
(Z)-2-cyano group-3-(3-chloro-4-fluoroanilino)-ethyl propenoate 20g (0.075mol) and whiteruss 700ml are joined in the 1000ml three-necked bottle N 2Protection, 270 ℃ were reacted 6 hours, and being cooled to room temperature has the brown solid to separate out, suction filtration, filter cake is washed till canescence with sherwood oil, uses re-crystallizing in ethyl acetate then, dry beige solid 12g, productive rate 60%, molecular formula: C10H4ClFN2O, the molecular weight: 222.61 of getting
Mp：＞250℃。
MS(EI)m/z222。
Embodiment 19
4,7-two chloro-6-fluoro-3-cyano quinolines (19)
With 6-fluoro-7 chloro-4-oxos-1,4-dihydro-3-cyano quinolines 5g (0.023mol) and phosphorus oxychloride 40ml add in the single neck bottle of 100ml, heating reflux reaction 4 hours, the pressure reducing and steaming phosphorus oxychloride is transferred PH to 7 with the unsaturated carbonate potassium solution, chloroform extraction, silica gel column chromatography gets product 3.8g, productive rate 75%, molecular formula: C10H3C12FN2, molecular weight: 241.05.。
MS(EI)m/z240。
Embodiment 20
4-anilino-6-fluoro-7-chlorine 3-cyano quinolines (20, CPU-Y003)
With aniline 0.2ml (0.2g, 2.2mmol) add in the single neck bottle of 50ml, be dissolved in dehydrated alcohol 10ml, then with 4, the ethanolic soln (2mmol) of 7-two chloro-6-fluoro-3-cyano quinolines 0.48g slowly splashes in the reaction flask, dropwise and be heated to backflow, react after 2 hours the adularescent solid and separate out, cooling suction filtration, filter cake recrystallizing methanol, dry product 0.53g, the productive rate 82% of getting.Molecular formula: C16H9ClFN3, molecular weight: 297.72.Mp：167℃。
MS(EI)m/z297。
1H-NMR(AV-300，δ，CDCl3)：7.15-7.16(m，2H)，7.28-7.31(m，1H)，7.39-7.46(m，3H)，8.12(d，1H)，8.71(s，1H)
Embodiment 21
4-anilino-6-methylpiperazine base-7-chlorine 3-cyano quinolines (21, CPU-Y016)
4-anilino-6-fluoro-7-chlorine 3-cyano quinolines 150mg (0.5mmol) and 0.1ml methylpiperazine (1.0mmol) are dissolved in the 6ml ethylene glycol, add copper powder and each 50mg of CuCl, 80 ℃ were reacted 36 hours.With in the reaction solution impouring water, have solid to separate out then, the dry crude product 100mg that gets gets product 60mg with the crude product column chromatography.Productive rate: 33%.Molecular formula: C20H19FN6, molecular weight: 362.41.
MS(EI)m/z361。
1H-NMR(AV-300，δ，DMSO-d 6)：2.44(s，3H)，2.75(b，4H)，3.18(b，4H)，7.30-7.32(t，3H)，7.41-7.47(m，2H)，7.85(s，1H)，7.96(s，1H)，8.44(s，1H)
Embodiment 23
Get gained compound 0.5g among the embodiment 10, starch 2g, dextrin 1g mixes, and makes wetting agent with an amount of 30% ethanol, granulates compressing tablet.

Claims (10)

1, the quinoline of general formula I or its pharmacy acceptable salt:
Figure A2007100199000002C1
Wherein Z represents O, S or NR; R represents the alkyl of hydrogen or 1 to 3 carbon atom;
X represents 5 yuan or 6 yuan of aromatic rings, described aromatic ring contains 1 to 3 heteroatoms that independently is selected from N, O and S, and aromatic ring can be replaced by 1 to 4 following substituting group: alkyl, halogenated methyl, hydroxyl, trifluoromethyl, trifluoromethoxy, itrile group, nitro, carboxyl, benzoyl, amino, alkoxyl group, phenoxy group or the sulfydryl of halogen, 1 to 3 carbon atom; Or X represents the bicyclic heteroaryl ring of 8 to 10 atoms, described heteroaryl ring contains 1 to 4 heteroatoms that independently is selected from N, O and S, and they can be replaced by 1 to 4 following substituting group: alkyl, halogenated methyl, hydroxyl, trifluoromethyl, trifluoromethoxy, itrile group, nitro, carboxyl or the benzoyl of halogen, l to 3 carbon atom;
G 1Or G 4Independently represent hydrogen or halogen separately;
G 2Or G 3Independently represent separately alkyl, methylol, the halogenated methyl of hydrogen, halogen, 1 to 6 carbon atom, 1 to 6 carbon atom alkoxyl group, hydroxyl, trifluoromethyl, trifluoromethoxy, itrile group, nitro, carboxyl, amino, hydroxylamino, phenoxy group, phenyl, benzyl, N-alkyl-carbamoyl, phenyl amino, benzylamino or
Figure A2007100199000002C2
, wherein Y represents O, NR or S, and R represents the alkyl of hydrogen or 1 to 3 carbon atom; The R1 representative contains the saturated heterocyclic of 4 to 7 atoms, described heterocycle contains 1 to 3 heteroatoms that independently is selected from N, O or S, can be replaced by 1 to 4 following substituting group on this heterocycle: methyl, ethyl, propyl group, halogen, hydroxyl, methylol, hydroxyethyl, aminomethyl, dimethylamino, aminoethyl, methylamino-, ethylamino or diethylin, m represents 0 to 4 integer;
N represents 0,1 or 2.
2, the quinoline of claim 1; wherein X represents phenyl ring, 2-pyridyl, replaces or does not have (2-[4-morpholinodithio) base or (2-benzoglyoxaline) base of replacement, and substituting group is selected from alkyl, halogenated methyl, hydroxyl, trifluoromethyl, trifluoromethoxy, itrile group, nitro, carboxyl or the benzoyl of halogen, 1 to 3 carbon atom.
3, the quinoline of claim 1, wherein Z represents NH, and n represents 0.
4, the quinoline of claim 1, wherein G 1Represent H, G 4Represent H or halogen.
5, the quinoline of claim 1, wherein G 2Represent methylidene, methoxyl group, oxyethyl group, dimethylamino, diethylin, halogen or first sulfydryl.
6, the quinoline of claim 1, wherein G 3Representative , wherein Y represents O, NH or S; The R1 representative contains the saturated heterocyclic of 5 to 6 atoms, described heterocycle contains 1 to 3 heteroatoms that independently is selected from N, O or S, and heterocycle can be replaced by 1 to 4 following substituting group: methyl, ethyl, propyl group, halogen, hydroxyl, methylol, hydroxyethyl, aminomethyl, dimethylamino, aminoethyl, methylamino-, ethylamino or diethylin; M represents 0,1,2,3.
7, the quinoline of claim 6, wherein heterocycle is piperazine, piperidines, morpholine or Pyrrolidine.
8, a kind of pharmaceutical composition contains in the claim 1 to 7 each quinoline or its salt and pharmaceutically acceptable carrier.
9, each quinoline is used to prepare the purposes of the medicine for the treatment of tumor disease in the claim 1 to 7.
10, the purposes of claim 9, wherein tumor disease is mammary cancer, kidney, bladder cancer, oral carcinoma, laryngocarcinoma, the esophageal carcinoma, cancer of the stomach, colorectal carcinoma, ovarian cancer, uterus carcinoma, lung cancer, carcinoma of the pancreas, prostate cancer, liver cancer, skin carcinoma or leukemia.
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