CN102532107B - 4-substituted aniline-7-substituted alcoxylhomopiperazine-quinazoline derivatives, and preparation method and application thereof - Google Patents
4-substituted aniline-7-substituted alcoxylhomopiperazine-quinazoline derivatives, and preparation method and application thereof Download PDFInfo
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- CN102532107B CN102532107B CN201010596305.5A CN201010596305A CN102532107B CN 102532107 B CN102532107 B CN 102532107B CN 201010596305 A CN201010596305 A CN 201010596305A CN 102532107 B CN102532107 B CN 102532107B
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- acceptable salt
- pharmacy acceptable
- quinazoline
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Abstract
The invention relates to 4-substituted aniline-7-substituted alcoxylhomopiperazine-quinazoline derivatives (shown as a general formula I), and a preparation method and application thereof. In the general formula, R1, R2 and n are respectively defined in the specifications. The invention also relates to a preparation method for the derivatives, physiologically acceptable salts formed by the derivatives and inorganic or organic acids, and medicinal compositions containing the derivatives and the salts. The compounds have valuable pharmacological properties, have an effect of inhibiting signal transduction caused by protein tyrosine kinase (PTK), particularly have high activity of inhibiting mutant epidermal growth factor receptor EGFR (L858R/T790M), and have low toxicity. The invention also relates to application of the derivatives in treatment of diseases, particularly tumor diseases, and a preparation method for the derivatives. The general formula I is shown in the specifications.
Description
Technical field
The present invention relates to the synthetic field of medicine, be specifically related to the preparation method of 4-substituted anilinic-7-substituted alcoxyl homopiperazine base-quinazoline derivant.
Background technology
Tumour is a series of with abnormal cells hyperplasia out of control and the disease that is diffused as feature, it is the major disease of serious threat human life health, according to statistics, annual global tumor mortality sum approximately more than 790 ten thousand people, China dies from tumour person more than 160 ten thousand people every year, and increase gradually, become first cause of the death of urban population.
Protein tyrosine kinase (PTK) is the enzyme that a class plays an important role in normal cell growth, and it can be transferred to the residue of protein substrate from ATP by catalysis phosphate group.Many EGF-R ELISA (EGFR) albumen all has the effect of protein tyrosine kinase, and the interaction of these acceptors and somatomedin is also that normal regulating Growth of Cells is necessary.Yet the overexpression of EGFR, by the effect of himself Tyrosylprotein kinase, can cause cell transition increment, finally leads oncogenic generation.
The vital role that receptor kinase based on imbalance is risen in cancer pathology, specific ptk inhibitor is the study hotspot of current carcinostatic agent as the exploitation of potential anticancer therapeutic agent.Therefore current many synthetic compounds all have the activity of inhibition epidermal growth factor recipient tyrosine kinase (EGFR-PTK), that especially with quinazoline compounds, studies is the most deep, wherein ZD1839 was used for the treatment of nonsmall-cell lung cancer (Ranson in 2003 by FDA approval listing, M.Epideraml growth factor receptor tyrosine kinase inhibitors.British J.Cancer 2004,90,2250-2255.).ZD6474 had both had the activity that suppresses EGFR, there is the activity that suppresses VEGFR simultaneously, in 2009, declare listing (Alessandro, M.Vandetanib (ZD6474), a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor (VEGFR) and Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase:Current Status and Future DirectionsThe Oncologist 2009,14,378-390.).The derivative that WO 99/06378, WO 2000/31048 and WO2000/06555 (Chinese patent CN99808949) also relate to the quinazoline of some replacement has irreversible ptk inhibitor activity.
In the disease that traditional quinazoline derivant causes at treatment cell hyperplasia, need a very large metering just can reach effective treatment, this tends to aggravate the side effects such as the dysentery of its generation and fash, needs to carry out the medicine that further research goes to find effective and low toxic side effect for this reason.
WO 97/30035 discloses that quinazoline derivative ZD6474 is usingd and as the application of ptk inhibitor.Experiment showed, that this compounds has good restraining effect to Human umbilical vein endothelial cells (HUVEC).
In China, homopiperazine is mainly used in pharmaceutical industry, and take its pharmaceuticals that are raw material has kind more than 20.At present, the medicinal efficacy of Foreign Epidemic exploitation homopiperazine derivative.Some derivative synthetic with homopiperazine can be used as antiphlogistic, and other derivative can reduce blood sugar, thereby to treatment diabetes, obesity etc. have good effect.The seven membered heterocyclic of homopiperazine is polygon ring, and their intermediate majority has strong biological activity and pharmaceutical use.Nitrogen-containing heterocycle compound homopiperazine is the synthetic important intermediate of medicine.Contained dinitrogen atom can with many organic compound reactions, especially in the structural modification of chemicals and transformation, have extremely important effect.Homopiperazine dinitrogen atom can be effectively combined with tumour target after quinazoline docking, and the activity of tumour medicine is significantly improved., compare with ZD6474 analog derivative meanwhile, comprise the side chains such as piperidines and piperazine, homopiperazine structure can improve the physical and chemical parameter of whole molecule preferably, improves its pharmacokinetic property, thereby the research of homopiperazine series compound is more and more come into one's own.
Therefore, homopiperazine and quinazoline parent nucleus are organically combined, the EGFR of T790M and L858R sudden change and VEGFR2 are shown to high tolerance activity, and toxic side effect is lower, obtained beyond thought action effect, its external activity is ZD6474 more than ten times, to having broad application prospects as drug research, as can be seen here it is synthesized and the research of derivative has practical value.
Summary of the invention
The object of this invention is to provide the novel 4-substituted anilinic-7-of class substituted alcoxyl homopiperazine base-quinazoline derivant, and this compounds in antitumor drug as the purposes of activeconstituents.
The present invention be quinazoline derivant as shown in general formula (I):
General formula (I)
Wherein:
R1 represents: hydrogen, methoxyl group, preferably from methoxyl group;
R2 represents: hydrogen, methyl, ethyl, preferably from hydrogen and methyl;
N represents: 1 or 2 or 3 or 4, and preferably from 3.
Be below the preparation method of the compounds of this invention, wherein initial compounds (II) can be purchased.
Compound (II) prepares compound III with sulfur oxychloride through chlorination reaction, and compound III is reacted and obtained compound IV through N-alkylation with the fluoro-4 bromo-aniline of 2-; Compound IV debenzylation under three fluoro acetic acid conditions obtains V, and compound V obtains compound VI from the reaction of different halogenated alkane again, then react with Boc-homopiperazine, take off Boc, N-alkylation obtains general formula (I) target compound.
R wherein
1, R
2with n as defined above.
The pharmacy acceptable salt of formula of the present invention (I) compound, according to different derivatives, can contain carboxyl or amido, carboxyl can react with alkaline matter (as the oxyhydroxide of basic metal or alkaline-earth metal, carbonate and supercarbonate), they include, but are not limited to: sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate etc. form pharmacy acceptable salt, as corresponding sodium salt, and sylvite or calcium salt etc.Also can adopt nontoxic organic bases as generation salt such as methylamine, triethylamine, meglumines; Amido can react with acidic substance (example hydrochloric acid, Hydrogen bromide, sulfuric acid etc.), and they include, but are not limited to: hydrochloric acid, and Hydrogen bromide, sulfuric acid, phosphoric acid etc. form pharmacy acceptable salt, also can adopt organic acid as generation salt such as acetic acid, oxalic acid, citric acids.The compound of formula (I) and the form of salt thereof have anti-tumor activity,
Formula of the present invention (I) compound or its pharmacy acceptable salt, can make pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made the formulations such as solid orally ingestible, liquid oral medicine, injection.
Described solid and liquid oral medicine comprise: tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, syrup, granule, oral solution.Can adopt lactose or starch as the carrier of described solid orally ingestible; Use gelatin, methylcellulose gum, hypromellose, polyvinylpyrrolidone, starch slurry etc. are as tackiness agent; Use starch, Xylo-Mucine, carboxymethylstach sodium, low-substituted hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, Microcrystalline Cellulose as disintegrating agent; Use talcum powder, micro-part of silica gel, stearin, calcium stearate or magnesium etc. are as antiadhesives and lubricant.The preparation method of described solid orally ingestible comprises the following steps: by activeconstituents and carrier and optionally with a disintegration additive composition mixture, then make the aqueous solution of this mixture and tackiness agent, alcohol or aqueous alcohol solution carry out wet method or dry granulation in suitable equipment, dried particles, adds other disintegrating agent, lubricant and antisticking agent to make suitable preparation subsequently.
Described injection comprises: little pin, freeze-dried powder and infusion solutions etc.The preparation method of described injection comprises the following steps: get water for injection, the auxiliary material that takes recipe quantity is stirred to dissolve, and adds sample stirring and dissolving, adjust pH is to proper range, add after the charcoal absorption certain hour of 0.1%-0.5% decarburization, filtration, then packing or freeze-drying.
The present invention shows by vitro homogeneous time-resolved fluorescence method (HTRF) test: the quinazoline derivant with general formula I structure has very strong restraining effect to EGFR (L858R/T790M) and VEGFR-2, Mice Body indoors modeling test is shown, this type of toxicity of compound is lower simultaneously.
Embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
The preparation of embodiment 17-(3-(Isosorbide-5-Nitrae-Diazesuberane-1-yl) propoxy-)-N-(the bromo-2-fluorophenyl of 4-)-6-methoxyl group quinazoline-4-amine (VIII)
The first step: 7-benzyloxy-6-methoxyl group quinazoline-4-one (5.0g, 0.018mol) is dissolved in DMF (20mL), drips thionyl chloride, reflux 3h.Steaming desolventizes, and re-crystallizing in ethyl acetate obtains the chloro-6-methoxyl group of white solid 7-benzyloxy-4-quinazoline (4.8g, 90.2%), m.p.247 ℃;
1h NMR (400MHz, DMSO): δ 3.84 (s, 3H, CH
3o), 5.26 (s, 2H, CH
2o), 7.23 (s, 1H, ArH), 7.41-7.55 (m, 7H, ArH), 7.99 (s, 1H, Ar) .ESI-MS:m/z 301[M+H]
+.
Second step: 7-benzyloxy-4-chloro-6-methoxyl group quinazoline (4.8g, 0.016mol) and the bromo-aniline of the fluoro-4-of 2-(3.0g, 0.016mol) are dissolved in Virahol (100mL) to reflux 2h.After solution is cooling, filter, Virahol and ether are washed, and are dried to obtain 7-benzyloxy-N-(the bromo-4-fluorophenyl of 2-)-6-methoxyl group quinazoline-4-amine (6.9g, 95.8%), m.p.231-233 ℃;
1hNMR (400MHz, DMSO): δ 3.99 (s, 3H, CH
3o), 5.26 (s, 2H, CH
2o), 7.38-7.50 (m, 10H, ArH), 8.13 (s, 1H, Ar), 8.77 (s, 1H, Ar) .ESI-MS:m/z455[M+H]
+.
The 3rd step: 7-benzyloxy-N-(the bromo-2-fluorophenyl of 4-)-6-methoxyl group quinazoline-4-amine (6.9g, 0.015mol) is dissolved in three fluoroacetic acids of 50mL to reflux 1h.After cooling, mixture is poured in trash ice, filters, and dissolution of solid is in methyl alcohol, with ammoniacal liquor, regulating pH is 11, concentrated rear filtration, and ether is washed, vacuum-drying, obtain white solid 4-(the bromo-2-fluoroaniline of 4-)-6-methoxyl group quinazoline-7-phenol (4.9g, 88.6%), m.p.145-147 ℃;
1h NMR (400MHz, DMSO): δ 3.94 (s, 3H, CH
3o), 7.33-7.55 (m, 4H, ArH), 7.56-7.88 (m, 2H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar) .ESI-MS:m/z 364[M+H]
+.
The 4th step: by 4-(the bromo-2-fluoroaniline of 4-)-6-methoxyl group quinazoline-7-phenol (4.9g, 0.013mol), 3-bromine n-propyl chloride (2.0g, 0.013mol), salt of wormwood (3.7g, 0.026mol) and 100mL DMF are heated to 60 ℃ of reaction 10h.Solvent evaporated, crude product column chromatography (ethyl acetate: sherwood oil=4: 1) obtain white solid N-(4-bromo-2-fluoroanilino)-7-(3-chloropropane base)-6-methoxyl group quinazoline-4 amine 5.0g, yield 71.0%, m.p.134-136 ℃;
1hNMR (400MHz, DMSO): δ 1.22-1.65 (m, 2H, CH
2), 1.98-1.2.01 (m, 2H, CH
2), 2.38-2.55 (m, 2H, CH
2), 3.94 (s, 3H, CH
3o), 7.33-7.55 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar), 8.77 (s, 1H, Ar) .ESI-MS:m/z 440[M+H]
+.
The 5th step: by 5.0g (11.36mmol) N-(4-bromo-2-fluoroanilino)-7-(3-chloropropane base)-6-methoxyl group quinazoline-4 amine and 2.8g (140mmol) N-BOC-homopiperazine, be dissolved in 70mlDMA, add salt of wormwood 4.7g (34.08mmol), be warming up to 70 ℃ of reaction 3h, TLC detection reaction is complete, be cooled to room temperature, reaction solution is poured in frozen water, there is yellow solid to separate out, filter, washing filter cake, dry, re-crystallizing in ethyl acetate obtains the yellow solid tertiary butyl-4-(3-((4-((4 bromo-2-fluorophenyl) amino)-6-methoxyl group quinazoline-7-yl) oxygen base) propyl group)-1, 4-Diazesuberane-1-carboxylicesters 5.49g, productive rate 80%, m.p.154-155 ℃,
1h NMR (400MHz, DMSO): δ 1.05 (s, 9H, 3 * CH
3), 1.22-1.65 (m, 2H, CH
2), 1.98-2.01 (m, 2H, CH
2), 2.38-2.55 (m, 2H, CH
2), 2.71-3.42 (m, 10H, 5 * CH
2), 3.94 (s, 3H, CH
3o), 7.33-7.55 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar), 8.77 (s, 1H, Ar) .ESI-MS:m/z 604[M+H]
+.
The 6th step: by 5.0g (8.28mmol) tertiary butyl-4-(3-((4-((4 bromo-2-fluorophenyl) amino)-6-methoxyl group quinazoline-7-yl) oxygen base) propyl group)-1, 4-Diazesuberane-1-carboxylicesters drops in reaction flask, add 60ml methylene dichloride, be partly dissolved, under stirring, add 60ml trifluoroacetic acid, reaction solution is clarified completely, reaction solution color becomes brown, stirring at room reaction 1h, TLC detection reaction is complete, decompression steams trifluoroacetic acid, with a small amount of ether, wash 2 times, discard ether layer, water layer is adjusted pH to 10 with 2M sodium hydroxide, dichloromethane extraction, which floor is associated with, anhydrous magnesium sulfate drying, filter, evaporated under reduced pressure methylene dichloride obtains yellow solid, (3-(1 by re-crystallizing in ethyl acetate, to obtain yellow solid 7-, 4-Diazesuberane-1-yl) propoxy-)-N-(the bromo-2-fluorophenyl of 4-)-6-methoxyl group quinazoline-4-amine (VIII) 3.75g, productive rate 90%, m.p.177-179 ℃,
1h NMR (400MHz, DMSO): δ 1.22-1.65 (m, 2H, CH
2), 1.98-2.01 (m, 2H, CH
2), 2.08-2.09 (m, 1H, NH), 2.38-2.55 (m, 2H, CH
2), 2.71-3.42 (m, 10H, 5 * CH
2), 3.94 (s, 3H, CH
3o), 7.33-7.55 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar), 8.77 (s, 1H, Ar) .ESI-MS:m/z 504[M+H]
+.
The preparation of embodiment 2N-(the bromo-2-fluorophenyl of 4-)-6-methoxyl group-7-(3-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) propoxy-) quinazoline-4-amine (I-1)
By 1.0g (3.96mmol) 7-, (3-(1, 4-Diazesuberane-1-yl) propoxy-)-N-(the bromo-2-fluorophenyl of 4-)-6-methoxyl group quinazoline-4-amine solvent is in 20ml formic acid, under stirring at room, add 10ml37% formaldehyde, it is brown finishing reaction solution, be warmed up to 95 ℃ of reaction 4h, TLC detection reaction is complete, decompression steams unreacted formic acid and formaldehyde, be dissolved in water, water layer is adjusted pH=11 with 2M sodium hydroxide, water layer is extracted with ethyl acetate, merge organic layer, anhydrous magnesium sulfate drying, filter, mother liquor is directly mixed sample, quick preparative column separation and purification (ethyl acetate/methanol=10: 1), obtain yellow solid N-(the bromo-2-fluorophenyl of 4-)-6-methoxyl group-7-(3-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) propoxy-) quinazoline-4-amine (I-1) 1.64g, productive rate 80%, , m.p.166-167 ℃,
1h NMR (400MHz, DMSO): δ 1.22-1.65 (m, 2H, CH
2), 1.98-2.01 (m, 2H, CH
2), 2.23 (S, 3H, CH
3n), 2.38-2.55 (m, 2H, CH
2), 2.71-3.42 (m, 10H, 5 * CH
2), 3.94 (s, 3H, CH
3o), 7.33-7.55 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar), 8.77 (s, 1H, Ar) .ESI-MS:m/z 518[M+H]
+.
Embodiment 3
Method for preparing tablet thereof is as follows:
Prescription consumption/sheet
I-1 100mg
Microcrystalline Cellulose 50mg
Starch 40mg
Polyvidone 8mg
Sodium starch glycolate 10mg
Magnesium Stearate qs
Technique: activeconstituents auxiliary material is crossed respectively to 100 mesh sieves; the main ingredient and the auxiliary material (half sodium starch glycolate) that take recipe quantity fully mix; add polyvinylpyrrolidone aqueous solution softwood processed in right amount; cross 24 mesh sieves; make wet granular dry about 2-3 hour in 50-60 ℃ of baking oven, residue sodium starch glycolate and Magnesium Stearate are mixed to whole grain with particle; measure intermediate content, with the shallow stamping of Φ 8mm.
Embodiment 4
The preparation of injection liquid
I-3 200mg
SODIUM PHOSPHATE, MONOBASIC 10mg
Citric acid 30mg
Water for injection 50ml
Technique: get water for injection 50ml, the citric acid, the SODIUM PHOSPHATE, MONOBASIC that take recipe quantity are stirred to dissolve, and add sample stirring and dissolving, is 4.0-5.0 with hydrochloric acid or the sodium hydroxide adjust pH of 0.1mol/L, adds 0.1% charcoal absorption 20 minutes.First with 0.45 μ m filter membrane, filter, then filter by 0.22 μ m essence.Press 5 milliliters of per ampoules filling, 105 ℃ of high-temperature sterilizations obtain injection liquid for 30 minutes.
The anxious poison test of mouse in the extracorporeal anti-tumor enzymic activity test of compound VI II and I-1 and body
One, extracorporeal anti-tumor enzymic activity test
(1) material and instrument:
1 experiment material: the test kit HTRF KinEASE-TK kit of Cisbio company (article No.: 62TKOPEB); Distilled water
2 detecting instruments: SpectraMax M5:Mplecular Devices product
(2) testing sequence:
1. the preparation of solution and reaction density
2. experimental procedure:
1) calculate all ingredients institute expense.
2) prepare the working fluid of ATP, TK Substrate-biotin.
3) ratio ATP by volume: TK Substrate-biotin: Kinase buffer=2: after getting liquid at 2: 1 and mixing, get mixed solution to BP pipe by 5 μ L/ holes.
4) add medicine, 2 μ L/ holes.Without 2 μ L kinase buffer polishings for medicine hole.Mix.
5) prepare the working fluid of enzyme.
6) add enzyme, 3 μ L/ holes.Without 3 μ L kinase buffer polishings for enzyme hole.Mix.
7) reaction solution is transferred in 384 orifice plates.
8) put 37 ℃ of incubation 30min.
9) working fluid of preparation Streptavidin-XL665, calculates consumption, by volume ratio Streptavidin-XL665: TK Antibody-Cryptate=1: 1 mixes.After incubation finishes, by 10 μ L/ holes, get mixed solution and add in reaction system, mix with termination reaction.
10) room temperature is placed 30min and is detected, in the mono-wavelength of microplate reader 314nm, excite, and mensuration 620nm and 665nm utilizing emitted light, test-results is in Table 1 and table 2.
Inhibiting rate (%)=[1-(experimental group
665nm/620nm-blank group
665nm/620nm)/(control group
665nm/620nm-blank group
665nm/620nm)] * 100%.Bliss method is calculated test-compound IC
50value.
3. result
The inhibiting rate (%) of table 1. couple EGFR (L858R/T790M) and VEGFR-2
The IC of table 2. couple EGFR (L858R/T790M) and VEGFR-2
50(nM)
Two, the anxious poison test of mouse in body
Laboratory animal: Kunming mouse (male and female half and half)
Experimental technique:
1. the last late fasting of experiment is 12 hours;
2. mouse random packet, male and female half and half, weigh in;
3. mouse arranges the administration of 2-3 dosage group, and medicine weighing adds tween-80 to grind, 1%CMC-Na dissolved dilution;
4. every mouse 0.5mL oral administration (ig);
5. after observing mouse administration, react; Record toxicity symptom, time length and recovery situation; As there is death, record death time of animal and dead front symptom etc.;
6. pair dead mouse is dissected inspection, records anatomical results;
7. Continuous Observation is 7 days, weighs Mouse Weight every day, records body weight changing conditions;
8. obtain medium lethal dose (LD50) or maximum tolerated dose (MTD).
Claims (9)
1. a logical formula I quinazoline derivant or its pharmacy acceptable salt:
Logical formula I
Wherein:
R1 represents: hydrogen, methoxyl group;
R2 represents: hydrogen, methyl, ethyl;
N represents: 1, or 2, or 3, or 4.
2. a kind of logical formula I quinazoline derivant according to claim 1 or its pharmacy acceptable salt, is characterized in that R1 is preferably from methoxyl group.
3. a kind of logical formula I quinazoline derivant according to claim 1 or its pharmacy acceptable salt, is characterized in that R2 is preferably from hydrogen and methyl.
4. a kind of logical formula I quinazoline derivant according to claim 1 or its pharmacy acceptable salt, is characterized in that n is preferably from 3.
5. according to the defined logical formula I compound of claim 1-4 any one or its pharmacy acceptable salt, described compound or its pharmacy acceptable salt are selected from,
N-(the bromo-2-fluorophenyl of 4-)-6-methoxyl group-7-(3-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) propoxy-) quinazoline-4-amine;
7-(3-(Isosorbide-5-Nitrae-Diazesuberane-1-yl) propoxy-)-N-(the bromo-2-fluorophenyl of 4-)-6-methoxyl group quinazoline-4-amine.
6. according to a kind of logical formula I quinazoline derivant or its pharmacy acceptable salt described in claim 1-4 any one, it is characterized in that pharmacy acceptable salt is: formula 1 compound H qX, X represents halogen, sulfate radical, nitrate radical, phosphate radical, organic acid, q is 1, or 2, or 3.
According to the compound described in claim 1-4 any one as the purposes of preparing antitumor drug.
8. a pharmaceutical composition, the defined logical formula I compound of the claim 1 that contains pharmacy effective dose or its pharmacy acceptable salt and suitable carrier or vehicle.
9. a kind of pharmaceutical composition claimed in claim 8, described composition comprises various solid orally ingestibles, liquid oral medicine, injection.
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| CN111909163B (en) * | 2020-04-21 | 2022-02-01 | 南开大学 | Quinolamine compound with IDO1 inhibition function and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995019774A1 (en) * | 1994-01-25 | 1995-07-27 | Warner-Lambert Company | Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family |
| CN1116286C (en) * | 1996-03-05 | 2003-07-30 | 曾尼卡有限公司 | 4-anilinoquinazoline derivatives |
| WO2007068552A1 (en) * | 2005-12-12 | 2007-06-21 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for the production thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995019774A1 (en) * | 1994-01-25 | 1995-07-27 | Warner-Lambert Company | Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family |
| CN1116286C (en) * | 1996-03-05 | 2003-07-30 | 曾尼卡有限公司 | 4-anilinoquinazoline derivatives |
| WO2007068552A1 (en) * | 2005-12-12 | 2007-06-21 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for the production thereof |
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