CN101857618B - As series of quinazoline sugar derivatives thing, its preparation method and the application of protein tyrosine kinase inhibitor - Google Patents
As series of quinazoline sugar derivatives thing, its preparation method and the application of protein tyrosine kinase inhibitor Download PDFInfo
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Abstract
The invention provides a kind of quinazoline sugar derivative and its preparation method and application, the problem that the suppression tyrosine kinase activity of prior art existence is not high can be solved, and the quinazoline sugar derivative that the present invention obtains is water-soluble, to human skin cancer cells A431 inhibit activities all better, can be applicable to the medicine preparing prevention or treatment tumour.Quinazoline sugar derivative provided by the invention is that a class formation is novel, quinazoline female ring 6-position side chain contains the compound enriching glycosyl fragment, the raw material of the glycosylation process of quinazoline ring is easy to get, synthetic method is simple, way of purification is simple and efficient, and quinazoline sugar derivative of the present invention is better water-soluble, there is better biological activity especially have EGFR and select inhibit activities significantly, there is significant antitumor efficacy, therefore this compounds prevention or treatment tumour medicine in have a wide range of applications.The structural formula of quinazoline sugar derivative is as figure.
Description
Technical field
The invention relates to a class tyrosine kinase inhibitor, particularly based on quinazoline female ring a series of sugar derivativess and preparation method thereof and preparing the application in antitumor drug.
Background technology
Targeted therapy utilizes tumour cell to express, and the expression product of the specific gene that normal cell seldom or is not expressed or gene, form relative or absolute target, to greatest extent killing tumor cell, and the methods for the treatment of very little to normal cell injury.Tyrosylprotein kinase is a class transmembrane protein, a kind of enzyme phosphate group being transferred to the tyrosine residues being positioned at protein substrate from ATP catalysis.Play an important role in normal cell growth.EGF-R ELISA (EGFR) in family tyrosine kinase is determined to be in most important enzyme in Growth of Cells reproductive process, at most tumors epidermal growth factor receptor overexpression, considerably beyond normal range.EGF-R ELISA has become the promising target of exploitation target therapeutic agent at present, wherein active with the micromolecular compound that quinazoline ditosylate salt structure is parent nucleus.
At present a lot of patent has set forth quinazoline and with the inhibit activities of quinazoline derivative to tyrosine kinase epidermal somatomedin (EGFR), such as: WO0212226, WO0340108, WO0340109, WO00/06555, WO99/35146 etc.But this area still needs exploitation more effectively to suppress EGFR, the better compound of physico-chemical property.
Summary of the invention
The invention provides a kind of quinazoline sugar derivative and its preparation method and application, the problem that the suppression tyrosine kinase activity of prior art existence is not high can be solved, and the quinazoline sugar derivative that the present invention obtains is water-soluble, to human skin cancer cell suppression activity all better, can be applicable to the medicine preparing prevention or treatment tumour.
For solving the problems of the technologies described above, the present invention adopts following technical proposals
A kind of quinazoline sugar derivative, is characterized in that having following structural formula:
In formula, female ring structure is the quinazoline female ring that the different anilino in 4-position replaces, R
1for the one in halogen, H, methoxyl group, 3-fluorine benzyloxy; R
2with R
3for the one in halogen, H, methoxyl group; Its 6-position side chain is the sugared ring connected by the aliphatic chain of different lengths, and wherein n is the integer of 0 ~ 9, represents that quinazoline female ring is directly connected with sugared ring during n=0; Sugar ring R is the one in D-Glucose base, D-galactosyl, D-lactose base, D-xylosyl, D-Fructose base, D-MANNOSE base, D-R base, D-ribopyranose base, 2-deoxidation-D-ribopyranose base, D-RIBOSE base, 2-deoxidation-ribofuranosyl, L-rhamanopyranosyl, L-fucose base, lactose base, malt-base.
In the above-mentioned glycosyl that sugared ring R in addition in described structural formula also can adopt, its hydroxyl all or part of by the form of methyl, propylidene base, ethanoyl, benzyl protection.
A preparation method for quinazoline sugar derivative, comprises the following two kinds situation:
As n=0, namely synthetic method when quinazoline female ring is directly connected with sugared ring is as follows, 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol, 4-(3-bromobenzene amido)-7-methoxyquinazoline hydrochloride-6-alcohol, one in 4-(3-chloro-4-fluorine benzyloxy-aniline base)-7-methoxyquinazoline hydrochloride-6-alcohol and acetyl bromo sugar, methyl bromo sugar, propylidene base bromo sugar or benzyl bromo sugar be raw material with 1: 1.2-2 mol ratio, with phase transfer catalysis process, at 40-60 DEG C, stir 10-12 hour, there is glycosylation reaction, gained reactant obtains all or part of by methyl of sugared ring hydroxyl by purification by silica gel column chromatography, propylidene base, ethanoyl, the derivative of benzyl protection.
When n is 1 ~ 9, namely when sugared ring is connected with quinazoline female ring by aliphatic chain, synthetic method is as follows, acetyl sugar, methyl sugar, propylidene base sugar or benzyl sugared with bromo fatty alcohol with the mol ratio of 1: 1.5-2.0, boron trifluoride diethyl etherate do catalyzer be obtained by reacting in methylene dichloride different lengths 1 bromo alkoxyl group acetyl sugar, methyl sugar, propylidene base sugar or benzyl sugared, silica column purification; By products therefrom and 4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride-6-alcohol, 4-(3-bromobenzene amido)-7-methoxyquinazoline hydrochloride-6-alcohol or 4-(3-chloro-4-fluorine benzyloxy-aniline base)-7-methoxyquinazoline hydrochloride-6-alcohol with 1.2-1.5: 1 mol ratio; in salt of wormwood or Sodium Hydroxide Alkaline condition; temperature is at 60-80 DEG C; stir 10-12 hour, on the glycosyl that coupling generation 1-position aliphatic chain connects, hydroxyl is all or part of by the derivative of methyl, propylidene base, ethanoyl, benzyl protection.
Further; described derivative removes in the basic conditions under ethanoyl, atmosphere of hydrogen and removes methyl or propylidene base under palladium carbon catalytic eliminating benzyl or acidic conditions; after stirred at ambient temperature 2-5 hour, gained reactant obtains quinazoline sugar derivative by purification by silica gel column chromatography.
Further, in described quinazoline sugar derivative synthetic method, when sugared ring 4, when 6-position is by being connected with quinazoline ring after the protection of propylidene base, can also by with above-mentioned quinazoline sugar derivative for raw material with 1: 10-20 mol ratio and 2-ethoxy propylene, acetone, 2, one or more mixing in 2-Propanal dimethyl acetal, at anhydrous N, in dinethylformamide solvent with tosic acid or the vitriol oil for catalyzer, anhydrous calciumsulphate or anhydrous magnesium sulfate are made water-removal agent and are at room temperature stirred 2-5 hour, gained reactant is obtained after purification by silica gel column chromatography.
Further, described raw material 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol, 4-(3-bromobenzene amido)-7-methoxyquinazoline hydrochloride-6-alcohol or 4-(3-chloro-4-fluorine benzyloxy-aniline base)-7-methoxyquinazoline hydrochloride-6-alcohol be with 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol ethyl ester for raw material with 1: 1.2-1.3 the mol ratio chloro-4-fluoroaniline with 3-respectively, m-bromoaniline or the mixing of 3-chloro-4-fluorine benzyloxy-aniline, solvent is removed under reduced pressure after stirring and refluxing 3-5 hour in Virahol or propyl carbinol, without the need to purifying, again reactant is dissolved in methyl alcohol and adds strong aqua 1-3 milliliter, stirred at ambient temperature is until silica gel thin-layer plate detection raw material reaction is complete, gained solid ether or sherwood oil after reaction solution evaporated under reduced pressure are fully washed obtained.
Quinazoline sugar derivative can be widely used in the medicine preparing prevention or treatment tumour.Quinazoline sugar derivative of the present invention has carried out the Experiment on therapy to drug target EGFR Inhibition test and human skin cancer cells A431, found that its IC50 value (concentration of IC50 refers to " reaction " suppressed half inhibitor, when specifically referring to that activity of EGFR is suppressed 50% by quinazoline sugar derivatives thing here when the concentration of sample and induction human skin cancer cells A431 apoptosis 50% concentration of sample) display compared with positive drug is better active or be at least in the same order of magnitude.
The invention has the advantages that: quinazoline sugar derivative provided by the invention is that a class formation novel quinazoline female ring 6-position side chain contains the compound enriching glycosyl fragment, the raw material of the glycosylation process of quinazoline ring is easy to get, synthetic method is simple, way of purification is simple and efficient, and quinazoline sugar derivative of the present invention is better water-soluble, there is better biological activity especially have EGFR and select inhibit activities significantly, there is significant antitumor efficacy, therefore this compounds prevention or treatment tumour medicine in have prospect widely.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.
Embodiment 1
Be prepared as follows the quinazoline sugar derivative of general formula, wherein female ring is 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol, glycosyl donor be glucose and lactose time:
1, the preparation of 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol
I) synthesis of 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol ethyl ester
In 100mL eggplant-shape bottle, add the chloro-7-methoxyquinazoline hydrochloride of 4--6-alcohol ethyl ester 2.0g, 3-chloro-4-fluoroaniline 1.16g, measures Virahol 40mL and adds stirring and dissolving in reaction flask, nitrogen protection, temperature of reaction is increased to 90 DEG C of return stirrings 5 hours.After reaction terminates, remove Virahol under reduced pressure, add ether 40mL, ultrasonic vibration, suction filtration in reaction flask, filter cake ether fully washs, and obtains yellow solid 2.7g.Productive rate 94.4%.
Ii) synthesis of 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol
In 100mL eggplant-shape bottle, add 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol ethyl ester 1.5g, measure methyl alcohol 60mL and solid material is dissolved, under agitation condition, dropwise add strong aqua 0.8mL, stirred at ambient temperature 12 hours.Then remove reaction solvent under reduced pressure, gained solid adds ether 30mL, ultrasonic vibration, suction filtration, and filter cake ether fully washs, and vacuum-drying obtains light yellow solid 1.27g, productive rate: 96.2%, fusing point: 284-286 DEG C.
2, the preparation of quinazoline sugar derivative
I) synthesis of compound 1
In 250mL eggplant-shape bottle, add Tetrabutyl amonium bromide 414mg, then add chloroform 6.5mL, distilled water 6.5mL.Stir in 40 DEG C of oil baths; Separately take 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol 400mg, Anhydrous potassium carbonate 520mg is in 50mL beaker, add distilled water 25mL, DMF4mL, proceed in eggplant-shape bottle after being heated to dissolve completely, stir 30 minutes, with dropping funnel, the chloroformic solution 24mL being dissolved with the full acetyl glucosamine 771mg of bromo is dropwise joined in reaction solution, 40 DEG C of stirring reactions 20 hours.Reaction solution is proceeded to 500mL separating funnel and leave standstill separatory, aqueous phase washes twice with chloroform 80mL again, and merge organic phase, use saturated aqueous common salt 30mL respectively, distilled water 30mL washs, and anhydrous magnesium sulfate drying, removes organic solvent under reduced pressure.Column chromatography purification (ethyl acetate: sherwood oil=3: 1) obtain light yellow solid 612mg.Productive rate: 75.2%.
1H-NMR(600MHz,CDCl
3):δ8.67(s,1H,ArH),8.49(brs,1H,NH),8.05-8.04(dd,1H,J=6.42,2.28Hz,1H,ArH),7.78(s,1H,ArH),7.72-7.71(m,1H,ArH),7.25(s,1H,ArH),7.16-7.13(t,J=8.70Hz,1H,ArH),5.29(d,J=1.38Hz,1H),5.28-5.27(d,J=3.18Hz,1H),5.21-5.19(m,1H),4.84-4.83(t,J=3.66Hz,1H),4.72-4.69(dd,J=11.88,2.76Hz,1H),4.12-4.10(tt,J=9.60,2.18Hz,1H),3.94(s,3H,OMe),3.69-3.67(m,1H),2.16(S,3H,OAc),2.13(S,3H,OAc),2.08(S,3H,OAc),2.06(S,3H,OAc)
The synthesis of compound 2, experimental implementation flow process is the same, and just change the sugar in reaction raw materials into bromo full acetyl lactose, productive rate is 55.3%.Structured data is
1h-NMR (600MHz, CDCl
3): δ 8.67 (brs, 1H, NH), 8.49 (s, 1H, ArH), 8.05-8.03 (dd, 1H, J=6.84, 2.7Hz, 1H, ArH), 7.77 (s, 1H, ArH), 7.75-7.73 (m, 1H, ArH), 7.25 (s, 1H, H-5), 7.16-7.13 (t, J=8.70Hz, 1H, ArH), 5.38-5.37 (d, J=2.76Hz, 1H), 5.32-5.28 (t, J=9.18Hz, 1H), 5.20-5.16 (m, 2H), 5.08-5.02 (m, 2H), 4.80-4.79 (d, J=7.80Hz, 1H), 4.67-4.65 (d, J=11.88, J=7.8Hz, 1H), 4.20-4.17 (t, J=6.0Hz, 1H), 4.14-4.11 (dd, J=10.2, 2.34Hz, 1H), 3.94-3.95 (m, 2H), 3.93 (S, 3H,-OMe), 3.59-3.57 (dd, J=10.08Hz, 1H), 2.19 (S, 3H,-OAc), 2.17 (S, 3H,-OAc), 2.16 (S, 3H,-OAc), 2.11 (S, 3H,-OAc), 2.07 (S, 3H,-OAc), 2.05 (S, 3H,-OAc), 1.99 (S, 3H,-OAc)
Ii) synthesis of Compound I
In 50mL eggplant-shape bottle, add embodiment 1 products therefrom 200mg, anhydrous methanol 20ml, then add NaOMe/MeOH (1g/100mL) 15, stirred at ambient temperature reacts 5 littlely to be completed up to silica gel thin-layer plate detection reaction.Add Zeo-karb 0.5g, stir 5 minutes, filter decationize exchange resin, evaporated under reduced pressure solvent, vacuum-drying obtains white solid 131mg.Productive rate: 93.3%.
1H-NMR(600MHz,DMSO-d
6):δ9.39(brs,1H,NH),8.51(s,1H,ArH),8.17-8.14(dd,1H,J=6.9,2.76Hz,1H,ArH),7.92(s,1H,ArH),7.79-7.77(m,1H,ArH),7.47-7.43(t,J=8.94Hz,1H,ArH),7.23(s,1H,ArH),5.51(brs,1H),5.32-5.31(d,J=7.32Hz),5.18(brs,1H),5.13-5.12(d,J=5.04Hz,1H),4.68(brs,1H),3.94(s,3H,OMe),3.69-3.67(d,J=10.98Hz,1H);3.52-3.54(m,1H),3.36-3.50(m,1H),3.22-3.21(m,1H)
The synthesis of Compound II per, experimental implementation flow process is the same, and just reaction raw materials changes compound 2 into.Productive rate is 92.3%, and structured data is
1h-NMR (600MHz, DMSO-d
6): δ 9.40 (brs, 1H, NH), 8.52 (s, 1H, ArH), 8.20-8.18 (dd, J=6.60Hz, 2.22Hz, 1H, ArH), 7.92 (s, 1H, ArH), 7.79-7.76 (tt, J=7.74, 4.38Hz, 1H, ArH), 7.47-7.44 (t, J=8.82Hz, 1H, ArH), 7.24 (s, 1H, ArH), 5.71-5.70 (d, J=5.46Hz, 1H), 5.37-5.36 (d, J=7.68Hz, 1H), 5.14 (br, s, 1H), 4.92 (s, 1H), 4.87 (br, s, 1H), 4.70-4.75 (m, 2H), 4.60-4.59 (d, J=3.3Hz, 2H), 4.25-4.24 (d, J=6.6Hz, 1H), 3.95 (s, 3H, OMe), 3.76-3.72 (m, 2H), 3.62-3.65 (m, 2H), 3.56-3.48 (m, 4H), 3.46-3.42 (m, 2H), 3.30-3.32 (m, 1H)
Embodiment 2
Be prepared as follows the quinazoline sugar derivative of general formula, wherein sugared ring portion is divided into D-Glucose or L-rhamnosyl.
1, the preparation of 1-(2-bromine oxethyl)-2,3,4,6-tetra--O-ethanoyl-β-D-Glucopyranose
In 100mL there-necked flask, add α-full acetyl glucosamine 6.0g, measure ethylene bromohyrin 1.35 milliliters, dry methylene dichloride 27 milliliters joins in reaction flask, stirs under ice bath.External dropping funnel, measures boron trifluoride ether solution 10 milliliters in dropping funnel, dropwise joins (time for adding 20 minutes) in reaction solution, lucifuge under ice bath.Stir after 1.5 hours, reacting liquid temperature is increased to room temperature and stirs 20 hours again.After reaction terminates, by reaction solution impouring 45 milliliters of frozen water, methylene dichloride (45mL × 2) extracting, merges organic phase, uses saturated sodium bicarbonate 45 milliliters successively, distilled water 45 milliliters washing. anhydrous magnesium sulfate drying, filter, and concentrated.Purification by silica gel column chromatography (sherwood oil: ethyl acetate=7: 3) obtain sterling 3.78g, productive rate 54.2%.Structured data is
1h-NMR (600MHz, CDCl
3): δ 5.24-5.21 (t, J=9.60Hz, 1H), (5.11-5.07 t, J=9.60Hz, 1H), (5.04-5.01 t, J=9.60Hz, 1H), (4.58-4.57 d, J=7.80Hz, 1H), 4.28-4.25 (dd, J=12.36,5.04Hz, 1H), 4.19-4.16 (m, 2H), (2.09 s, 3H, OAc), (2.08 s, 3H, OAc), (2.03 s, 3H, OAc), (2.01 s, 3H, OAc)
1-(3-bromine propoxy-)-2,3,4,6-tetra--O-ethanoyl-β same the 1-of-D-Glucopyranose preparation method (2-bromine oxethyl)-2,3,4, the preparation of 6-tetra--O-ethanoyl-β-D-Glucopyranose, just changes α-full acetyl glucosamine and the bromo-1-propyl alcohol of 3-into by raw material; Preparation method is the same for 1-(9-bromo oxygen base in the positive ninth of the ten Heavenly Stems)-2,3,4,6-tetra--O-ethanoyl-β-D-Glucopyranose, just raw material is changed into α-full acetyl glucosamine and the bromo-1 nonyl alcohol of 9-; The preparation method of 1-(2-bromoethoxy)-2,3,4-tri--O-ethanoyl-L-rhamnosyl is the same, just changes raw material into full acetyl L-rhamnosyl and ethylene bromohyrin; Preparation method is the same for 1-(3-bromo propoxy)-2,3,4-tri--O-ethanoyl-L-rhamnosyl, just changes raw material into full acetyl L-rhamnosyl and the bromo-1-propyl alcohol of 3-; The preparation method of 1-(9-bromo oxygen base in the positive ninth of the ten Heavenly Stems)-2,3,4-tri--O-ethanoyl-L-rhamnosyl is the same, just changes raw material into full acetyl L-rhamnosyl and the bromo-1 nonyl alcohol of 9-.
2, the preparation of quinazoline sugar derivatives thing
I) preparation of compound 3:
The synthetic method of raw material 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol is with embodiment 1, 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol 140mg is added in 100mL eggplant-shape bottle, salt of wormwood 121.6mg, be dissolved in DMF15mL, react 20 minutes in 40 DEG C of oil baths, then 1-(2-bromine oxethyl)-2 is added, 3, 4, 6-tetra--O-ethanoyl-β-D-Glucopyranose 240.4mg, nitrogen protection, temperature of reaction is increased to 80 DEG C, react 7 hours, reaction solvent is removed under reduced pressure after reaction terminates, purification by silica gel column chromatography (ethyl acetate: sherwood oil=3: 1) obtain yellow solid 200mg, productive rate 65.5%.
1H-NMR(600MHz,CDCl
3):δ8.64(s,1H,ArH),8.44(br,s,1H,NH),8.02(s,1H,ArH),7.90-7.88(dd,J=8.80,2.16Hz,1H,ArH),7.63-7.60(m,1H,ArH),7.44(s,1H,ArH),7.24(s,1H,ArH),7.16-7.13(t,J=8.76Hz,1H,ArH),5.26-5.24(t,J=8.82Hz,1H),5.12-5.08(m,2H),4.67-4.65(d,J=7.68Hz,1H),4.37-4.35(m,2H),5.25-4.24(d,J=4.38Hz,1H),4.22-4.18(m,1H),4.15-4.08(m,2H),3.99(s,3H),3.73-3.71(m,1H),2.06(s,3H,-OAc),2.05(s,3H,-OAc),2.02(s,3H,-OAc),1.94(s,3H,-OAc)
The preparation experiment operating process of compound 4-8 is with the preparation of compound 3.Sugar just in reaction raw materials does not change into: 1-(3-bromine propoxy-)-2; 3; 4; 6-tetra--O-ethanoyl-β-D-Glucopyranose, 1-(9-bromo oxygen base in the positive ninth of the ten Heavenly Stems)-2; 3; 4; 6-tetra--O-ethanoyl-β-D-Glucopyranose, 1-(2-bromoethoxy)-2; 3,4-tri--O-ethanoyl-L-rhamnosyl, 1-(3-bromo propoxy)-2,3; 4-tri--O-ethanoyl-L-rhamnosyl; 1-(9-bromo oxygen base in the positive ninth of the ten Heavenly Stems)-2,3,4-tri--O-ethanoyl-L-rhamnosyl
Compound 4 productive rate is 68.2%, and structured data is
1h-NMR (600MHz, CDCl
3): δ 8.62 (s, 1H, ArH), 8.43 (br, s, 1H, NH), 7.88-7.87 (dd, J=6.42, 2.76Hz, 1H, ArH), 7.65-7.63 (m, 1H, ArH), 7.35 (s, 1H, ArH), 7.28 (s, 1H, ArH), 7.16-7.13 (t, J=8.70Hz, 1H, ArH), 5.26-5.23 (t, J=9.60Hz, 1H), 5.09-5.07 (t, J=9.60Hz, 1H), 5.03-5.02 (t, J=7.74Hz, 1H), 4.54-4.53 (d, J=7.80Hz, 1H), 4.29-4.27 (dd, J=10.07, 4.62Hz, 1H), 4.24-4.22 (m, 1H), 4.20-4.19 (d, J=2.28Hz, 1H), 4.19-4.18 (m, 1H), 4.09-4.06 (m, 1H), 3.99 (s, 3H, OMe), 3.74-3.71 (m, 2H), 2.24-2.20 (m, 1H), 2.16-2.12 (m, 1H), 2.07 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.03 (s, 3H, OAc)
Compound 5 productive rate is 71.5%, and structured data is
1h-NMR (600MHz, CDCl
3): δ 8.65 (s, 1H, ArH), 7.88-7.87 (dd, J=6.42, 2.76Hz, 1H), 7.76 (br, s, 1H, NH), 7.57-7.55 (m, 1H, ArH), 7.24 (s, 1H, ArH), 7.21 (s, 1H, ArH), 7.17-7.14 (t, J=8.70Hz, 1H, ArH), 5.20-5.18 (t, J=9.60Hz, 1H), 5.10-5.08 (t, J=10.08Hz, 1H), 5.00-4.98 (t, J=7.80Hz, 1H), 4.49-4.48 (d, J=7.80Hz, 1H), 4.27-4.24 (dd, J=7.32, 5.04Hz, 1H), 4.14-4.12 (dd, J=11.76, 2.03Hz, 1H), 4.07-4.05 (t, J=6.90Hz, 2H), 3.98 (s, 3H,-OMe), 3.88-3.86 (m, 1H), 3.69-3.67 (m, 1H), 3.49-3.46 (m, 1H), 2.09 (s, 3H,-OAc), 2.03 (s, 3H,-OAc), 2.01 (s, 3H,-OAc), 1.99 (s, 3H,-OAc), 1.92-1.88 (m, 2H), 1.57-1.54 (m, 2H), 1.46-1.42 (m, 2H), 1.36-1.28 (m, 8H)
Compound 6 productive rate is 67.2%, and structured data is
1h-NMR (600MHz, CDCl
3): δ 8.64 (s, 1H, ArH), 8.27 (br, s, 1H, NH), 8.02 (s, 1H, ArH), 7.88-7.87 (dd, J=6.42, 2.34Hz, 1H, ArH), 7.65-7.64 (m, 1H, ArH), 7.50 (s, 1H, ArH), 7.24 (s, 1H, ArH), 7.16-7.13 (t, J=8.70Hz, 1H, ArH), 5.32-5.20 (m, 2H), 5.11-5.08 (t, J=9.66Hz, 1H), 4.95 (s, 1H), 4.32-4.30 (m, 1H), 4.20-4.19 (m, 1H), 4.05-4.01 (m, 1H), 3.97-3.96 (m, 1H), 3.96 (s, 3H,-OMe), 3.91-3.88 (m, 1H), 2.17 (s, 3H,-OAc), 2.03 (s, 3H,-OAc), 1.98 (s, 3H,-OAc), 1.22-1.21 (d, J=6.36Hz, 3H)
Compound 7 productive rate is 66.3%, and structured data is
1h-NMR (600MHz, CDCl
3): δ 8.63 (s, 1H, ArH), 8.17 (br, s, 1H, NH), 7.89-7.87 (dd, J=6.90, 2.76Hz, 1H, ArH), 7.64-7.62 (m, 1H, ArH), 7.38 (s, 1H, ArH), 7.23 (s, 1H, ArH), 7.16-7.13 (t, J=8.70Hz, 1H, ArH), 5.28-5.27 (dd, J=9.78, 2.36, 1H), 5.21-5.20 (t, J=1.32Hz, 1H), 5.02-4.99 (t, J=10.08Hz, 1H), 4.77 (s, 1H), 4.32-4.33 (d, J=6.84Hz, 1H), 4.15-4.14 (m, 1H), 4.01-3.99 (m, 1H), 3.97 (s, 3H,-OMe), 3.75-3.72 (m, 1H), 3.64-3.62 (m, 1H), 2.20-2.17 (m, 2H), 2.11 (s, 3H,-OAc), 1.94 (s, 3H,-OAc), 1.82 (s, 3H,-OAc), 1.13-1.12 (d, J=5.94Hz, 3H)
Compound 8 productive rate is 60.3%, and structured data is
1h-NMR (600MHz, CDCl
3): δ 8.65 (s, 1H, ArH), 7.88-7.87 (dd, J=6.42, 2.28Hz, 1H, ArH), 7.73 (br, s, 1H, NH), 7.55-7.53 (m, 1H, ArH), 7.24 (s, 1H, ArH), 7.19 (s, 1H, ArH), 7.16-7.13 (t, J=8.70Hz, 1H, ArH), 5.32-5.29 (dd, J=10.74, 3.12Hz, 1H), 5.23-5.22 (q, J=1.8Hz, 1H), 5.08-5.05 (t, J=9.60Hz, 1H), 4.71 (q, J=1.38Hz, 1H), 4.08-4.06 (t, J=6.84Hz, 2H), 3.98 (s, 3H, OMe), 3.88-3.85 (m, 1H), 3.68-3.66 (m, 1H), 3.42-3.40 (m, 1H), 2.15 (s, 3H, OAc), 2.05 (s, 3H, OAc), 1.97 (s, 3H, OAc), 1.92-1.88 (m, 2H), 1.59-1.56 (m, 2H), 1.47-1.43 (m, 2H), 1.39-1.31 (m, 8H), 1.23-1.22 (d, J=6.36Hz, 3H)
The synthetic method of raw materials 4-(3-bromobenzene the amido)-7-methoxyquinazoline hydrochloride-6-alcohol of compound 9, with the preparation flow of 4-in embodiment 1 (the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol, just changes chloro-for reaction raw materials 3-4-fluoroaniline into m-bromoaniline.4-(3-bromobenzene amido)-7-methoxyquinazoline hydrochloride-6-alcohol 225mg is added in 100mL eggplant-shape bottle; salt of wormwood 179.7mg; be dissolved in DMF20mL; stir 20 minutes in 40C oil bath; then compound 1-(2-bromine oxethyl)-2 is added; 3; 4; 6-tetra--O-ethanoyl-β-D-Glucopyranose 355.3mg; nitrogen protection, is increased to 80 DEG C by oil bath temperature, stir 7 hours; reaction solvent is removed under reduced pressure, column chromatography purification (ethyl acetate: sherwood oil=3: 1) obtain white solid 374mg after reaction terminates.Productive rate 80.0%.Structured data is
1h-NMR (600MHz, CDCl
3): δ 8.67 (s, 1H, ArH), 8.38 (br, s, NH), 7.99 (s, 1H, ArH), 7.74-7.73 (m, 1H, ArH), 7.44 (s, 1H, ArH), 7.26-7.24 (m, 3H), 5.27-5.24 (t, J=9.60Hz, 1H), 5.14-5.10 (m, 2H), 4.66-4.65 (d, J=7.80Hz, 1H), 4.39-4.37 (m, 2H), 4.24-4.22 (m, 2H), 4.14-4.11 (m, 2H), 3.99 (s, 3H), 3.74-3.73 (m, 1H), 2.07 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.02 (s, 3H, OAc), 1.95 (s, 3H, OAc)
The preparation method of compound 10, with compound 9, just changes the sugar moieties in raw material into 1-(3-bromine propoxy-)-2,3,4,6-tetra--O-ethanoyl-β-D-Glucopyranose.Productive rate: 71.1%.Structured data
1h-NMR (600MHz, CDCl
3): δ 8.66 (s, 1H, ArH), 8.37 (br, s, 1H), 7.99 (s, 1H, ArH), 7.77-7.76 (m, 1H, ArH), 7.38 (s, 1H, ArH), 7.25 (s, 1H, ArH), 7.24 (s, 1H, ArH), 7.24-7.23 (dd, J=1.82Hz, 1H, ArH), 5.26-5.22 (t, J=9.60Hz, 1H), 5.10-5.07 (t, J=9.60HZ, 1H), 5.04-5.02 (dd, J=7.80, 9.96Hz, 1H), 4.54-4.53 (d, J=7.74Hz, 1H), 3.29-3.26 (dd, J=11.46, 2.18Hz, 1H), 4.25-4.22 (m, 1H), 4.20 (dd, J=2.76Hz, 1H), 4.18 (d, J=2.12Hz, 1H), 4.08-4.06 (m, 1H), 4.00 (s, 3H), 3.78-3.76 (m, 1H), 3.72-3.70 (m, 1H)
The synthetic method of raw materials 4-(3-chloro-4-fluorine benzyloxy-aniline the base)-7-methoxyquinazoline hydrochloride-6-alcohol of compound 11, with the preparation flow of 4-in embodiment 1 (the chloro-4-fluoroanilino of 3-)-7-methoxyl group-6-alcohol, just changes chloro-for reaction raw materials 3-4-fluoroaniline into 3-chloro-4-fluorine benzyloxy-aniline.Compound 4-(3-chloro-4-fluorine benzyloxy-aniline base)-7-methoxyquinazoline hydrochloride-6-alcohol 333.7mg is added in 100mL eggplant-shape bottle; salt of wormwood 217mg; be dissolved in DMF30mL; stir 20 minutes in 40 DEG C of oil baths; then 1-(3-bromo propoxy)-2 is added; 3; 4-tri--O-ethanoyl-L-rhamnosyl 645mg; nitrogen protection; oil bath temperature is increased to 80 DEG C; stir 8 hours, after reaction terminates, remove reaction solvent under reduced pressure, silicagel column column chromatography purification (ethyl acetate: sherwood oil=2: 1) obtain white solid 420mg after evaporated under reduced pressure.Productive rate 70.8%.Structured data is
1h-NMR (600MHz, CDCl
3): δ 8.61 (s, 1H, ArH), 7.95 (br, s, 1H, NH), 7.76-7.75 (d, J=2.76Hz, 1H, ArH), 7.58-7.56 (dd, J=8.70, 2.28Hz, 1H, ArH), 7.36-7.35 (m, 1H, ArH), 7.32 (s, 1H, ArH), 7.24-7.23 (d, J=5.52Hz, 2H, ArH), 7.22-7.20 (d, J=11.18Hz, 1H, ArH), 7.03-7.01 (dt, J=7.26, 2.34Hz, 1H, ArH), 6.96-6.94 (d, J=9.18Hz, 1H, ArH), 5.31-5.28 (dd, J=11.46, 3.66Hz, 1H), 5.21-5.20 (m, 1H), 5.14 (s, 2H), 5.02-4.99 (t, J=10.08Hz, 1H), 4.78-4.77 (d, J=1.32Hz, 1H), 4.33-4.31 (q, J=5.94Hz, 1H), 4.15-4.14 (m, 1H), 4.01-3.99 (m, 1H), 3.98 (s, 3H), 3.75-3.74 (m, 1H), 3.64-3.61 (m, 1H), 2.21-2.16 (m, 2H), 2.11 (s, 3H, OAc), 1.93 (s, 3H, OAc), 1.82 (s, 3H, OAc), 1.14-1.12 (d, J=6.42Hz, 3H)
Ii) synthesis of compound III:
The preparation method of raw material 3 is with embodiment 2, embodiment 1 compound 3200mg is added in 50mL eggplant-shape bottle, anhydrous methanol 20ml, then adds NaOMe/MeOH (1g/100mL) 15, and stirred at ambient temperature reacts 5 little complete up to silica gel thin-layer plate detection reaction.Add Zeo-karb 0.5g, stir 5 minutes, filter decationize exchange resin, evaporated under reduced pressure solvent, vacuum-drying obtains white solid 131mg.Productive rate: 93.3%.Structured data is
1h-NMR (600MHz, DMSO-d
6): δ 9.60 (brs, 1H, NH), 8.52 (s, 1H, ArH), 8.12-8.10 (dd, J=6.84, 2.28Hz, 1H, ArH), 7.82 (s, 1H, ArH), 7.79-7.78 (m, 1H, ArH), 7.46-7.43 (t, J=8.70Hz, 1H, ArH), 7.20 (s, 1H, ArH), 5.11 (br, s, 1H), 4.99 (br, s, 1H), 4.95 (br, s, 1H), 4.57 (br, s, 1H), 3.34-3.30 (m, 3H), 4.24-4.19 (m, 1H), 4.97-4.96 (m, 1H), 4.95 (s, 3H), 3.70-3.68 (d, J=10.08, 1H), 3.48-3.46 (q, J=5.94Hz, 1H), 3.17-3.14 (m, 2H), 3.08-3.07 (d, J=5.94Hz, 1H), 3.03-3.01 (t, J=8.22, 1H)
The compound experiment operating process of compound IV-XI, with the synthesis of compound III, just changes compound 4-11 in reaction raw materials respectively
Compound IV productive rate is 91.2%, and structured data is
1h-NMR (600MHz, DMSO-d
6): δ 9.68 (brs, 1H, NH), 8.53 (s, 1H, ArH), 8.13-8.11 (dd, J=6.42, 2.28Hz, 1H, ArH), 7.83 (s, 1H, ArH), 7.81-7.77 (m, 1H, ArH), 7.47-7.44 (t, J=9.18Hz, 1H, ArH), 7.21 (s, 1H, ArH), 5.04 (br, s, 1H), 4.98 (br, s, 1H), 4.94 (br, s, 1H), 4.53 (br, s, 1H), 4.38 (br, s, 2H), 4.26-4.23 (m, 2H), 4.21-4.09 (d, J=7.80Hz, 1H), 3.99-3.98 (m, 1H), 3.95 (s, 3H,-OMe), 3.71-3.67 (m, 2H), 3.13-3.11 (dd, J=5.94, 2.23Hz, 1H), 3.05-3.04 (d, J=9.18Hz, 1H), 2.98-2.96 (t, J=8.70Hz, 1H), 2.13-2.11 (t, J=6.42Hz, 2H)
Compound V productive rate is 93.8%, and structured data is
1h-NMR (600MHz, DMSO-d
6): δ 9.55 (brs, 1H, NH), 8.49 (s, 1H, ArH), 8.14-8.12 (dd, J=6.90, 2.76Hz, 1H, ArH), 7.81-7.79 (m, 2H, ArH), 7.46-7.43 (t, J=9.18Hz, 1H, ArH), 7.19 (s, 1H, ArH), 4.97 (br, s, 2H), 4.93 (br, s, 1H), 4.50 (br, s, 1H), 4.13-4.10 (t, J=8.46Hz, 3H), 3.94 (s, 3H), 3.77-3.75 (m, 1H), 3.68-3.66 (d, J=11.46Hz, 1H), 3.48-3.42 (m, 2H), 3.14-3.12 (t, J=9.36Hz, 1H), 3.08-3.05 (m, 2H), 2.96-2.93 (t, J=8.28Hz, 1H), 1.85-1.80 (m, 2H), 1.53-1.51 (m, 2H), 1.48-1.46 (m, 2H), 1.38-1.34 (m, 2H), 1.33-1.28 (m, 6H)
Compound VI productive rate is 95.8%, and structured data is
1h-NMR (600MHz, DMSO-d
6): δ 9.58 (brs, 1H, NH), 8.51 (s, 1H, ArH), 8.14-8.13 (dd, J=6.90, 2.76Hz, 1H, ArH), 7.84 (s, 1H, ArH), 7.82-7.80 (m, 1H, ArH), 7.47-7.44 (t, J=9.18Hz, 1H, ArH), 7.21 (s, 1H), 4.83 (br, s, 2H), 4.71 (br, s, 2H), 4.32-4.29 (m, 2H), 3.98-3.97 (m, 1H), 3.96 (s, 3H), 3.87-3.85 (m, 1H), 3.65 (s, 1H), 3.53-3.50 (m, 1H), 3.45-3.44 (m, 1H), 3.23-3.21 (t, J=9.181H), 1.15-1.14 (d, J=6.42Hz, 3H)
Compound VI I productive rate is 90.6%, and structured data is
1h-NMR (600MHz, DMSO-d
6): δ 9.64 (brs, 1H, NH), 8.50 (s, 1H, ArH), 8.15-8.13 (dd, J=6.36, 2.28Hz, 1H, ArH), 7.84 (s, 1H, ArH), 7.82-7.80 (m, 1H, ArH), 7.45-7.42 (t, J=9.18Hz, 1H, ArH), 7.20 (s, 1H, ArH), 4.80 (br, s, 2H), 4.67 (br, s, 1H), 4.60 (s, 1H), 4.22-4.20 (t, J=5.94Hz, 2H), 3.95 (s, 3H), 3.83-3.81 (m, 1H), 3.63 (s, 1H), 3.57-3.54 (m, 1H), 3.44-3.43 (t, J=7.80Hz, 2H), 3.20-3.17 (t, J=9.121H), 2.10-2.07 (m, 2H), 1.11-1.10 (d, J=6.42Hz, 3H)
Compound VI II productive rate is 94.5%, and structured data is
1h-NMR (600MHz, DMSO-d
6): δ 9.55 (brs, 1H, NH), 8.50 (s, 1H, ArH), 8.14-8.13 (dd, J=6.84, 2.28Hz, 1H, ArH), 7.82-7.79 (m, 2H, ArH), 7.46-7.43 (t, J=9.18Hz, 1H, ArH), 7.20 (s, 1H, ArH), 4.77 (br, s, 1H), 4.74 (br, s, 1H), 4.59 (br, s, 1H), 4.52 (s, 1H), 4.14-4.11 (t, J=6.42Hz, 2H), 3.94 (s, 3H), 3.59 (s, 1H), 3.55-3.51 (m, 1H), 3.44-3.38 (m, 2H), 3.33-3.29 (m, 1H), 3.20-3.17 (t, J=9.12Hz, 1H), 1.84-1.81 (m, 2H), 1.49-1.47 (m, 4H), 1.37-1.35 (m, 2H), 1.32-1.28 (m, 6H), 1.14-1.13 (d, J=5.94Hz, 3H)
Compound I X productive rate is 91.9%, and structured data is
1h-NMR (600MHz, DMSO-d
6): δ 9.58 (br, s, 1H, NH), 8.52 (s, 1H, ArH), 8.16-8, 15 (t, J=2.28Hz, 1H, ArH), 7.89-7.87 (dd, J=9.18, 1.38Hz, 1H, ArH), 7.86 (s, 1H, ArH), 7.35-7.33 (t, J=8.28Hz, 1H, ArH), 7.28-7.26 (d, J=7.50Hz, 1H, ArH), 7.21 (s, 1H, ArH), 5.11 (br, s, 3H), 4.58 (s, br, 1H), 4.36-4.33 (m, 2H, ArH), 4.32-4.31 (d, J=7.80Hz, 1H), 4.23-4.19 (m, 1H), 3.96-3.95 (m, 1H), 3.94 (s, 3H), 3.70-3.68 (dd, J=10.08, 1.38Hz, 1H), 3.49-3.48 (d, J=5.94Hz, 1H), 3.47-3.46 (d, J=6.90Hz, 1H), 3.13-3.15 (dd, J=7.80, 2.16Hz, 1H), 3.09-3.07 (t, J=8.70Hz, 1H), 3.03-3.00 (t, J=8.22Hz, 1H)
Compounds X productive rate is 94.2%, and structured data is
1h-NMR (600MHz, CDCl
3): δ 8.66 (s, 1H, ArH), 8.37 (br, s, 1H), 7.99 (s, 1H, ArH), 7.77-7.76 (m, 1H, ArH), 7.38 (s, 1H, ArH), 7.25 (s, 1H, ArH), 7.24 (s, 1H, ArH), 7.24-7.23 (dd, J=1.82Hz, 1H, ArH), 5.26-5.22 (t, J=9.60Hz, 1H), 5.10-5.07 (t, J=9.60HZ, 1H), 5.04-5.02 (dd, J=7.80, 9.96Hz, 1H), 4.54-4.53 (d, J=7.74Hz, 1H), 3.29-3.26 (dd, J=11.46, 2.18Hz, 1H), 4.25-4.22 (m, 1H), 4.20 (dd, J=2.76Hz, 1H), 4.18 (d, J=2.12Hz, 1H), 4.08-4.06 (m, 1H), 4.00 (s, 3H), 3.78-3.76 (m, 1H), 3.72-3.70 (m, 1H)
Compounds X I productive rate is 95.2%, and structured data is
1h-NMR (600MHz, DMSO-d
6): δ 9.51 (br, s, 1H, NH), 8.14 (s, 1H, ArH), 7.95-7.94 (d, J=2.70Hz, 1H), 7.82 (s, 1H, ArH), 7.67-7.66 (dd, J=8.70, 1.80Hz, 1H, ArH), 7.49-7.46 (q, J=7.74Hz, 1H, ArH), 7.35-7.31 (t, J=7.80Hz, 2H, ArH), 7.25-7.24 (d, J=9.18Hz, 1H, ArH), 7.19-7.18 (dt, J=9.20, 2.28Hz, 1H, ArH), 7.15 (s, 1H, ArH), 5.24 (s, 2H), 4.79 (br, s, 2H), 4.65 (br, s, 1H), 4.59 (s, 1H), 4.20-4.18 (t, J=6.42Hz, 2H), 3.93 (s, 3H), 3.82-3.80 (m, 1H), 3.63-3.62 (d, J=1.80Hz, 1H), 3.55-3.52 (m, 1H), 3.46-3.44 (m, 2H), 3.19-3.17 (t, J=9.60Hz, 1H), 2.08-2.06 (m, 2H), 1.11-1.10 (d, J=5.94Hz, 3H)
Embodiment 3
Be prepared as follows the quinazoline sugar derivative of general formula, wherein sugared ring portion is divided into a sugar derivative of D-Glucose 4,6-position propylidene base protection
The preparation of compounds X II
The preparation method of compound III, with embodiment 2, adds compound III 100mg in 100mL eggplant-shape bottle, tosic acid monohydrate 5.0mg, anhydrous calciumsulphate 100mg, diethoxy propene 260mg.Measure dry DMF 35mL to dissolve, stirred at ambient temperature 4 hours.With DIPEA, reacting liquid pH value is equaled 7, remove reaction solvent under reduced pressure, (acetone: ethyl acetate=1: 1) obtain white solid 72mg after purification by silica gel column chromatography.Productive rate: 66.4% compound structure data are
1h-NMR (DMSO-d
6): δ 9.57 (brs, 1H, NH), 8.51 (s, 1H, ArH), 8.14-8.12 (dd, J=6.84, 2.28Hz, 1H, ArH), 7.82 (s, 1H, ArH), 7.81-7.80 (m, 1H, ArH), 7.47-7.44 (t, J=9.15Hz, 1H, ArH), 7.22 (s, 1H, ArH), 5.37 (br, s, 1H), 5.21 (br, s, 1H), 4.46-4.44 (d, J=7.80Hz, 1H), 4.33-4.31 (m, 2H), 4.16-4.13 (m, 1H), 3.98-3.97 (m, 1H), 3.95 (s, 3H), 3.77-3.75 (q, J=5.16, 5.04, 2H), 3.70-3.68 (t, J=10.08, 1H), 3.44-3.40 (m, 2H), 3.12-3.11 (t, J=9.18Hz, 1H), 1.43 (s, 3H), 1.32 (s, 3H)
The preparation experiment operating process of compounds X III is with the synthesis of compound XII, and just changing Compound I X productive rate in reaction raw materials is 61.5%, and structured data is
1h-NMR (600MHz, DMSO-d
6): δ 9.53 (br, s, 1H, NH), 8.53 (s, 1H, ArH), 8.15 (s, 1H, ArH), 7.89-7.88 (d, J=8.28Hz, 1H, ArH), 7.84 (s, 1H, ArH), 7.37-7.35 (t, J=8.22Hz, 1H, ArH), 7.29-7.28 (d, J=7.80Hz, 1H, ArH), 7.22 (s, 1H, ArH), 5.37-5.36 (d, J=5.04Hz, 1H), 5.20-5.19 (d, J=5.04Hz, 1H), 4.46-4.44 (d, J=7.80Hz, 1H), 4.34-4.31 (m, 2H), 4.16-4.14 (m, 1H), 3.99-3.97 (m, 1H), 3.95 (s, 3H), 3.77-3.75 (q, J=5.04Hz, 1H), 3.70-3.68 (t, J=10.08Hz, 1H), 3.46-3.44 (m, 1H), 3.30-3.28 (m, 1H), 3.22-3.20 (m, 1H), 3.13-3.11 (m, 1H), 1.43 (s, 3H), 1.32 (s, 3H)
The inhibiting tumor assay method of Compound I-XIII and compound 1 is as follows:
Compound I-XIII in the present invention and compound 1 are configured to 5 concentration gradients,
1, according to enzyme-linked immunosorbent assay, by the sample I-XIII of 5 different concns echelons and 1, application of sample is ready containing in 96 orifice plates of EGFR in respectively, react 2 hours under room temperature, colour developing, measure the optical density value in every hole, calculate inhibiting rate, record the half effective inhibition concentration (IC of compound
50value), experimental result is in table 1.
2, with reference to Sulforhodamine B (SRB) the protein staining method of viable cell and enzyme-linked immunosorbent assay by 1 × 10
5a431 (human skin cancer cells) suspension 100 μ L is inoculated on 96 orifice plates, then the liquid 10 μ L of different concns is added, be placed in 37 DEG C of moist incubators, within 72 hours, take out culture plate, every hole adds Sulforhodamine B again, continues cultivation 6 hours, records the optical density value in every hole by automatic microplate reader, calculate inhibiting rate, record the half effective inhibition concentration (IC of compound
50value), experimental result sees the following form.
Result display compound III, V, VIII, XI are to the inhibition IC of external free EGF-R ELISA EGFR
50value is all better than positive control drug Gefitinib, and the inhibition of compound VI I and XIII to human skin cancer cells A431 is better than positive control drug Gefitinib (IC
50=1.790 μMs), compound III, IV, V, IX, X, XI and XII are to the inhibition (IC of human skin cancer cells A431
51< 10 μMs) suitable with Gefitinib.Verify by experiment, above-mentioned quinazoline sugar derivative water-soluble significantly better than Gefitinib.
The above is only preferred embodiment of the present invention, and be not restriction the present invention being made to other form, any those skilled in the art may utilize the technology contents of above-mentioned announcement to be changed or be modified as the Equivalent embodiments of equivalent variations.But everyly do not depart from technical solution of the present invention content, any simple modification, equivalent variations and the remodeling done above embodiment according to technical spirit of the present invention, still belong to the protection domain of technical solution of the present invention.
Claims (3)
1. a quinazoline sugar derivative, is characterized in that having following structural formula:
In formula, female ring structure is the quinazoline female ring that the different anilino in 4-position replaces, R
1for the one in fluorine, 3-fluorine benzyloxy; R
2for chlorine; R
3for H; Its 6-position side chain is the sugared ring connected by the aliphatic chain of different lengths, and wherein n is the integer of 2 ~ 9, and sugared ring R is the one in D-Glucose base, L-rhamanopyranosyl.
2. the preparation method of a quinazoline sugar derivative according to claim 1, it is characterized in that: acetyl sugar, methyl sugar, propylidene base sugar or benzyl sugared with bromo fatty alcohol with the mol ratio of 1: 1.5-2.0, boron trifluoride diethyl etherate do catalyzer be obtained by reacting in methylene dichloride different lengths 1 bromo alkoxyl group acetyl sugar, methyl sugar, propylidene base sugar or benzyl sugared, silica column purification; By products therefrom and 4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride-6-alcohol or 4-(3-chloro-4-fluorine benzyloxy-aniline base)-7-methoxyquinazoline hydrochloride-6-alcohol with 1.2-1.5: 1 mol ratio, in salt of wormwood or Sodium Hydroxide Alkaline condition, temperature is at 60-80 DEG C, stir 10-12 hour, on the glycosyl that coupling generation 1-position aliphatic chain connects, hydroxyl is all or part of by the derivative of methyl, propylidene base, ethanoyl, benzyl protection; Described derivative removes in the basic conditions under ethanoyl, atmosphere of hydrogen and removes methyl, propylidene base under palladium carbon catalytic eliminating benzyl or acidic conditions; stir after 2-5 hour, gained reactant obtains quinazoline sugar derivative according to claim 1 by purification by silica gel column chromatography.
3. according to the preparation method described in claim 2, it is characterized in that: described raw material 4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride-6-alcohol or 4-(3-chloro-4-fluorine benzyloxy-aniline base)-7-methoxyquinazoline hydrochloride-6-alcohol be with 4-chloro-7-methoxyquinazoline hydrochloride-6-alcohol ethyl ester for raw material with 1: 1.2-1.3 mol ratio 4-fluoroaniline chloro-with 3-or 3-chloro-4-fluorine benzyloxy-aniline mix respectively, solvent is removed under reduced pressure after stirring and refluxing 3-5 hour in Virahol or propyl carbinol, without the need to purifying, again reactant is dissolved in methyl alcohol and adds strong aqua 1-3 milliliter, stirred at ambient temperature is until silica gel thin-layer plate detection raw material reaction is complete, gained solid ether or sherwood oil after reaction solution evaporated under reduced pressure are fully washed obtained.
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WO2007082434A1 (en) * | 2006-01-20 | 2007-07-26 | Shanghai Allist Pharmaceutical., Inc. | Quinazoline derivatives,preparation methods and uses thereof |
CN101289445A (en) * | 2007-04-18 | 2008-10-22 | 中国科学院上海药物研究所 | Aniline quinazoline derivatives, preparation method and uses thereof |
CN101367793A (en) * | 2008-09-26 | 2009-02-18 | 中国科学院广州生物医药与健康研究院 | Amino-quinazoline derivative with antineoplastic activity and its salts |
WO2009090661A1 (en) * | 2008-01-18 | 2009-07-23 | Natco Pharma Limited | 6.7-dialkoxy ouinazoline derivatives useful for treatment of cancer related disorders |
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2010
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Patent Citations (4)
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WO2007082434A1 (en) * | 2006-01-20 | 2007-07-26 | Shanghai Allist Pharmaceutical., Inc. | Quinazoline derivatives,preparation methods and uses thereof |
CN101289445A (en) * | 2007-04-18 | 2008-10-22 | 中国科学院上海药物研究所 | Aniline quinazoline derivatives, preparation method and uses thereof |
WO2009090661A1 (en) * | 2008-01-18 | 2009-07-23 | Natco Pharma Limited | 6.7-dialkoxy ouinazoline derivatives useful for treatment of cancer related disorders |
CN101367793A (en) * | 2008-09-26 | 2009-02-18 | 中国科学院广州生物医药与健康研究院 | Amino-quinazoline derivative with antineoplastic activity and its salts |
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蔡孟深,等.第4章 苷键的生成 第9章 糖类药物.《糖化学—基础、反应、合成、分离及结构》.化学工业出版社,2007,(第1版),第114-118、343、348页. * |
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