CN1278176A - Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps - Google Patents

Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps Download PDF

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CN1278176A
CN1278176A CN98810806A CN98810806A CN1278176A CN 1278176 A CN1278176 A CN 1278176A CN 98810806 A CN98810806 A CN 98810806A CN 98810806 A CN98810806 A CN 98810806A CN 1278176 A CN1278176 A CN 1278176A
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quinazolyl
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P·弗洛斯特
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Wyeth Holdings LLC
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American Cyanamid Co
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    • A—HUMAN NECESSITIES
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Abstract

This invention provides a method of treating or inhibiting colonic polyps in a mammal in need thereof which comprises administering to said mammal a compound having formula (I), wherein X is phenyl which is optionally substituted; R and R1 are each independently, hydrogen, halogen, alkyl, alkoxy, hydroxy or trifluoromethyl; R2 is hydrogen, alkyl, alkoxy, hydroxy or trifluoromethyl; Y is a radical selected from the group consisting of formulae (II), (III), (IV), (V), (VI), (VII) and (VIII). R3 is independently hydrogen, alkyl, carboxy, carboalkoxy, phenyl, or carboalkyl; n = 2-4; or a pharmaceutically acceptable salt thereof, with the proviso that each R3 of Y may be the same or different.

Description

Quinazoline derivant is as the application that is used for the treatment of the tyrosine kinase inhibitor of polyp of colon
The present invention relates to the application of some quinazoline compounds in treatment and inhibition polyp of colon.
Polyp of colon be divided into familial form pattern (familial adenomatous polyposis) (FAP) and distribute type.Although annually according to estimates suffer from sporadic adenoma polyp (SAP) the U.S. 2 million peoples that only have an appointment, the U.S. has nearly 25000 patient to suffer from FAP.These patients exist the danger that adenoma of colon worsens.In the situation of FAP, in fact this danger reach 100%, and these patients usually have to just accept at an early age colectomy.Suffering from the patient who distributes the type polyp can treat and need carry out regular colonoscopy with polypectomy, because also there is the danger that worsens to the recurrence polyp.In fact, it is also higher that these patients' father and mother and siblings suffer from the danger of colorectal carcinoma.
The sudden change that exists in the hereditary basis of FAP and the apc gene is relevant.In the patient who distributes the type polyp, had found that similar APC sudden change.From biochemical angle, it is relevant that the increasing of the generation and the cyclo-oxygenase, particularly COX-2 of APC sudden change expressed.These enzymes are very important for the generation of prostaglandins material (PG class).The prostaglandins material mediates multiple function at enteral, comprising mobility, vasotonia, angiogenesis and mucous membrane protection.PG class material can also hinder programmed cell death, and this can be used as is the explanation that polyp is formed.
Treatment to FAP and SAP mainly is to suppress the COX enzyme.Have clear evidence to prove, the COX inhibitor is effective in the minimizing polyp forms.These COX inhibitor mainly find and NSAID class medicine, for example sulindac, Su Linda, piroxicam and etodolac, and as if these medicines all be equivalent using.The subject matter of NSAID therapy is to produce serious adverse, comprises peptic ulcer, cholestasis type hepatitis and necrosis of renal papillae.Therefore for a long time treat polyp and be considered to impracticable with NSAID class medicine.
Up to now, the activation of COX-2 and overexpression should be activated owing to EGF-R ELISA (EGFR) in the adenoma polyp.It is that targeting discharges PG class material with nuclear that a kind of part-amphiregulin (AR) in the EGFR part can bring out COX-2 to the stimulation of EGFR, and causes mitosis subsequently in polar colon epithelial cell.Cox 2 inhibitor has the effect that prevents this a series of activities.
Detailed Description Of The Invention the invention provides a kind of treatment or suppresses the method for polyp of colon in the mammal, and this method comprises the chemical compound to described administration formula 1, or its officinal salt, but condition be each R3 of Y can be identical or different.
Figure A9881080600071
Wherein: X is by the optional phenyl that replaces of one or more substituent groups, and described substituent group is selected from halogen, contain the alkyl of 1-6 carbon atom, contain alkoxyl, hydroxyl, trifluoromethyl, cyano group, nitro, carboxyl, the alkoxy carbonyl group that contains 2-7 carbon atom, the alkyl-carbonyl that contains 2-7 carbon atom, the amino of 1-6 carbon atom and contain the alkanoyl amino of 1-6 carbon atom; R and R 1Be hydrogen, halogen independently respectively, contain the alkyl of 1-6 carbon atom, the alkoxyl that contains 1-6 carbon atom, hydroxyl or trifluoromethyl; R 2Be hydrogen, contain the alkyl of 1-6 carbon atom, the alkoxyl that contains 1-6 carbon atom, hydroxyl, trifluoromethyl; Y is selected from following group:
Figure A9881080600072
Figure A9881080600073
And R 3Be hydrogen independently, contain alkyl, the carboxyl of 1-6 carbon atom, the alkoxy carbonyl group that contains 1-6 carbon atom, phenyl or contain the alkyl-carbonyl of 2-7 carbon atom; N=2-4.
Described officinal salt be those derived from salt as organic acid or mineral acid, described acid is acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, malonic acid, gluconic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, methanesulfonic acid and similarly knownly accept acid for example.
Moieties in the amino substituent group of alkyl, alkoxyl, alkoxy carbonyl group, alkyl-carbonyl and alkanoyl comprises the carbochain of straight chain and side chain, for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl or n-hexyl.Carboxyl is defined as-CO 2The H group.The alkoxy carbonyl group that contains 2-7 carbon atom is defined as-CO 2R " group, wherein R " is the alkyl that contains 1-6 carbon atom.Alkyl-carbonyl is defined as-COR ", wherein R " is the alkyl that contains 1-6 carbon atom.Term used herein " halogen " is meant chlorine, bromine, iodine or fluorine.When X is substituted, preferably this group coverlet-, two-or three replace and first-selected coverlet replaces.When chemical compound of the present invention had asymmetric center, the present invention had comprised enantiomer and the relevant racemic modification of this chemical compound of various R and S.
Preferred in chemical compound of the present invention: those are R, R wherein 1And R 2It is the chemical compound of hydrogen; With those wherein R, R 1And R 2Be that hydrogen and X are unsubstituted or by halogen or contain the mono-substituted phenyl of alkyl of 1-6 carbon atom.One group of chemical compound among the present invention is those wherein 3 chemical compounds of going up the coverlet replacement of X, is preferably replaced by halogen, is more preferably replaced by bromine.Among the present invention another the group chemical compound be those wherein Y be-CH=CH-CO 2H ,-CH=CH-CO 2Et ,-CH=C (Me) 2,-CH=CH-Et ,-CH=CH-CH 3,-CH=CH-CH=CH-CH 3,-CH=CH 2,-CH=CH-Ph ,-CH ≡ CH-CH 3Or 2-cyclopentenes.Preferred R 3Be hydrogen, methyl, ethyl, phenyl ,-CO 2H or-CO 2Et.
A kind of preparation method of formula as defined above 1 chemical compound, comprising: a) with wherein R, the R shown in the formula 6 1, R 2With X definition 6-amino-4-phenylamino quinazoline as above:
Figure A9881080600081
With:
I) acyl chlorides of formula 7 reduction, wherein Y such as above-mentioned definition
Figure A9881080600091
The ii) reduction of the mixed anhydride shown in the formula 8, wherein Y such as above-mentioned definition
Figure A9881080600092
Or iii) with the reduction of the cyclic anhydride shown in the formula 11, wherein each R 5Be hydrogen, phenyl or the alkyl that contains 1-6 carbon atom independently:
Figure A9881080600093
B) with the chemical compound of formula 17, wherein R, R 1, R 2With Y such as above-mentioned definition and Hal be any suitable halogen:
Figure A9881080600094
With the aniline reaction shown in the formula 18, wherein X such as above-mentioned definition
X-NH 2
18 or c) with the chemical compound of formula 24, wherein R, R 1, R 2Define as above with Y With the aniline reaction of formula 25,
H 2N-X
25 wherein X definition is as above.
The preparation of the The compounds of this invention shown in the formula 9 has been described, wherein R, R among the synthetic route chart A below 1, R 2, R 3, X and n definition as above and R 4It is the alkyl (preferred isobutyl group) that contains 1-6 carbon atom.Y ' is selected from following group:
Figure A9881080600103
With Each R ' wherein 3Be alkyl, the carboxyl that contains 1-6 carbon atom, the alkoxy carbonyl group that contains 1-6 carbon atom, phenyl or the alkyl-carbonyl that contains 2-7 carbon atom independently.According to program listed among the synthetic route A, the 5-nitro-anthranilo nitrile shown in the formula 2 is heated to about 100 ℃ with contained excessive dimethylformamide dimethyl acetal under dispensable solvent, obtain the amidine of formula 3.Solution heating in acetic acid is 1-5 hour with amidine 3 and aniline 4, obtains the 6-nitro-4-phenylamino quinazoline of formula 5.In the mixed liquor of acetic acid-alcohol, under high temperature, the nitroreduction in the formula 5 is obtained the 6-amino-4-phenylamino quinazoline compounds of formula 6 with Reducing agent such as ferrum.In atent solvent such as oxolane (THF), in the presence of organic base such as pyridine or triethylamine with the acyl chlorides of formula 7 or 6 acidylates are obtained the The compounds of this invention of formula 9 representatives with the mixed anhydride of formula 8 (suitable make) by corresponding carboxylic acid.Wherein 7 or 8 have in the situation of asymmetric carbon atom at those, when chemical compound of the present invention is racemic form or R and S optically-active form respectively, can adopt 7 or 8 racemic modification or each R or S enantiomer.5-nitro-anthranilo nitrile can be an affiliated field known substances shown in the necessary formula 2 of preparation The compounds of this invention, maybe can prepare by the known method in affiliated field, detailed content can be referring to following list of references: Baudet, " Dutch chemical paper collection " 43,710 (1924); Hartmans, " Dutch chemical paper collection " 65,468,469 (1946); People such as Taylor, " american Journal of the Chemical Society " 82,6058,6063 (1960); People such as Taylor, " american Journal of the Chemical Society " 82,3152,3154 (1960); Deshpande; Seshadri, " India's The Chemicals ", 11,538 (1973); Katritzky, Alan R.; Laurenzo, Kathleen S., " organic chemistry magazine " 51 (1986); Niclas, Hans-Joachim; Bohle, Matthias; Rick, Jens-Detlev; Zeuner, Frank; Zoelch.Lothar, Z.Chem., 25 (4), 137-138 (1985).
Synthetic route A
Figure A9881080600111
The preparation of the The compounds of this invention shown in the formula 12 has been described, wherein R, R among the synthetic route B below 1, R 2, X and n as mentioned above.Each R 5Be hydrogen, phenyl or the alkyl that contains 1-6 carbon atom independently.According to the listed reaction of synthetic route B, the 6-amino of formula 10-4-phenylamino quinazoline compounds (by synthetic route A preparation) in atent solvent such as oxolane, in the presence of base catalyst such as pyridine or triethylamine by the cyclic anhydride acidylate of formula 11.
Synthetic route B
Figure A9881080600121
In some standard pharmacological experiments representative compounds of the present invention is assessed, the result shows that chemical compound of the present invention has the effective active as protein tyrosine kinase inhibitors, and is anti-proliferative agent.Therefore, based on the activity that is shown in standard pharmacological experiment method, chemical compound of the present invention is effective anti-vegetation (tumor) medicine.The experimental technique that is adopted and the result of gained will be described below.
The preparation of the The compounds of this invention shown in the formula 19 has been described below, wherein Y ', R among the synthetic route C 4With X as mentioned above.According to the listed reaction of synthetic route C, use Reducing agent such as sodium sulfite 4-chloro-6-nitro-quinazoline (Morley, JS ﹠amp in the two-phase system of forming by oxolane and water, in the presence of a small amount of phase transfer catalyst with formula 13; Simpson, " Chemical Society can will " (Britain) 360 (1948)) be reduced to 6-amino-4-chloro quinazoline.In atent solvent such as oxolane (THF), in the presence of organic base such as pyridine or N-methylmorpholine, chemical compound 14 acidylates are obtained the chemical compound of formula 17 with the mixed anhydride (making) of the acyl chlorides of formula 15 or formula 16 from corresponding carboxylic acid.15 or 16 have in the situation of asymmetric carbon atom at those, when chemical compound of the present invention is racemic modification or R and S optically-active form respectively, can adopt 15 or 16 racemic modification or each R or S enantiomer.In atent solvent such as isopropyl alcohol, the chemical compound of formula 17 aniline with formula 18 is heated, obtain the The compounds of this invention of formula 19 representatives.
Synthetic route C
Following synthetic route D has described the preparation of the The compounds of this invention shown in the formula 26, wherein Y ', R 4With X as mentioned above.According to reaction listed among the synthetic route D, be corresponding amino-compound 21 with the nitroreduction in 20 (according to the synthetic route A preparations) with palladium catalyst and hydrogen raw material (can be hydrogen itself or cyclohexene).In atent solvent such as oxolane (THF), in the presence of organic base such as pyridine or N-methylmorpholine with the mixed anhydride (making) of the acyl chlorides of formula 22 or formula 23 from corresponding carboxylic acid with chemical compound 21 acidylates, obtain the chemical compound of formula 24.22 or 23 have in the situation of asymmetric carbon atom at those, when chemical compound of the present invention is racemic modification or R and S optically-active form respectively, can adopt 22 or 23 racemic modification or each R or S enantiomer.In atent solvent such as acetic acid, the chemical compound of formula 24 aniline with formula 25 is heated, obtain the The compounds of this invention of formula 26 representatives.
Synthetic route D
Figure A9881080600141
The performance of The compounds of this invention treatment or inhibition polyp of colon is confirmed in body internal standard pharmacological experiment method as described below.Assess the familial adenomatous polyposis (FAP) of this experimental technique simulation human body in the method as representative compounds of the present invention with the chemical compound of embodiment 9.The normally Min mice of best model has been adopted for FAP in this experiment, and these mices are strains of forfeiture apc gene template.Make these animals form multiple polyposis intestinalis (adenoma) and finally develop into adenocarcinoma.The polyp that forms in the Min mice is expressed as EGFR and it is activated by COX-2.As if NSAID class medicine such as sulindac or etodolac can reduce the formation of polyposis intestinalis in (but can't eradicate) above-mentioned animal, and this final generation that shows COX-2 and PG class material has reaction to these effects.Used experimental technique will simply be described below and the result of gained in this standard pharmacological experiment method.
With the chemical compound of embodiment 9 with standard Muridae feedstuff mixes and make animal arbitrarily obtain these foods.Based on the evaluation to food consumption quantity, embodiment 9 compound concentrations that join in the feedstuff equal to make animal picked-up 20mg/kg/ days.At the 30th day, 4 processed animals and 4 control animals (only absorbing feedstuff) are put to death, estimate its polyp quantity.All control animals suffer from polyp more than 30 at its enteral, but treated animal none polyp is arranged.When to 15 animals/when group experimentizes, observed identical result at the 60th day.The above polyp of 30 (bigger) appears in control animal, but processed animal none polyp is arranged.
These digital proofs, chemical compound of the present invention can effectively suppress polyp and form in the animal that suddenling change appears in its apc gene.Based on the result of gained in this standard pathology experimental technique, the formation of polyp of colon can effectively be treated or suppress to chemical compound of the present invention.
Chemical compound of the present invention when being used for administration, can prepare separately or with one or more pharmaceutically suitable carrier formulated in combination.Described carrier for example is solvent, diluent etc., but and when the oral administration administration, can adopt as tablet, capsule dispersed powders, granule, contain for example about 0.05-5% suspending agent suspension, contain the syrup of for example about 10-50% sugar and contain form such as alcoholic acid elixir of 20-50% (weight) according to appointment; Or waiting sterile solution for injection or the suspension that oozes the parenterai administration that contains the 0.05-5% suspending agent of having an appointment in the medium.The said medicine preparation for example can contain in the active component of about 0.05-of carrier combinations about 90% (weight), the about 5%-60% of more normal employing (weight).
The change of the effective dose of used active component is depended on used specific compound, administering mode and is treated severity of disease.But, usually when chemical compound of the present invention with the daily dose administration of the about 1000mg/kg the weight of animals of about 0.5-and randomly divide 2-4 administrations every day or can obtain optimal effect during with the slow release formulation administration.For most mammals, total daily dose is about 1-1000mg, preferably about 2-500mg.The dosage form that is fit to use in the body contains have an appointment 0.5-1000mg and the well-mixed reactive compound of solid-state or liquid pharmaceutically suitable carrier.This dosage regimen should be regulated and control so that produce best treatment replys.For example, can be divided into several dosed administrations every day, or suitably reduce dosage according to the indication in the emergency treatment situation.
These reactive compounds can the oral administration administration and through intravenous, intramuscular or subcutaneous route administration.Described solid-state carrier comprises starch, lactose, dicalcium phosphate, microcrystalline Cellulose, sucrose and Kaolin, and liquid carrier comprises aquesterilisa, Polyethylene Glycol, nonionic surfactant and edible oil such as Semen Maydis oil, Oleum Arachidis hypogaeae semen and Oleum sesami, because described carrier is suitable for the character and the predetermined specific administration form of active component.The suitable adjuvant of using always in the drug combination preparation that adopts is comprising for example correctives, coloring agent, antiseptic and antioxidant, as vitamin E, ascorbic acid, BHT and BHA.
Consider that from being easy to prepare preferred pharmaceutical composition is a solid composite, concrete as tablet, the capsule of filling or liquid filling firmly with the position of administration.The administration of preferred compound oral administration.
In some cases, chemical compound suits with aerosol form directly to respiratory tract administration.
These reactive compounds also can be through non-intestinal or intraperitoneal administration.Can in water, suitably mix, make solution or the suspension of above-mentioned reactive compound as free alkali or officinal salt with surfactant such as hydroxypropyl cellulose.Can also prepare dispersion at glycerol, liquid macrogol and the mixture in oil thereof in addition.Under daily condition, store and when using, above-mentioned preparation contains antiseptic to prevent growth of microorganism.
The medicament forms that is fit to injection comprises sterile water solution or dispersion and the sterile powder that is used for being formulated as immediately sterilizing injecting solution or dispersion.In all situations, pharmaceutical dosage form must and must be the fluid that reaches convenient syringeability degree through sterilization.Under manufacturing and condition of storage, also must stablize and prevent the contamination of microorganism such as antibacterial and fungus.Described carrier can be solvent or dispersion medium, comprises for example water, ethanol, polyhydric alcohol (for example glycerol, propylene glycol and liquid macrogol), its suitable mixture and vegetable oil.
It hereinafter is the preparation of compounds represented example of the present invention.
Embodiment 1
N '-(2-cyano group-4-nitrobenzophenone)-N, N-dimethyl carbonamidine
With the 5-nitro-anthranilo nitrile and the 40ml N of 40.8g part, N dimethyl methyl ' the amide dimethyl-acetal heated in steam bath 2 hours.Decompression is down except that desolvating and residue being dissolved in the dichloromethane.Make this solution desolvate to remove by (chromatographic column with) Magnesol.With obtaining 50.8g N '-(2-cyano group-4-nitrobenzophenone)-N, N-dimethyl-carbonamidine after the ether washing.
Embodiment 2
N-(3-bromo phenyl)-6-nitro-4-quinazoline amine
With 23.74ml 3-bromo aniline and 40.5g N '-(2-cyano group-4-nitrobenzophenone)-N, N dimethyl carbonamidine in the 100ml glacial acetic acid solution stirring and in 148 ℃ oil bath the heating 1.5 hours.After the cooling,, quantitatively obtain N-(3-bromo phenyl)-6-nitro-4-quinazoline amine: mp=267-270 ℃ with the gained solid filtering; Mass spectrum (m/e): 345.
Embodiment 3
N-(3-bromo phenyl)-4,6-quinazoline diamidogen
34.5g N-(3-bromo phenyl)-6-nitro-4-quinazoline amine and the mixture of 16.8g iron powder in 150ml ethanol and 150ml glacial acetic acid were heated 2 hours in 120 ℃ oil bath.After leaching solid, in filtrate, add solid sodium carbonate, obtain solid.Filter, with methanol extraction gained solid.Solid is handled and flashed to extracting solution with charcoal.After washing this solid with ether, obtain 27.5g N-(3-bromo phenyl)-4,6-quinazoline diamidogen: mass spectrum (m/e): 315.
Embodiment 44-[[4-[(3-bromo phenyl)-amino]-the 6-quinazolyl] amino]-the 4-oxa--(Z)-2-butylene acid
The pyridine of 15ml part is joined 1.6g N-(3-bromo phenyl)-4, in 6-quinazoline diamidogen and the 0.6g maleic anhydride.After stirring is spent the night, on rotary evaporator, steam and desolventize.Be dissolved in solid in about 400ml hot ethanol and, obtain 0.33g 4-[[4-[(3-bromo phenyl insoluble raw material filtering)-amino]-the 6-quinazolyl] amino]-the 4-oxa--(Z)-2-butylene acid: mass spectrum (m/e): M+H 413,415.
Embodiment 54-[[4-[(3-bromo phenyl) amino]-the 6-quinazolyl] amino]-the 4-oxa--(E)-2-butylene acid
Ethyl ester
N-(3-bromo phenyl)-4, the solution of 6-quinazoline diamidogen in the 15ml pyridine cool off in ice bath and drip the solution of 1.22g ethyl fumaryl chloride in the 10ml dichloromethane.Stir after 1.5 hours, the order reaction rises to room temperature.Under reduced pressure except that desolvating and using the water treatment residue.Leach red solid and extract in the hot acetone.Behind the insoluble raw material of filtering, filtrate is concentrated, obtains 0.45g4-[[4-[(3-bromo phenyl) amino]-the 6-quinazolyl] amino]-4-oxa--(E)-2-butylene acetoacetic ester: mp=259-263 ℃, mass spectrum (m/e): M+H 441,443.
Embodiment 6
N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-3-methyl-2-butene amide
With 1.58g N-(3-bromo phenyl)-4, the solution of 6-quinazoline diamidogen in the 15ml pyridine cools off in ice bath and drips 0.67ml 3, the solution of 3-dimethyl acryloyl chloride in the 7ml ether.After stirring and cooling off 2 hours, decompression removes down and desolvates.With the water treatment residue and with gained solid recrystallization in methylcellulose, obtain 0.97g N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-3-methyl-2-butene amide: mp=300-301 ℃, mass spectrum (m/e): 396,398.
Embodiment 7
N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-(E)-the 2-butylene amide
With 1.6g N-(3-bromo phenyl)-4, the solution of 6-quinazoline diamidogen in the 15ml pyridine cools off in ice bath and drips 0.57ml and is dissolved in anti--crotonyl chloride solution in the 6ml ether.After stirring and cooling off 2 hours, decompression removes down and desolvates.Use the water treatment residue, and, obtain 0.69g N-[4-[(3-bromo phenyl gained solid recrystallization in n-butyl alcohol) amino]-the 6-quinazolyl]-(E)-and 2-butylene amide: mp=153-160 ℃, mass spectrum (m/e): M+H 383,385.
Embodiment 8
N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-2-methyl-2-acrylamide
With 1.6g N-(3-bromo phenyl)-4, the solution of 6-quinazoline diamidogen in the 15ml pyridine cools off in ice bath and drips the solution of 0.59ml methacrylic chloride in the 6ml ether.After stirring and cooling off 2 hours, under reduced pressure remove and desolvate.Use the water treatment residue, and the gained solid is dissolved in (warm) n-butyl alcohol.Ether is joined in the refrigerative solution, obtains 0.44g N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-2-methyl-2-acrylamide: mp=40-245 ℃, mass spectrum (m/e): M+H 383,385.
Embodiment 9
N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-the 2-butyne amide
The solution of 0.50g tetrolic acid in the 10ml oxolane is cooled off in ice bath.The isobutyl chlorocarbonate that adds 0.79ml part subsequently, the N-methylmorpholine that adds 0.66ml part again.After about 1 minute, add 1.6g N-(3-bromo phenyl)-4, the solution of 6-quinazoline diamidogen in the 10ml pyridine.Reaction is risen to room temperature and stirring is spent the night.Decompression removes down and desolvates, and gained solid recrystallization in n-butyl alcohol obtains 1.07g N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-the 2-butyne amide: mass spectrum (m/e): 381,383.
Embodiment 104-[[4-[(3-bromo phenyl) amino]-the 6-quinazolyl] amino]-the 4-oxa--(E)-2-butylene acid
The 10N sodium hydrate aqueous solution of 2.5ml part is joined the 2.3g4-[[4-[(3-bromo phenyl that is present in the 25ml ethanol) amino]-the 6-quinazolyl] amino]-4-oxa--(E)-2-butylene acetoacetic ester (embodiment 5) in.Stir after 1 hour, add the 2.1ml concentrated hydrochloric acid, will react restir 2 hours.Gained solid recrystallization in n-butyl alcohol obtains 0.97g 4-[[4-[(3-bromo phenyl) amino]-the 6-quinazolyl] amino]-the 4-oxa--(E)-2-butylene acid: mass spectrum (m/e): M+H 413.
Embodiment 11
N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-2,4-hexadiene amide
With 0.67g 2, the solution of 4-hexadienoic acid in the 10ml oxolane cools off in ice bath.The isobutyl chlorocarbonate that adds 0.79ml part subsequently, the N-methylmorpholine that adds 0.66ml part again.After about 1 minute, add 1.6g N-(3-bromo phenyl)-4, the solution of 6-quinazoline diamidogen in the 10ml pyridine.Reaction is risen to room temperature and stirring is spent the night.Decompression removes down desolvates and with gained solid recrystallization, obtains 1.0g N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-2,4-hexadiene amide: mp=258-260 ℃.
Embodiment 12
N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-2-cyclopentenes amide
The solution of 0.43g 2-cyclopentene acid in the 5ml oxolane is cooled off in ice bath.The isobutyl chlorocarbonate that adds 0.49ml part subsequently, the N-methylmorpholine that adds 0.41ml part again.After about 1 minute, add 1.0g N-(3-bromo phenyl)-4, the solution of 6-quinazoline diamidogen in the 10ml pyridine.Reaction is risen to room temperature and stirring is spent the night.Add 0.5 normal mixed anhydride again.This mixture was stirred 5 hours.Decompression removes down and desolvates, and the gained solid is purified through silica gel chromatography, obtains 0.30g N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-2-cyclopentenes amide: mass spectrum (m/e): 409 (M+H, EI).
Embodiment 13
N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-the 2-acrylamide
With 2.0g N-(3-bromo phenyl)-4, the solution of 6-quinazoline diamidogen in the 10ml pyridine cools off and drips the solution of methacrylic chloride in the 30ml ether of 0 ℃ of 0.61ml in ice bath.After at room temperature stirring 3.5 hours, decompression removes down and desolvates.Residue utilizes chromatographic purification, obtains 0.2g N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-the 2-acrylamide: mass spectrum (m/e): M+H 369.
Embodiment 14
N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-(3-phenyl-2-propine amide)
The 0.93g 3-phenyl-solution of 2-acetylenecarboxylic acid in the 10ml oxolane is cooled off in ice bath.The isobutyl chlorocarbonate that adds 0.82ml part subsequently, the N-methylmorpholine that adds 0.69ml part again.After about 1 minute, add 1.0g N-(3-bromo phenyl)-4, the solution of 6-quinazoline diamidogen in the 7ml pyridine.Be reflected at and carried out under 0 ℃ 1 hour.Decompression removes down and desolvates and the gained solid is purified through silica gel chromatography, obtains 0.01g N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-(3-phenyl-2-propine amide): mass spectrum (m/e): 443.2,445.2 (M+H, electron sprays).
Embodiment 15
6-amino-4-chloro quinazoline
Will be by 3.25g 4-chloro-6-nitro-quinazoline, 10.8g sodium sulfite and 0.3g phase transfer catalyst (C 8H 17) 3NCH 3 +The mixture that Cl forms in 97ml oxolane and 32ml water stirred 2 hours fast.Dilute this mixture and isolate organic layer with ether.Organic solution is with the salt water washing and use dried over mgso.Make this solution by a little silicagel column.Remove under 30 ℃ and decompression and desolvate, obtain 6-amino-4-chloro quinazoline, this chemical compound need not further be purified and just be can be used for next step reaction.
Embodiment 16
[4-chloro-6-quinazolyl]-2-butyne amide
The solution of 1.64g tetrolic acid in the 46ml oxolane is cooled off in ice bath.The isobutyl chlorocarbonate that adds 2.34ml part subsequently, the N-methylmorpholine that adds 4.13ml part again.After about 10 minutes, in its impouring 6-amino-solution of 4-chloro quinazoline in the 46ml oxolane.This mixture was at room temperature stirred 2 hours.In the mixed liquor with mixture impouring saline and saturated sodium bicarbonate, use ether extraction.With this ethereal solution of dried over mgso and filtration.Remove and to desolvate, obtain [4-chloro-6-quinazolyl]-2-butyne amide, this chemical compound is water white oil and need not to be further purified and just can be used for next step reaction.
Embodiment 17
N-[4-[(3-bromo phenyl) amino]-the 6-quinazoline]-the 2-butyne amide
Will be by 1.76g[4-chloro-6-quinazoline]-solution that 2-butyne amide and 1.23g 3-bromaniline are formed in the 23ml isopropyl alcohol refluxed 40 minutes under inert atmosphere.Mixture be cooled under the room temperature and add the 200ml ether, obtain 0.4g N-[4-[(3-bromo phenyl)-amino]-the 6-quinazolyl]-hydrochlorate of 2-butyne amide.With the sodium bicarbonate solution neutralization, use ethyl acetate extraction, remove and desolvate, by recrystallization in the 1-butanols, obtain 0.4g N-[4-[(3-bromo phenyl)-amino]-the 6-quinazolyl]-the 2-butyne amide, be free alkali.
Embodiment 18
N '-(4-amino-2-cyano-phenyl)-N, N-dimethyl carbonamidine
With N '-(2-cyano group-4-nitrobenzophenone)-N of 6.0g (27.5mmol), (41.8ml, 412.4mmol) solution of the 10%Pd/C of cyclohexene and 0.6g in 360ml methanol refluxed 4 hours for N-dimethyl carbonamidine, 33.9g.This hot mixture is through diatomite filtration.Except that desolvating and with residue recrystallization in chloroform-carbon tetrachloride, obtaining 4.9g (95%) title compound, this chemical compound is light grey crystalloid solid.Mass spectrum (m/e): 188.9 (M+H, electron sprays).
Embodiment 19
N-[3-cyano group-4-[[(dimethylamino) methylene] amino] phenyl]-the 2-butyne amide
Under blanket of nitrogen, in 3 minutes introversive in 0 ℃ of 2.01g (23.9mmol) tetrolic acid that stirs down and 2.9ml (22.3mmol) carbonochloridic acid isobutyl ester are dissolved in solution in the 30ml oxolane adding 2.42g (2.63ml, N-methylmorpholine 22.3mmol).After stirring 15 minutes, in 4 minutes, add N '-(4-amino-2-the cyano-phenyl)-N that is dissolved in the 25ml oxolane, N-dimethyl carbonamidine and 1.6g (1.75ml, 15.9mmol) N-methylmorpholine solution.This mixture was stirred 30 minutes down and at room temperature stirred 30 minutes at 0 ℃.In the mixed liquor of mixture with the dilution of 70ml ethyl acetate and impouring saline and saturated sodium bicarbonate.Organic layer filters with dried over mgso and through silicagel pad.Remove and desolvate, residue and 50ml ether are stirred together.Collect suspended solid, obtain 3.61g (89%) beige solid.Mass spectrum (m/e): 255.0 (M+H, electron sprays).
Embodiment 20
N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-the 2-butyne amide
Will be by 3.0g (11.8mmol) N-[3-cyano group-4-[[(dimethylamino)-methylene] amino] phenyl]-2-butyne amide and the solution of 2.23g (12.98mmol) 3-bromaniline in 18ml acetic acid refluxed under the condition of blanket of nitrogen and gentle agitation 1 hour 15 minutes.Mixture is cooled off in ice bath, generate solid.Solid collected by filtration is also used the washing in 1: 1 of ether-acetonitrile, obtains yellow solid, with its recrystallization in ethanol, obtains 2.51g N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-the 2-butyne amide.Mass spectrum: (m/e): 381,383.

Claims (9)

1. a treatment or suppress the method for polyp of colon in the mammal, this method comprises the chemical compound to described administration formula 1: Wherein: X is by the optional phenyl that replaces of one or more substituent groups, and described substituent group is selected from halogen, contain the alkyl of 1-6 carbon atom, contain alkoxyl, hydroxyl, trifluoromethyl, cyano group, nitro, carboxyl, the alkoxy carbonyl group that contains 2-7 carbon atom, the alkyl-carbonyl that contains 2-7 carbon atom, the amino of 1-6 carbon atom and contain the alkanoyl amino of 1-6 carbon atom; R and R 1Be hydrogen, halogen independently respectively, contain the alkyl of 1-6 carbon atom, the alkoxyl that contains 1-6 carbon atom, hydroxyl or trifluoromethyl; R 2Be hydrogen, contain the alkyl of 1-6 carbon atom, the alkoxyl that contains 1-6 carbon atom, hydroxyl, trifluoromethyl; Y is selected from following group:
Figure A9881080600022
Figure A9881080600023
With
Figure A9881080600024
R 3Be hydrogen independently, contain 1-6 carbon atom alkyl, carboxyl, contain 1-6 carbon atom
Alkoxy carbonyl group, phenyl or contain the alkyl-carbonyl of 2-7 carbon atom; N=2-4; Or its officinal salt, but condition is each R of Y 3Can be identical or different.
2. the method for claim 1, wherein R, R 1And R 2Be hydrogen or its officinal salt.
3. method as claimed in claim 1 or 2, wherein X is not substituted phenyl or by halogen or contain the phenyl that the alkyl of 1-6 carbon atom replaces.
4. as each described method of claim 1-3, what wherein use is: amino N-[4-[(3-bromo phenyl)]-the 6-quinazolyl]-the 2-butyne amide; N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-2-methyl-2-acrylamide; N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-2,4-hexadiene amide; N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-(E)-the 2-butylene amide; N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-3-methyl-2-butene amide; 4-[[4-[(3-bromo phenyl) amino]-the 6-quinazolyl] amino]-the 4-oxa--(Z)-2-butylene acid; 4-[[4-[(3-bromo phenyl) amino]-the 6-quinazolyl] amino]-the 4-oxa--(E)-2-butylene acid; 4-[[4-[(3-bromo phenyl) amino]-the 6-quinazolyl] amino]-the 4-oxa--(E)-the 2-butylene acetoacetic ester; N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-2-cyclopentenes amide; N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-the 2-acrylamide; N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-(3-phenyl 2-propine amide); Or its any officinal salt.
5. formula 1 compound or pharmaceutically acceptable salt thereof is used for the treatment of or suppresses application in the medicine of polyp of colon in the mammal in preparation:
Figure A9881080600031
Wherein: X is by the optional phenyl that replaces of one or more substituent groups, and described substituent group is selected from halogen, contain the alkyl of 1-6 carbon atom, contain alkoxyl, hydroxyl, trifluoromethyl, cyano group, nitro, carboxyl, the alkoxy carbonyl group that contains 2-7 carbon atom, the alkyl-carbonyl that contains 2-7 carbon atom, the amino of 1-6 carbon atom and contain the alkanoyl amino of 1-6 carbon atom; R and R 1Be hydrogen, halogen independently respectively, contain the alkyl of 1-6 carbon atom, the alkoxyl that contains 1-6 carbon atom, hydroxyl or trifluoromethyl; R 2Be hydrogen, contain the alkyl of 1-6 carbon atom, the alkoxyl that contains 1-6 carbon atom, hydroxyl, trifluoromethyl; Y is selected from following group:
Figure A9881080600041
Figure A9881080600042
With
Figure A9881080600043
R 3Be hydrogen independently, contain alkyl, the carboxyl of 1-6 carbon atom, the alkoxy carbonyl group that contains 1-6 carbon atom, phenyl or contain the alkyl-carbonyl of 2-7 carbon atom; N=2-4; But condition is each R of Y 3Can be identical or different.
6. method as claimed in claim 5, wherein R, R 1And R 2Be hydrogen or its officinal salt.
7. as claim 5 or 6 described methods, wherein X is not substituted phenyl or by halogen or contain the phenyl that the alkyl of 1-6 carbon atom replaces.
8. as each described method of claim 5-7, wherein the chemical compound of institute's administration is a N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-the 2-butyne amide; N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-2-methyl-2-acrylamide; N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-2,4-hexadiene amide; N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-(E)-the 2-butylene amide; N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-3-methyl-2-butene amide; 4-[[4-[(3-bromo phenyl) amino]-the 6-quinazolyl] amino]-the 4-oxa--(Z)-2-butylene acid; 4-[[4-[(3-bromo phenyl) amino]-the 6-quinazolyl] amino]-the 4-oxa--(E)-2-butylene acid; 4-[[4-[(3-bromo phenyl) amino]-the 6-quinazolyl] amino]-the 4-oxa--(E)-the 2-butylene acetoacetic ester; N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-2-cyclopentenes amide; N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-the 2-acrylamide; N-[4-[(3-bromo phenyl) amino]-the 6-quinazolyl]-(3-phenyl 2-propine amide).
9. pharmaceutical composition that is used for the treatment of or suppresses polyp of colon in the mammal, said composition contain formula 1 chemical compound and optional pharmaceutically suitable carrier as defined in claim 5.
CN98810806A 1997-11-06 1998-11-04 Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps Pending CN1278176A (en)

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