CN102344444A - Optically pure quinazoline compounds - Google Patents
Optically pure quinazoline compounds Download PDFInfo
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- CN102344444A CN102344444A CN2011101939780A CN201110193978A CN102344444A CN 102344444 A CN102344444 A CN 102344444A CN 2011101939780 A CN2011101939780 A CN 2011101939780A CN 201110193978 A CN201110193978 A CN 201110193978A CN 102344444 A CN102344444 A CN 102344444A
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- furans
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- amine
- ethyl
- methylsulfonyl
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- UBRJOJKCAVYQSH-UHFFFAOYSA-N OS(c(cc1)ccc1I)(=O)=O Chemical compound OS(c(cc1)ccc1I)(=O)=O UBRJOJKCAVYQSH-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention relates to optically pure quinazoline compounds, especially compounds of the general formula (I), and pharmaceutical compositions containing a therapeutically effective amount of the compounds, as well as application of the compositions in preparing medicaments treating and regulating c-erbB-2 and/or EGF-R protein tyrosine kinase activity related diseases.
Description
Technical field
The present invention relates to optical pure quinazoline compound, and the medicinal compositions that contains this compound of treating significant quantity, and the purposes in the medicine of preparation treatment adjusting c-erbB-2 and/or EGF-R protein tyrosine kinase activity relative disease.
Background technology
The phosphorylation of specific tyrosine residues in the relevant various albumen of the adjusting of growth of protein tyrosine kinase catalysis and cell and differentiation.Protein tyrosine kinase can roughly be divided into acceptor (like EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) or non-acceptor (like c-src, lck, zap70) kinases.Shown many these type of kinase whose improper or uncontrolled activation, that is, for example can cause uncontrolled cells produce by the unusual protein tyrosine kinase activity due to overexpression or the sudden change.
Protein tyrosine kinase, relevant like the abnormal activity of c-erbB-2, c-src, c-met, EGFr, PDGFr with people's malignant tumour.For example, the EGFr of rising is active relevant with the neck cancer with nonsmall-cell lung cancer, bladder cancer and head, the c-erbB-2 activity of rising and the related to cancer of mammary gland, ovary, stomach and pancreas.Therefore, the arrestin Tyrosylprotein kinase should be able to provide above-mentioned tumor treatment.
The paraprotein tyrosine kinase activity is also relevant with other various diseases: like psoriasis, fibroid degeneration, atherosclerosis, restenosis, autoimmune disorder, allergy, asthma etc., shown through the effect of some receptor tyrosine kinases and can control these diseases.
Chinese patent 99803887.3 public reported a series of compounds, they have protein tyrosine kinase and suppress active; Chinese patent 20081000815 also public reported a series of new quinazoline compounds, but all with racemic modification form exploitation, its optically pure isomer is not studied.
Summary of the invention
The object of the invention is to provide optical pure quinazoline compound shown in the general formula (I) and uses thereof.
The object of the invention also is to provide a kind of pharmaceutical composition that contains the optical pure quinazoline compound shown in the effective dose general formula (I), and their application in diseases such as treatment cancer, malignant tumour and psoriasis;
The invention discloses general formula (I) compound:
Wherein
R
1Expression
Wherein by 1 or 2 substituted furans of substituting group or thiazole, described substituting group is selected from halogen atom, C to Ar for randomly
1-4Alkyl or C
1-4Alkoxyl group;
R
2, R
3Be independently from each other hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, alkoxyalkyl, cycloalkyl or cycloalkylalkyl;
Y is for randomly by R
4, R
5Substituted phenyl or 1H-indazolyl; Wherein, R
4Be selected from benzyl, halo-, dihalo-or three halogeno-benzyls, benzyloxy, halo-, dihalo-or three halo benzyloxies; R
5Be selected from hydrogen, hydroxyl, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, amino, cyanic acid or trifluoromethyl;
Band * carbon atom is a chiral carbon atom, with (S) single enantiomer form or be rich in (S) single enantiomer form and exist;
B is selected from tartrate, lactic acid, phosphoric acid, Hydrocerol A, acetate, trifluoroacetic acid, oxysuccinic acid, nitric acid, hydrochloric acid, sulfuric acid, oxalic acid, Succinic Acid, methylsulfonic acid, toxilic acid or tosic acid.
In preferred version of the present invention, Ar is selected from unsubstituted furans or thiazole, more preferably unsubstituted furans.
In the preferred scheme of the present invention, R
2, R
3Be independently from each other hydrogen, C
1-4Alkyl, C
2-5Thiazolinyl, C
1-4Alkoxyl group, C
1-4Alkoxy C
1-4Alkyl, C
3-8Cycloalkyl or C
3-8Cycloalkyl-C
1-4Alkyl.
In preferred version of the present invention, R
4Be selected from benzyl, halo-benzyl, halo-benzyloxy, preferred halo-benzyl, halo-benzyloxy; R
5Be selected from hydrogen, halogen atom, C
1-4Alkyl or C
1-4Alkoxyl group.
In preferred version of the present invention, band * carbon atom exists with single enantiomer form (S), or exists to be rich in (S) form, if to be rich in (S) when form exists, preferred (S) configuration content >=90%.
In scheme of the present invention, preferred compound comprises the tosilate of following compound:
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 92)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 93)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 94)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propyl group is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 95)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 96)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 97)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-diethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 98)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, the N-dipropyl is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 99)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 100)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(allyl amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 101)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propargyl is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 102)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 144)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 145)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 146)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propyl group is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 147)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(N, N-dimethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 149)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(cyclopropyl methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 148)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(allyl amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; (compound 153)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propargyl is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine.(compound 154)
In scheme of the present invention, preferred compound is suc as formula shown in (IX):
In the present invention:
" be rich in a kind of enantiomorph " and refer to content >=60% of wherein a kind of enantiomorph (S) configuration;
" alkyl " refers to side chain or straight chain representative examples of saturated aliphatic hydrocarbon-based; Preferred carbon atom is 1-4 side chain or a straight chain representative examples of saturated aliphatic alkyl, like methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-etc.;
" thiazolinyl " refers to contain at least side chain, straight chain or the ring-type non-aromatic hydrocarbon group of a carbon-carbon double bond, like vinyl, propenyl, allyl group, butenyl, tetrahydrobenzene etc.;
" alkynyl " refers to contain at least carbon carbon triple-linked side chain, straight chain or a ring-type hydrocarbon group, like ethynyl, proyl, butynyl, 3-methyl butynyl, alkynes butyl, propargyl etc.
" cycloalkyl " refers to contain monocyclic representative examples of saturated aliphatic hydrocarbon-based, and preferred carbon atom is 3-8 a cycloalkyl, like cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, ethyl-cyclopentyl, cyclohexyl etc.;
" alkoxyl group " refers to the group that the straight or branched alkyl links to each other with Sauerstoffatom, like methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy etc.;
" halogen atom " refers to fluorine, chlorine, bromine, iodine atom.
The method for preparing formula (I) compound may further comprise the steps:
1) general formula (II) compound and tertiary butyl sulfinyl amine reaction obtains general formula (III) compound;
2) general formula (III) compound and general formula (IV) compound reaction must logical formula V compound;
3) logical formula V compound reacts under acidic conditions, gets general formula (VI) compound;
4) general formula (VI) compound and reagent R
2-L or R
3-L reaction gets general formula (VII) compound;
5) general formula (VII) compound and oxidant reaction get general formula (VIII) compound;
6) general formula (VIII) compound and acid-respons get general formula (I) compound;
Wherein,
R
1, Y, Ar, R
2, R
3, the band * carbon atom and acid such as general formula (I) definition;
T is sulphur atom or sulfinyl;
Tertiary butyl sulfinyl amine is an optical purity, with (S) single enantiomer form or be rich in (S) single enantiomer form and exist;
L is a leavings group, is selected from halogen atom or sulfonyloxy.
In the preparation of general formula (III) compound, be reflected under the metal reagent existence and carry out.Metal reagent comprises purity titanium tetraethoxide, tetraisopropoxy titanium etc., preferred tetraisopropoxy titanium; Temperature of reaction is controlled at 0-100 ℃, preferred 0-50 ℃.
In the preparation of general formula (VI) compound, be reflected under the acidic conditions and carry out, used acid is selected from the mixing acid of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid or above-mentioned acid, preferred hydrochloric acid.
In the preparation of general formula (I) compound; The reaction that sulphur atom or sulfinyl is oxidized to alkylsulfonyl is well-known to those skilled in the art; Used oxygenant is selected from: metachloroperbenzoic acid, Peracetic Acid, ydrogen peroxide 50, potassium hydrogen persulfate etc., but potassium hydrogen persulfate preferably.
Another method of preparation formula (I) compound may further comprise the steps:
1) general formula (II) compound and tertiary butyl sulfinyl amine reaction obtains general formula (III) compound;
2) general formula (III) compound and general formula (A) compound reaction gets general formula (B) compound;
3) general formula (B) compound reacts under acidic conditions, gets general formula (C) compound;
4) general formula (C) compound and reagent R
2-L or R
3-L reaction gets general formula (VIII) compound;
5) general formula (VIII) compound and acid-respons get general formula (I) compound;
Wherein,
R
1, Y, Ar, band * carbon atom such as general formula (I) definition;
Tertiary butyl sulfinyl amine, L are like above-mentioned definition;
M is alkalimetal ion or halo-alkaline-earth metal ions, is selected from Li
+, Na
+, K
+, [MgCl]
+Or [MgBr]
+
In the preparation of general formula (I) compound, L represents leavings group well-known to those skilled in the art, like halogen atom (like fluorine, chlorine, bromine, iodine atom), and preferred bromine, iodine atom; Sulfonyloxy (like mesyloxy, tolysulfonyl oxygen base) etc.;
In the preparation of general formula (C) compound, be reflected under the acidic conditions and carry out, used acid is selected from the mixing acid of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid or above-mentioned acid, preferred hydrochloric acid.
This reacts the 4th) go on foot and under alkaline condition, carry out, used alkali is selected from mineral alkali (like sodium hydrogencarbonate, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide etc.) or organic bases (like ethamine, triethylamine, diisopropylethylamine etc.).
Another purpose of the present invention provides a kind of pharmaceutical composition, and it contains general formula (I) compound and the pharmaceutically acceptable carrier of effective dose.
Another purpose of the present invention provides formula (I) compound or contains the purposes of pharmaceutical composition in the medicine of preparation treatment adjusting c-erbB-2 and/or EGF-R protein tyrosine kinase activity relative disease of this compound.
Another purpose of the present invention provides formula (I) compound or contains the purposes of pharmaceutical composition in the medicine of preparation treatment cancer and malignant tumour of this compound.
Another purpose of the present invention provides general formula (I) compound or contains the purposes of pharmaceutical composition in preparation antipsoriatics thing of this compound.
Compound provided by the invention has excellent anti tumor activity in vitro, curative effect and pharmacokinetic property.
Medicinal preparations involved in the present invention can exist with unit dosage form, and per unit dosage contains the activeconstituents of predetermined amount.Such unit can contain, for example 0.5mg-1g, specifically many factors such as the age of how much depending on the disease, route of administration and the patient that receive treatment of consumption, body weight, the state of an illness.
Medicinal preparations can any suitable way give, and gives like approach such as oral, rectum, nasal cavity, part or parenteral (comprising subcutaneous, muscle, vein or transdermal).Above-mentioned various preparation can pass through the known any method of pharmacy field, for example, and through activeconstituents and carrier or mixed with excipients are prepared.
The compounds of this invention or its pharmacy acceptable salt can give separately or unite use with the other treatment agent of the above-mentioned disease of treatment.Especially, in antineoplastic treatment, considered and other chemotherapeutics, hormone or antibody drug drug combination.
Embodiment
In order to illustrate in greater detail the present invention, provide following instance.But scope of the present invention is not to be defined in this.
(Enantionmeric excesses e.e) refers to the relative populations of every kind of enantiomorph to the excessive value of enantiomorph in following examples.This value defined is two kinds of differences between the relative percentage ratio of enantiomorph.Therefore, for example the content percentage ratio when (R) enantiomorph is 90%, and (S) the content percentage ratio of enantiomorph is 10%, and (R) enantiomeric excess is 80%, and promptly the e.e value is: 80%.
The composition of each compound enantiomorph is measured with chirality HPLC, and condition is following:
Pillar: the AD post of DAICEL company;
Moving phase: normal hexane-ethanol-diethylamine (50: 50: 0.1).
The preparation of preparation example 1 N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-iodine quinazoline-4-amine
In the 2000mL flask, add 6-iodo-3H-quinazoline-4-one (100g), be dissolved in thionyl chloride (1000ml) and N, in the mixed solvent of dinethylformamide (20ml), reflux to reaction solution clear.Steam thionyl chloride, do twice with the toluene band, subsequent use.
Subsequent use intermediate is dissolved in the Virahol (2000ml), adds 3-chloro-4-(3-fluoro-benzyloxy)-anilinechloride (70g), add anhydrous K under the mechanical stirring
2CO
3(150g), reflux is spent the night.Be cooled to room temperature with reaction solution next day, and decompress filter is with filter cake water making beating flush away K
2CO
3To neutral, decompress filter, vacuum-drying obtains title product: 95g, off-white color solid.
m/z(M+1)
+：506。
The preparation of preparation example 2 N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-iodine quinazoline-4 amine
Method is with preparation example 1, and difference is to change 3-chloro-4-(3-fluoro-benzyloxy)-anilinechloride into 1-(3-luorobenzyl)-1H-indazole-5 amine hydrochlorate.
m/z(M+1)
+：496。
The preparation of preparation example 3 5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-aldehyde
To prepare example 1 compound (50g), 5-boric acid-2-furfural (21g), Pd (PPh
3)
2Cl
2(6.2g), triethylamine (62ml), methyl alcohol (1000ml) is put in the reaction flask, back flow reaction 2 hours.Cool to room temperature filters, and filter cake then in 50 ℃ of oven dry, gets title compound: 40g, yellow solid earlier with the small amount of methanol washing.
m/z(M+1)
+：473。
The preparation of preparation example 4 5-(4-(1-(3-luorobenzyl)-1H-indazole-5-base is amino) quinazoline-6-yl) furans-2-aldehyde
Method is with preparation example 3, and difference is to change raw material into preparation example 2 compounds by preparation example 1 compound.m/z(M+1)
+：464。
The preparation of preparation example 5 2-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) thiazole-5-aldehyde
To prepare example 1 compound (50g), 2-boric acid-5-thiazole aldehyde (21g), Pd (PPh
3)
2Cl
2(6.2g), triethylamine (62ml), methyl alcohol (1000ml) is put in the reaction flask, back flow reaction 2 hours.Cool to room temperature filters, and filter cake then in 50 ℃ of oven dry, gets title compound: 30g earlier with the small amount of methanol washing.
m/z(M+1)
+：490。
The preparation of preparation example 6 2-(4-(1-(3-luorobenzyl)-1H-indazole-5-base is amino) quinazoline-6-yl) thiazole-5-aldehyde
Method is with preparation example 5, and difference is to change raw material into preparation example 2 compounds by preparation example 1 compound.
m/z(M+1)
+：480。
Embodiment one
(S)-preparation of N-((5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-amino) quinazoline-6-yl) furans-2-yl) methylene radical)-2-methylpropane-2-sulfinyl amine
(47.3g, 0.1mol), (14.5g, 0.12mol), (85g 0.3mol) puts in the reaction flask with anhydrous THF (1000ml) tetraisopropoxy titanium S-tertiary butyl sulfinyl amine, and room temperature reaction spends the night will to prepare example 3 compounds.Next day, handle: add water (50ml), ethyl acetate (500ml) stirs 10min, filters, and filter cake is washed 3 times with THF.Filtrating adds anhydrous magnesium sulfate drying.Filter, filtrate decompression concentrate title compound: 50g.m/z(M+1)
+：577。
Embodiment two
(R)-preparation of N-((5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-amino) quinazoline-6-yl) furans-2-yl) methylene radical)-2-methylpropane-2-sulfinyl amine
The preparation method is with embodiment one, and difference is to change reaction raw materials into R-tertiary butyl sulfinyl amine by S-tertiary butyl sulfinyl amine.m/z(M+1)
+：577。
Embodiment three
(S)-preparation of N-((2-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-amino) quinazoline-6-yl) thiazole-5-yl) methylene radical)-2-methylpropane-2-sulfinyl amine
The preparation method is with embodiment one, and difference is to change reaction raw materials into preparation example 5 compounds by preparation example 3 compounds.m/z(M+1)
+：594。
Embodiment four
(R)-preparation of N-((2-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-amino) quinazoline-6-yl) thiazole-5-yl) methylene radical)-2-methylpropane-2-sulfinyl amine
The preparation method is with embodiment three, and difference is to change reaction raw materials into R-tertiary butyl sulfinyl amine by S-tertiary butyl sulfinyl amine.m/z(M+1)
+：594。
Embodiment five
(S)-preparation of N-((5-(4-(1-(3-luorobenzyl)-1H-indazole-5-base amino) quinazoline-6-yl) furans-2-yl) methylene radical)-2-methylpropane-2-sulfinyl amine
The preparation method is with embodiment one, and difference is to change reaction raw materials into preparation example 4 compounds by preparation example 3 compounds.m/z(M+1)
+：567。
Embodiment six
(R)-preparation of N-((5-(4-(1-(3-luorobenzyl)-1H-indazole-5-base amino) quinazoline-6-yl) furans-2-yl) methylene radical)-2-methylpropane-2-sulfinyl amine
The preparation method is with embodiment two, and difference is to change reaction raw materials into preparation example 4 compounds by preparation example 3 compounds.m/z(M+1)
+：567。
Embodiment seven
(S)-preparation of N-((2-(4-(1-(3-luorobenzyl)-1H-indazole-5-base amino) quinazoline-6-yl) thiazole-5-yl) methylene radical)-2-methylpropane-2-sulfinyl amine
The preparation method is with embodiment one, and difference is to change reaction raw materials into preparation example 6 compounds by preparation example 3 compounds.m/z(M+1)
+：584。
Embodiment eight
(R)-preparation of N-((2-(4-(1-(3-luorobenzyl)-1H-indazole-5-base amino) quinazoline-6-yl) thiazole-5-yl) methylene radical)-2-methylpropane-2-sulfinyl amine
The preparation method is with embodiment one, and difference is to change reaction raw materials into preparation example 6 compounds by preparation example 3 compounds.m/z(M+1)
+：584。
Embodiment nine
(S)-preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine
Methylthiomethyl magnesium chloride/THF solution (0.3mol) is put in the reaction flask, and cooling reaction liquid is to below-80 ℃, insulation 5min, and (57.6g 0.1mol) with the solution of anhydrous THF (200ml), keeps below Nei Wen-80 ℃ to add embodiment one compound fast.Insulated and stirred 10min handles.In reaction solution impouring saturated aqueous common salt (3000ml), add ethyl acetate (2000ml), separatory, organic layer is with saturated aqueous common salt (2000ml) washing, anhydrous magnesium sulfate drying.Filter, filtrate decompression concentrate yellow solid 50g.
To go up step gained yellow solid and be dissolved among the THF (1000ml), and transfer pH=1 with HCl-ethanol, stirring at room 2 hours is handled.Add strong aqua and transfer pH=9, add saturated aqueous common salt (2000ml) and ethyl acetate (1500ml), separatory, organic layer anhydrous magnesium sulfate drying.Filter, filtrate decompression concentrates, and the resistates silica gel column chromatography (eluent: ethyl acetate-ethyl acetate/THF=10/1), collect qualified component, concentrate, get title compound: 30g, be numbered compound 1.m/z(M+1)
+：535。
Embodiment ten
(S)-preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine
Method A: with embodiment nine gained compounds (2.0g), methyl iodide (0.5g) and triethylamine (0.7g) are dissolved among the THF (150ml), are heated to back flow reaction 2h.Stop heating, in reaction solution, add saturated aqueous common salt, add ethyl acetate extraction, organic phase saturated aqueous common salt washed twice, anhydrous magnesium sulfate drying.Filter, filtrate decompression concentrates, and resistates column chromatography purification (chloroform/methanol=100: 1) gets title compound 1.5g, is numbered compound 2.
Method B: embodiment nine compounds (5.4g) are dissolved among the DMSO (50ml), add formaldehyde (6ml), formic acid (3ml), the stirring at room reaction is spent the night.Reaction solution is punched in the frozen water (500ml), filters, drain, after filter cake dissolves with THF, silica gel system sand, column chromatography purification gets title compound: 4.2g is numbered compound 2.m/z(M+1)
+：549。
Pressing the preparation method of embodiment ten, is starting raw material with embodiment nine gained compounds, with the reaction reagent reaction, accomplishes the preparation of following compound:
Embodiment 11
(S)-preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(amino)-2-(methylthio group) ethyl) thiazol-2-yl) quinazoline-4-amine
The preparation method is with embodiment nine, and difference is to change reaction raw materials into embodiment three compounds by embodiment one compound, is numbered compound 14.m/z(M+1)
+：552。
Pressing the method for embodiment ten, is starting raw material with embodiment 11 compounds, with the reaction reagent reaction, accomplishes the preparation of following compound:
Embodiment 12
(S)-preparation of N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine
The preparation method is with embodiment nine, and difference is to change reaction raw materials into embodiment five compounds by embodiment one compound, is numbered compound 27.m/z(M+1)
+：525。
Pressing the method for embodiment ten, is starting raw material with embodiment 12 compounds, with the reaction reagent reaction, accomplishes the preparation of following compound:
Embodiment 13
(R)-preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine
The preparation method is with embodiment nine, and difference is to change reaction raw materials into embodiment two compounds by embodiment one compound, is numbered compound 40.m/z(M+1)
+：535。
Pressing the preparation method of embodiment ten, is starting raw material with embodiment 13 gained compounds, with the reaction reagent reaction, accomplishes the preparation of following compound:
Embodiment 14
(R)-preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(amino)-2-(methylthio group) ethyl) thiazol-2-yl) quinazoline-4-amine
The preparation method is with embodiment nine, and difference is to change reaction raw materials into embodiment Four Modernizations compound by embodiment one compound, is numbered compound 53.m/z(M+1)
+：552。
Pressing the method for embodiment ten, is starting raw material with embodiment ten Four Modernizations compounds, with the reaction reagent reaction, accomplishes the preparation of following compound:
Embodiment 15
(S)-preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine
Methyl-sulphoxide (0.4mol) is dissolved in anhydrous THF (2000ml), is cooled to-20 ℃ under the nitrogen protection, drip n-BuLi (0.3mol).Drip and finish insulated and stirred 30min.Cooling reaction liquid is to below-80 ℃, insulation 5min, and (57.6g 0.1mol) with the solution of anhydrous THF (200ml), keeps below Nei Wen-80 ℃ to add embodiment one compound fast.Insulated and stirred 10min handles.In reaction solution impouring saturated aqueous common salt 3000ml, add ethyl acetate 2000ml, separatory, organic layer is washed with saturated aqueous common salt 2000ml, anhydrous magnesium sulfate drying.Filter, filtrate decompression concentrate yellow solid 42g.
To go up step gained yellow solid and be dissolved among the THF (1000ml), and transfer pH=1 with HCl-ethanol, stirring at room 2 hours is handled.Add strong aqua and transfer pH=9, add saturated aqueous common salt (2000ml) and ethyl acetate (1500ml), separatory, organic layer anhydrous magnesium sulfate drying.Filter, filtrate decompression concentrates, and the resistates silica gel column chromatography (eluent: ethyl acetate-ethyl acetate/THF=5/1), collect qualified component, concentrate, get title compound: 20g, be numbered compound 66.m/z(M+1)
+：551。
Embodiment 16
(S)-preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine
The preparation method is with embodiment ten, and difference is that reaction raw materials changes embodiment 15 compounds into by embodiment seven compounds, is numbered compound 67.m/z(M+1)
+：566。
Pressing the preparation method of embodiment ten, is starting raw material with embodiment 15 gained compounds, with the reaction reagent reaction, accomplishes the preparation of following compound:
Embodiment 17
(R)-preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine
The preparation method is with embodiment 15, and difference is to change reaction raw materials into embodiment two compounds by embodiment one compound, numbering compound 79.m/z(M+1)
+：551。
Pressing the preparation method of embodiment ten, is starting raw material with embodiment 17 gained compounds, with the reaction reagent reaction, accomplishes the preparation of following compound:
Embodiment 18
(S)-preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine
Method A: (37.6g 0.4mol) is dissolved in anhydrous THF (2000ml), is cooled to-20 ℃ under the nitrogen protection, drips n-BuLi (0.3mol) with dimethyl sulfone.Drip and finish insulated and stirred 30min.Cooling reaction liquid is to below-80 ℃, insulation 5min, and (57.6g 0.1mol) with the solution of anhydrous THF (200ml), keeps below Nei Wen-80 ℃ to add embodiment one compound fast.Insulated and stirred 10min handles.In reaction solution impouring saturated aqueous common salt 3000ml, add ethyl acetate 2000ml, separatory, organic layer is washed with saturated aqueous common salt 2000ml, anhydrous magnesium sulfate drying.Filter, filtrate decompression concentrate yellow solid 42g.
To go up step gained yellow solid and be dissolved among the THF (1000ml), and transfer pH=1 with HCl-ethanol, stirring at room 2 hours is handled.Add strong aqua and transfer pH=9, add saturated aqueous common salt (2000ml) and ethyl acetate (1500ml), separatory, organic layer anhydrous magnesium sulfate drying.Filter, filtrate decompression concentrates, and (eluent: ethyl acetate--ethyl acetate/THF=5/1), collect qualified component concentrates the resistates silica gel column chromatography, gets title compound: 20g, is numbered compound 92.
Method B: with the mixed solvent of embodiment nine or embodiment 15 each 50g of gained compound and methanol (7: 3,1000ml) put in the reaction flask, after the dissolving, gradation adds oxone (100g), adds continued in stirring at room reaction 2 hours.Filter, filter cake is with the mixing solutions washing of methanol, and filtrating is transferred pH=8 with saturated sodium bicarbonate solution, and concentrating under reduced pressure adds ethyl acetate (500ml * 2) and extracts, and merges organic layer, uses anhydrous sodium sulfate drying again.Filter, filtrate decompression concentrates to be done, column chromatography purification (eluent: chloroform/methanol=100: 1) get title compound: 40g, yellow solid.M/z (M+1)
+: 567; E.e value: 95.2%[(S): 97.6%, (R): 2.4%].
Pressing the preparation method of embodiment ten, is starting raw material with embodiment 18 gained compounds, with the reaction reagent reaction, accomplishes the preparation of following compound:
Embodiment 19
(R)-preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine
Method A: with embodiment ten all directions method A, difference is to change starting raw material into embodiment two compounds by embodiment one compound, is numbered compound 105; M/z (M+1)
+: 567; E.e value: 95.8%[(R): 97.9%, (S): 2.1%].
Method B: with embodiment ten all directions method B, difference is that starting raw material changes embodiment 13 or embodiment 17 compounds into by embodiment nine, embodiment 15 compounds.
Pressing the preparation method of embodiment ten, is starting raw material with embodiment 19 gained compounds, with the reaction reagent reaction, accomplishes the preparation of following compound:
Embodiment 20
(S)-preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(amino)-2-(methylsulfonyl) ethyl) thiazol-2-yl) quinazoline-4-amine
The preparation method is with embodiment ten all directions method A, and difference is to change reaction raw materials into embodiment three compounds by embodiment one compound, is numbered compound 118.
M/z (M+1)
+: 584; E.e value: 91.4%[(S): 95.7%, (R): 4.3%].
Pressing the method for embodiment ten, is starting raw material with embodiment 20 compounds, with the reaction reagent reaction, accomplishes the preparation of following compound:
Embodiment 21
(R)-preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(amino)-2-(methylsulfonyl) ethyl) thiazol-2-yl) quinazoline-4-amine
The preparation method is with embodiment ten all directions method A, and difference is to change reaction raw materials into embodiment Four Modernizations compound by embodiment one compound, is numbered compound 131.
M/z (M+1)
+: 584; E.e value: 92.2%[(R): 96.1%, (S): 3.9%].
Pressing the method for embodiment ten, is starting raw material with embodiment 21 compounds, with the reaction reagent reaction, accomplishes the preparation of following compound:
Embodiment 22
(S)-preparation of N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine
Method A: the preparation method is with embodiment ten all directions method A, and difference is to change reaction raw materials into embodiment five compounds by embodiment one compound, is numbered compound 144.
M/z (M+1)
+: 557; E.e value: 93.0%[(S): 96.5%, (R): 3.5%].
Method B: the preparation method is with embodiment method A, and difference is to change reaction raw materials into embodiment 12 compounds by embodiment nine, embodiment 15 compounds.
Pressing the method for embodiment ten, is starting raw material with embodiment 22 compounds, with the reaction reagent reaction, accomplishes the preparation of following compound:
Embodiment 23
The preparation of formula (IX) compound
Adding compound 97 in the reaction flask (931.3g, 1.56mol), THF (14L), adding one hydration tosic acid under stirring (754.0g, 3.96mol), stirred overnight at room temperature.Filter, forced air drying (60 ℃, 6h) formula (IX) compound (yellow solid, 1370.2g), productive rate 147.2%, the e.e value is 95.2.
1HNMR(DMSO-D
6，400M)δ：2.274(s，6H，38)，2.836(s，6H，30)，2.994(s，3H，29)，4.065(d，1H，28a)，7.480-7.500(m，5H，10)，7.944(d，1H，25)。
Test Example one
Anti tumor activity in vitro is estimated
Test method: SRB
Cell strain: A431; MCF-7
Test design: cell and different concns compound incubation 72 hours, the inhibition degree of employing srb assay assessing compound on cell proliferation is calculated inhibiting rate, adopts the Logit method to calculate IC according to inhibiting rate
50, the anti tumor activity in vitro of comparative compound.
Inhibiting rate method of calculation: inhibiting rate (%)=(control group OD value-medication group OD value)/control group OD value * 100%
Test-results is seen table 1.
Table 1
Test Example two
The pharmacokinetics test of formula (IX) compound
Beasle dog and rat pharmacokinetics research display type (IX) compound oral absorption rate can rise because of dosage raises.Can metabolism produce two active metabolite D1 and D2 after getting in the body.This metabolism activation effect and positive drug lapatinibditosylate are different.
After the rat oral gavage administration, above-mentioned lot number is that medicine blood plasma peak time in the rat body of 20090219 is about 1.33～5.50h, increases with dosage to prolong.It is 1.32～2.72h that blood plasma is eliminated the transformation period, no dose-dependently.Far above the original shape medicine, and the metabolite plasma concentration is 80% of original shape medicine in the intravenously administrable group, points out these two kinds of N-to go the alkyl metabolite mainly to be generated by first pass metabolism at each plasma concentration of irritating stomach dose groups metabolite D1 and D2.In 10～90mg/kg dosage range, above-mentioned lot number is that the AUC0-t value of 20090219 medicine and metabolite D1, D2 increases far above dosage and increases ratio.Behind the continuous gastric infusion of rat, original shape medicine and metabolite do not have in the rat body obviously to be accumulated.Above-mentioned lot number is that 20090219 medicine and metabolite D1, D2 are higher than male rat (P 0.05) in the intravital plasma exposure amount of female rats.After dosage is proofreaied and correct, with the mean value calculation of original shape medicine with the AUC0-t summation of metabolite D1, D2, the rat single irritate stomach give 10,30 and 90mg/kg formula (IX) compound after absolute bioavailability be respectively 6.02%, 23.3% and 67.0%.
Behind the beasle dog oral administration, above-mentioned lot number be 20090219 medicine in vivo the average blood plasma peak time be about 1.17～1.42h, it is 0.89～2.01h that blood plasma is eliminated the transformation period.The plasma concentration of metabolite D1 and D2 is higher than the original shape medicine, and the metabolite plasma concentration is 22% of original shape medicine in the intravenously administrable group, shows that these two kinds of metabolites are mainly generated by first pass metabolism.Above-mentioned lot number is that 20090219 medicine and metabolite D1, D2 reveal bigger individual difference at the intravital pharmacokinetics property list of beasle dog, and in 8.0～32mg/kg dosage range, the AUC0-t value increases a little more than dosage and increases ratio.After dosage is proofreaied and correct; Mean value calculation with the AUC0-t summation of original shape medicine and metabolite D1, D2; The beasle dog single irritate stomach give 8.0,16 with the above-mentioned lot number of 32mg/kg be that the absolute bioavailability of 20090219 medicine is respectively 6.43%, 12.1% and 14.6%.
Above-mentioned lot number is that 20090219 medicine, D1 and D2 and dog plasma protein binding rate are about 97.5%～98.5%, with the rat plasma protein binding rate be 98.1%～98.4%.
It is behind 20090219 the medicine that rat oral gavage gives above-mentioned lot number, and above-mentioned lot number is that the tissue that 20090219 drug main will distribute has tissues such as digestive tube, suprarenal gland, lung, liver; The tissue that metabolite D1 and D2 mainly distribute has tissues such as liver, kidney, lung, suprarenal gland and spleen, and in the great majority tissue, metabolite concentration is higher than the original shape drug level.It is very low that above-mentioned lot number is that 20090219 medicine and meta-bolites see through the hemato encephalic barrier degree.Mice with tumor is irritated stomach, and to give above-mentioned lot number be that original shape medicine and the metabolite concentration in tumor tissues is higher than the concentration in each comfortable blood plasma behind 20090219 the medicine, and the AUC of original shape medicine and metabolite increase is directly proportional with the dosage increase basically in the blood plasma.
Above-mentioned lot number is that 20090219 medicine is in the rat body and the main metabolic pathway in people, monkey, dog, rat and Mouse Liver microsome hatching system is the N-demethyl, N-removes two methyl and takes off the 3-luorobenzyl; Mainly by CYP 1A2,2C19,2D6; 2E1, the common catalysis of 3A4 and 3A5.
Behind the gastric infusion, above-mentioned lot number is that 20090219 drug main will be discharged from excrement with the form of original shape medicine and metabolite.The overall excretion of original shape medicine and metabolite accounts for 54.2% of dosage in the excrement, in the urine sample 0.1% of the not enough dosage of overall excretion; In the 0-24h, the overall excretion in the bile accounts for 1.17% of dosage.
Above-mentioned lot number is that 20090219 medicine does not have obvious restraining effect to main CYP450 enzyme, to the active no remarkable inducing action of rat CYP1A, CYP2C, CYP2D and CYP3A.Be that medicine metabolic stability test in each kind hepatomicrosome incubation system of 20090219 is derived and obtained corresponding CLint value according to above-mentioned lot number, show that formula (IX) compound all belongs to high definition except that medicine in people, monkey, dog, rat and mouse body.
Test Example 3
Formula (IX) compound is to the curative effect of people's lung cancer Calu-3 Nude Mice
Experiment purpose
Estimate and comparison expression (IX) compound, lapatinibditosylate (Lapatinib) to the curative effect of people's lung cancer Calu-3 Nude Mice.
Be subjected to the reagent thing
Medicine name and lot number: formula (IX) compound (being called for short HER-036), bright yellow powder, content 99.5%, lot number: 20090201; Lapatinibditosylate biconjugate tosylate is called for short lapatinibditosylate (Lapatinib ditosylate is called for short Lapatinib), khaki color powder, lot number: 20090105.
The unit of providing: Jiangsu Haosen Pharmaceutical Co., Ltd.
Compound method: HER-036, Lapatinib all are made into desired concn with the distilled water that contains 0.1% tween-80.
Laboratory animal
The BALB/cA-nude nude mouse, in 6-7 week, ♀ is available from Shanghai Slac Experimental Animal Co., Ltd..Conformity certification number: SCXK (Shanghai) 2007-0005.Feeding environment: SPF level.
Experimental procedure
Nude mouse subcutaneous vaccination people lung cancer Calu-3 cell treats that tumor growth is to 60-150mm
3After, with animal random packet (d0).Dosage and dosage regimen are seen table 2.Survey the knurl volume weekly 2-3 time, claim that mouse is heavy, record data.Gross tumor volume (V) calculation formula is: V=1/2 * a * b2, wherein a, b represent length and width respectively.
Conclusion
HER-036, Lapatinib all obviously suppress the growth of people's lung cancer Calu-3; No matter from tumour inhibiting rate still be the tumor regression rate relatively, HER-036 all is better than Lapatinib to the curative effect of Calu-3.
Claims (13)
1. the compound shown in the general formula (I):
Wherein
R
1Expression
Wherein by 1 or 2 substituted furans of substituting group or thiazole, said substituting group is selected from halogen atom, C to Ar for randomly
1-4Alkyl or C
1-4Alkoxyl group;
R
2, R
3Be independently from each other hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, alkoxyalkyl, cycloalkyl or cycloalkylalkyl;
Y is for randomly by R
4, R
5Substituted phenyl or 1H-indazolyl, wherein, R
4Be selected from benzyl, halo-, dihalo-or three halogeno-benzyls, benzyloxy, halo-, dihalo-or three halo benzyloxies, R
5Be selected from hydrogen, hydroxyl, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, amino, cyanic acid or trifluoromethyl;
Band * carbon atom is a chiral carbon atom, with the S configuration or be rich in S configuration enantiomeric form and exist;
B is selected from tartrate, lactic acid, phosphoric acid, Hydrocerol A, acetate, trifluoroacetic acid, oxysuccinic acid, nitric acid, hydrochloric acid, sulfuric acid, oxalic acid, Succinic Acid, methylsulfonic acid, toxilic acid or tosic acid.
2. compound according to claim 1 is characterized in that said Ar is selected from unsubstituted furans or thiazole.
3. compound according to claim 1 and 2 is characterized in that R
2, R
3Be independently from each other hydrogen, C
1-4Alkyl, C
2-5Thiazolinyl, C
1-4Alkoxyl group, C
1-4Alkoxy C
1-4Alkyl, C
3-8Cycloalkyl or C
3-8Cycloalkyl-C
1-4Alkyl.
4. compound according to claim 3 is characterized in that R
4Be selected from benzyl, halo-benzyl, halo-benzyloxy, R
5Be selected from hydrogen, halogen atom, C
1-4Alkyl or C
1-4Alkoxyl group.
5. compound according to claim 4 is characterized in that R
4Be selected from halo-benzyl or halo-benzyloxy.
6. according to any described compound of claim 1-5, it is characterized in that being with the * carbon atom to exist with the S configuration.
7. according to any described compound of claim 1-5, it is characterized in that being with the * carbon atom to exist to be rich in S configuration form, and S configuration content >=90%.
8. according to any described compound of claim 1-7, it is characterized in that described compound comprises the tosilate of following compound:
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propyl group is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-diethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, the N-dipropyl is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(allyl amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propargyl is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propyl group is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(N, N-dimethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(cyclopropyl methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(allyl amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine; With
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propargyl is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine.
9. compound according to claim 8 is characterized in that its structure is suc as formula shown in (IX):
Wherein, band * carbon atom is a chiral carbon atom, exists with S configuration enantiomeric form.
10. compound according to claim 8 is characterized in that its structure is suc as formula shown in (IX):
Wherein, band * carbon atom is a chiral carbon atom, exists to be rich in S configuration enantiomeric form.
11. a medicinal compositions, said composition contain the treatment effective dose like any described compound of claim 1-10 and pharmaceutically acceptable carrier.
12. like any described compound of claim 1-10 or the purposes of medicinal compositions as claimed in claim 11 in the medicine of preparation treatment adjusting c-erbB-2 and/or EGF-R protein tyrosine kinase activity relative disease.
13. purposes according to claim 12 is characterized in that said disease is malignant tumour or psoriasis.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999035146A1 (en) * | 1998-01-12 | 1999-07-15 | Glaxo Group Limited | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
| WO2006066267A2 (en) * | 2004-12-17 | 2006-06-22 | Smithkline Beecham (Cork) Limited | Cancer treatment method |
| CN101735200A (en) * | 2008-11-17 | 2010-06-16 | 岑均达 | Quinazoline compound |
| CN101787017A (en) * | 2009-01-23 | 2010-07-28 | 岑均达 | Optical pure quinazoline compound |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999035146A1 (en) * | 1998-01-12 | 1999-07-15 | Glaxo Group Limited | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
| WO2006066267A2 (en) * | 2004-12-17 | 2006-06-22 | Smithkline Beecham (Cork) Limited | Cancer treatment method |
| CN101735200A (en) * | 2008-11-17 | 2010-06-16 | 岑均达 | Quinazoline compound |
| CN101787017A (en) * | 2009-01-23 | 2010-07-28 | 岑均达 | Optical pure quinazoline compound |
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Effective date of registration: 20160718 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. Address before: 222047 tenth Industrial Zone, Lianyungang economic and Technological Development Zone, Jiangsu Patentee before: Cen Junda Patentee before: Jiangsu Hansoh Medical Group Co.,Ltd. |