CN102344444B - Optically pure quinazoline compounds - Google Patents
Optically pure quinazoline compounds Download PDFInfo
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- CN102344444B CN102344444B CN201110193978.0A CN201110193978A CN102344444B CN 102344444 B CN102344444 B CN 102344444B CN 201110193978 A CN201110193978 A CN 201110193978A CN 102344444 B CN102344444 B CN 102344444B
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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
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 contain the medicinal compositions of this compound for the treatment of significant quantity, and regulate the purposes in the medicine of c-erbB-2 and/or EGF-R protein tyrosine kinase activity relative disease in preparation treatment.
Background technology
The phosphorylation of specific tyrosine residues in the various albumen that the adjustment of protein tyrosine kinase catalysis and Growth of Cells and differentiation is relevant.Protein tyrosine kinase can be roughly divided into acceptor (as EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) or non-acceptor (as c-src, lck, zap70) kinases.Shown this type of kinase whose improper or uncontrolled activation many, that is, the protein tyrosine kinase activity of the exception such as, caused by overexpression or sudden change can cause uncontrolled cells produce.
Protein tyrosine kinase, as relevant with the malignant tumour of people in the abnormal activity of c-erbB-2, c-src, c-met, EGFr, PDGFr.Such as, the EGFr of rising is active relevant with 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, arrestin Tyrosylprotein kinase should be able to provide the treatment to above-mentioned tumour.
Aberrant protein tyrosine kinase activity also disease various with other is relevant: as psoriasis, fibroid degeneration, atherosclerosis, restenosis, autoimmune disorder, allergy, asthma etc., shown can control these diseases by the effect of some receptor tyrosine kinases.
Chinese patent 99803887.3 openly reports a series of compound, and they have protein tyrosine kinase inhibit activities; Chinese patent 20081000815 also openly reports a series of new quinazoline compound, but all with racemate forms exploitation, does not study its optically pure isomer.
Summary of the invention
The object of the invention is to provide optical pure quinazoline compound shown in general formula (I) and uses thereof.
The object of the invention is also to provide a kind of pharmaceutical composition containing the optical pure quinazoline compound shown in effective dose general formula (I), and their application in the diseases such as Therapeutic cancer, malignant tumour and psoriasis;
The invention discloses general formula (I) compound:
Wherein
R
1represent
wherein Ar is that described substituting group is selected from halogen atom, C optionally by the furans of 1 or 2 substituting group replacement or thiazole
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 optionally by R
4, R
5the phenyl replaced or 1H-indazolyl; Wherein, R
4be selected from benzyl, halo-, dihalo-or three halogeno-benzyls, benzyloxy, halo-, dihalo-or three halobenzyloxy; R
5be selected from hydrogen, hydroxyl, halogen atom, C
1-4alkyl, C
1-4alkoxyl group, amino, cyano group or trifluoromethyl;
Band * carbon atom is 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, citric acid, acetic acid, 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 preferred embodiments 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 be rich in (S) form exist time, preferably (S) structure contents >=90%.
In the solution 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-base) quinazoline-4-amine; (compound 92)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methylsulfonyl) ethyl) furans-2-base) quinazoline-4-amine; (compound 93)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-2-(methylsulfonyl) ethyl) furans-2-base) quinazoline-4-amine; (compound 94)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propylcarbamic)-2-(methylsulfonyl) ethyl) furans-2-base) quinazoline-4-amine; (compound 95)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(Cyclopropyl-methyl-amino)-2-(methylsulfonyl) ethyl) furans-2-base) 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-base) 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-base) quinazoline-4-amine; (compound 98)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dipropylamino)-2-(methylsulfonyl) ethyl) furans-2-base) 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-base) quinazoline-4-amine; (compound 100)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(allyl amino)-2-(methylsulfonyl) ethyl) furans-2-base) quinazoline-4-amine; (compound 101)
(S)-N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propargyl-amino)-2-(methylsulfonyl) ethyl) furans-2-base) quinazoline-4-amine; (compound 102)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-base)-6-(5-(1-(amino)-2-(methylsulfonyl) ethyl) furans-2-base) quinazoline-4-amine; (compound 144)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-base)-6-(5-(1-(methylamino)-2-(methylsulfonyl) ethyl) furans-2-base) quinazoline-4-amine; (compound 145)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-base)-6-(5-(1-(ethylamino)-2-(methylsulfonyl) ethyl) furans-2-base) quinazoline-4-amine; (compound 146)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-base)-6-(5-(1-(propylcarbamic)-2-(methylsulfonyl) ethyl) furans-2-base) quinazoline-4-amine; (compound 147)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-base)-6-(5-(1-(N, N-dimethylamino)-2-(methylsulfonyl) ethyl) furans-2-base) quinazoline-4-amine; (compound 149)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-base)-6-(5-(1-(Cyclopropyl-methyl-amino)-2-(methylsulfonyl) ethyl) furans-2-base) quinazoline-4-amine; (compound 148)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-base)-6-(5-(1-(allyl amino)-2-(methylsulfonyl) ethyl) furans-2-base) quinazoline-4-amine; (compound 153)
(S)-N-(1-(3-luorobenzyl)-1H-indazole-5-base)-6-(5-(1-(propargyl-amino)-2-(methylsulfonyl) ethyl) furans-2-base) quinazoline-4-amine.(compound 154)
In the solution of the present invention, preferred compound is such 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 side chain or the straight chain representative examples of saturated aliphatic alkyl of 1-4, as methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-etc.;
" thiazolinyl " refers at least containing the side chain of a carbon-carbon double bond, straight chain or cyclic non-aromatic hydrocarbon group, as vinyl, propenyl, allyl group, butenyl, tetrahydrobenzene etc.;
" alkynyl " refers at least containing the side chain of a carbon carbon triple bond, straight chain or cyclic hydrocarbon groups, as ethynyl, proyl, butynyl, 3-methylbutynyl, alkynes butyl, propargyl etc.
" cycloalkyl " refers to the representative examples of saturated aliphatic hydrocarbon-based containing monocycle, and preferred carbon atom is the cycloalkyl of 3-8, as cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, ethyI-cyclopentyl, cyclohexyl etc.;
" alkoxyl group " refers to the group that straight or branched alkyl is connected with Sauerstoffatom, as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy etc.;
" halogen atom " refers to fluorine, chlorine, bromine, atomic iodine.
The method of preparation formula (I) compound comprises the following steps:
1) general formula (II) compound and t-butyl sulfonamide react, and obtain general formula (III) compound;
2) general formula (III) compound and general formula (IV) compound react, and obtain logical formula V compound;
3) logical formula V compound reacts in acid condition, obtains general formula (VI) compound;
4) general formula (VI) compound and reagent R
2-L or R
3-L reacts, and obtains general formula (VII) compound;
5) general formula (VII) compound and oxidant reaction, obtains general formula (VIII) compound;
6) general formula (VIII) compound and acid-respons, obtains general formula (I) compound;
Wherein,
R
1, Y, Ar, R
2, R
3, band * carbon atom and acid as general formula (I) define;
T is sulphur atom or sulfinyl;
T-butyl sulfonamide is optical purity, with (S) single enantiomer form or be rich in (S) single enantiomer form exist;
L is leavings group, is selected from halogen atom or sulfonyloxy.
In the preparation of general formula (III) compound, react and carry out under metal reagent exists.Metal reagent comprises purity titanium tetraethoxide, tetraisopropoxy titanium etc., preferred tetraisopropoxy titanium; Temperature of reaction controls at 0-100 DEG C, preferred 0-50 DEG C.
In the preparation of general formula (VI) compound, reaction is carried out in acid condition, and acid used 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; reaction sulphur atom or sulfinyl being oxidized to alkylsulfonyl is well-known to those skilled in the art; oxygenant used is selected from: metachloroperbenzoic acid, Peracetic Acid, hydrogen peroxide, potassium hydrogen persulfate etc., but preferably potassium hydrogen persulfate.
The other method of preparation formula (I) compound comprises the following steps:
1) general formula (II) compound and t-butyl sulfonamide react, and obtain general formula (III) compound;
2) general formula (III) compound and general formula (A) compound react, and obtain general formula (B) compound;
3) general formula (B) compound reacts in acid condition, obtains general formula (C) compound;
4) general formula (C) compound and reagent R
2-L or R
3-L reacts, and obtains general formula (VIII) compound;
5) general formula (VIII) compound and acid-respons, obtains general formula (I) compound;
Wherein,
R
1, Y, Ar, band * carbon atom as general formula (I) define;
T-butyl sulfonamide, L define as above-mentioned;
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, as halogen atom (as fluorine, chlorine, bromine, atomic iodine), and preferred bromine, atomic iodine; Sulfonyloxy (as mesyloxy, tolysulfonyl oxygen base) etc.;
In the preparation of general formula (C) compound, reaction is carried out in acid condition, and acid used 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 reaction the 4th) step carries out in the basic conditions, and alkali used is selected from mineral alkali (as sodium bicarbonate, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide etc.) or organic bases (as ethamine, triethylamine, diisopropylethylamine etc.).
Another object of the present invention is to provide a kind of pharmaceutical composition, and it contains general formula (I) compound of effective dose and pharmaceutically acceptable carrier.
Another object of the present invention is to provide formula (I) compound or the purposes of the pharmaceutical composition containing this compound in the medicine of preparation treatment adjustment c-erbB-2 and/or EGF-R protein tyrosine kinase activity relative disease.
Another object of the present invention is to provide formula (I) compound or the purposes of pharmaceutical composition in the medicine preparing Therapeutic cancer and malignant tumour containing this compound.
Another object of the present invention is to provide general formula (I) compound or the pharmaceutical composition containing this compound is preparing the purposes in antipsoriatics thing.
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 in a unit, and per unit dosage contains the activeconstituents of predetermined amount.Such unit can contain, such as 0.5mg-1g, and the number of concrete consumption depends on the factors such as age, body weight, the state of an illness meeting subject disease, route of administration and patient.
Medicinal preparations can give by any suitable approach, as the approach such as oral, rectum, nasal cavity, local or parenteral (comprising subcutaneous, muscle, vein or transdermal) give.Above-mentioned various preparation can pass through the known any method of pharmacy field, such as, by activeconstituents and carrier or mixed with excipients being prepared.
The compounds of this invention or its pharmacy acceptable salt can give separately or with treatment above-mentioned disease other treatment agent conbined usage.Especially, in antineoplastic treatment, should consider and other chemotherapeutics, hormone or antibody drug drug combination.
Embodiment
In order to illustrate in greater detail the present invention, provide following Examples.But scope of the present invention is not defined in this.
In following examples, the excessive value (Enantionmeric excesses, e.e) of enantiomorph refers to the relative populations of often kind of enantiomorph.This value is defined as the difference between two kinds of enantiomorph relative percentages.Therefore, such as, when the content percentage ratio of (R) enantiomorph is 90%, the content percentage ratio of (S) enantiomorph is 10%, and (R) enantiomeric excess is 80%, and namely e.e value is: 80%.
The composition chirality HPLC of each compound enantiomorph measures, and condition is as follows:
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 2000mL flask, add the iodo-3H-quinazoline-4-one (100g) of 6-, be dissolved in the mixed solvent of thionyl chloride (1000ml) and DMF (20ml), reflux is to reaction solution clear.Steam thionyl chloride, with toluene band dry twice, for subsequent use.
Intermediate for subsequent use is dissolved in Virahol (2000ml), adds the chloro-4-of 3-(the fluoro-benzyloxy of 3-)-anilinechloride (70g), under mechanical stirring, add anhydrous K
2cO
3(150g), heated overnight at reflux.Reaction solution is cooled to room temperature by next day, decompress filter, and the making beating of filter cake water is washed 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-base)-6-iodine quinazoline-4 amine
Method is with preparation example 1, and difference is to change chloro-for 3-4-(the fluoro-benzyloxy of 3-)-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-chlorphenylamino) quinazoline-6-base) furans-2-aldehyde
By preparation 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 reaction flask, back flow reaction 2 hours.Cool to room temperature, filter, a small amount of methanol wash first used by filter cake, then in 50 DEG C of oven dry, obtains title compound: 40g, yellow solid.
m/z(M+1)
+：473。
The preparation of preparation example 4 5-(4-(1-(3-luorobenzyl)-1H-indazole-5-base is amino) quinazoline-6-base) furans-2-aldehyde
Method is with preparation example 3, and difference is to change raw material into preparation example 2 compound by preparation example 1 compound.m/z(M+1)
+：464。
The preparation of preparation example 5 2-(4-(4-(3-fluorine benzyloxy)-3-chlorphenylamino) quinazoline-6-base) thiazole-5-aldehyde
By preparation 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 reaction flask, back flow reaction 2 hours.Cool to room temperature, filter, a small amount of methanol wash first used by filter cake, then in 50 DEG C of oven dry, obtains title compound: 30g.
m/z(M+1)
+：490。
The preparation of preparation example 6 2-(4-(1-(3-luorobenzyl)-1H-indazole-5-base is amino) quinazoline-6-base) thiazole-5-aldehyde
Method is with preparation example 5, and difference is to change raw material into preparation example 2 compound by preparation example 1 compound.
m/z(M+1)
+：480。
Embodiment one
(S) preparation of-N-((5-(4-(4-(3-fluorine benzyloxy)-3-chlorphenylamino) quinazoline-6-base) furans-2-base) methylene radical)-2-methylpropane-2-sulfinyl amine
By preparation example 3 compound (47.3g, 0.1mol), S-t-butyl sulfonamide (14.5g, 0.12mol), tetraisopropoxy titanium (85g, 0.3mol) and anhydrous THF (1000ml) put in reaction flask, and room temperature reaction spends the night.Next day, process: add water (50ml), ethyl acetate (500ml), stirs 10min, and filter, filter cake THF washes 3 times.Filtrate adds anhydrous magnesium sulfate drying.Filter, filtrate reduced in volume obtains title compound: 50g.m/z(M+1)
+：577。
Embodiment two
(R) preparation of-N-((5-(4-(4-(3-fluorine benzyloxy)-3-chlorphenylamino) quinazoline-6-base) furans-2-base) methylene radical)-2-methylpropane-2-sulfinyl amine
Preparation method is with embodiment one, and difference is to change reaction raw materials into R-t-butyl sulfonamide by S-t-butyl sulfonamide.m/z(M+1)
+：577。
Embodiment three
(S) preparation of-N-((2-(4-(4-(3-fluorine benzyloxy)-3-chlorphenylamino) quinazoline-6-base) thiazole-5-base) methylene radical)-2-methylpropane-2-sulfinyl amine
Preparation method is with embodiment one, and difference is to change reaction raw materials into preparation example 5 compound by preparation example 3 compound.m/z(M+1)
+：594。
Embodiment four
(R) preparation of-N-((2-(4-(4-(3-fluorine benzyloxy)-3-chlorphenylamino) quinazoline-6-base) thiazole-5-base) methylene radical)-2-methylpropane-2-sulfinyl amine
Preparation method is with embodiment three, and difference is to change reaction raw materials into R-t-butyl sulfonamide by S-t-butyl sulfonamide.m/z(M+1)
+：594。
Embodiment five
(S) preparation of-N-((5-(4-(1-(3-luorobenzyl)-1H-indazole-5-base is amino) quinazoline-6-base) furans-2-base) methylene radical)-2-methylpropane-2-sulfinyl amine
Preparation method is with embodiment one, and difference is to change reaction raw materials into preparation example 4 compound by preparation example 3 compound.m/z(M+1)
+：567。
Embodiment six
(R) preparation of-N-((5-(4-(1-(3-luorobenzyl)-1H-indazole-5-base is amino) quinazoline-6-base) furans-2-base) methylene radical)-2-methylpropane-2-sulfinyl amine
Preparation method is with embodiment two, and difference is to change reaction raw materials into preparation example 4 compound by preparation example 3 compound.m/z(M+1)
+：567。
Embodiment seven
(S) preparation of-N-((2-(4-(1-(3-luorobenzyl)-1H-indazole-5-base is amino) quinazoline-6-base) thiazole-5-base) methylene radical)-2-methylpropane-2-sulfinyl amine
Preparation method is with embodiment one, and difference is to change reaction raw materials into preparation example 6 compound by preparation example 3 compound.m/z(M+1)
+：584。
Embodiment eight
(R) preparation of-N-((2-(4-(1-(3-luorobenzyl)-1H-indazole-5-base is amino) quinazoline-6-base) thiazole-5-base) methylene radical)-2-methylpropane-2-sulfinyl amine
Preparation method is with embodiment one, and difference is to change reaction raw materials into preparation example 6 compound by preparation example 3 compound.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-base) quinazoline-4-amine
By methylthiomethyl magnesium chloride/THF solution (0.3mol) is put in reaction flask, cooling reaction solution is to less than-80 DEG C, insulation 5min, add embodiment one compound (57.6g fast, 0.1mol) and the solution of anhydrous THF (200ml), Nei Wen less than-80 DEG C is kept.Insulated and stirred 10min, process.By in reaction solution impouring saturated aqueous common salt (3000ml), add ethyl acetate (2000ml), separatory, organic layer saturated aqueous common salt (2000ml) washing, anhydrous magnesium sulfate drying.Filter, filtrate reduced in volume obtains yellow solid 50g.
Upper step gained yellow solid is dissolved in THF (1000ml), adjusts pH=1 with HCl-ethanol, stirring at room temperature 2 hours, process.Add strong aqua and adjust pH=9, add saturated aqueous common salt (2000ml) and ethyl acetate (1500ml), separatory, organic over anhydrous dried over mgso.Filter, filtrate reduced in volume, resistates silica gel column chromatography (eluent: ethyl acetate acetic acid ethyl ester/THF=10/1), collects qualified component, concentrated, obtains title compound: 30g, is 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-base) quinazoline-4-amine
Method A: by embodiment nine gained compound (2.0g), methyl iodide (0.5g) and triethylamine (0.7g) are dissolved in THF (150ml), are heated to back flow reaction 2h.Stop heating, in reaction solution, add saturated aqueous common salt, add ethyl acetate and extract, organic phase saturated aqueous common salt washes twice, anhydrous magnesium sulfate drying.Filter, filtrate reduced in volume, resistates column chromatography purification (chloroform/methanol=100: 1) obtain title compound 1.5g, be numbered compound 2.
Method B: be dissolved in DMSO (50ml) by embodiment nine compound (5.4g), adds formaldehyde (6ml), formic acid (3ml), and stirring at room temperature reaction is spent the night.Be punched into by reaction solution in frozen water (500ml), filter, drain, after filter cake dissolves with THF, silica gel sand, column chromatography purification obtains title compound: 4.2g, is numbered compound 2.m/z(M+1)
+：549。
By the preparation method of embodiment ten, with embodiment nine gained compound for starting raw material, react with reaction reagent, complete 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
Preparation method is with embodiment nine, and difference is to change reaction raw materials into embodiment three compound by embodiment one compound, is numbered compound 14.m/z(M+1)
+：552。
By the method for embodiment ten, with embodiment 11 compound for starting raw material, react with reaction reagent, complete the preparation of following compound:
Embodiment 12
(S) preparation of-N-(1-(3-luorobenzyl)-1H-indazole-5-base)-6-(5-(1-(amino)-2-(methylthio group) ethyl) furans-2-base) quinazoline-4-amine
Preparation method is with embodiment nine, and difference is to change reaction raw materials into embodiment five compound by embodiment one compound, is numbered compound 27.m/z(M+1)
+：525。
By the method for embodiment ten, with embodiment 12 compound for starting raw material, react with reaction reagent, complete 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-base) quinazoline-4-amine
Preparation method is with embodiment nine, and difference is to change reaction raw materials into embodiment two compound by embodiment one compound, is numbered compound 40.m/z(M+1)
+：535。
By the preparation method of embodiment ten, with embodiment 13 gained compound for starting raw material, react with reaction reagent, complete 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
Preparation method is with embodiment nine, and difference is to change reaction raw materials into embodiment four compound by embodiment one compound, is numbered compound 53.m/z(M+1)
+：552。
By the method for embodiment ten, with embodiment 14 compound for starting raw material, react with reaction reagent, complete 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-base) quinazoline-4-amine
Methyl-sulphoxide (0.4mol) is dissolved in anhydrous THF (2000ml), under nitrogen protection, is cooled to-20 DEG C, drip n-BuLi (0.3mol).Drip and finish, insulated and stirred 30min.Cooling reaction solution is to less than-80 DEG C, and insulation 5min, adds the solution of embodiment one compound (57.6g, 0.1mol) and anhydrous THF (200ml) fast, keeps Nei Wen less than-80 DEG C.Insulated and stirred 10min, process.By in reaction solution impouring saturated aqueous common salt 3000ml, add ethyl acetate 2000ml, separatory, organic layer saturated aqueous common salt 2000ml washes, anhydrous magnesium sulfate drying.Filter, filtrate reduced in volume obtains yellow solid 42g.
Upper step gained yellow solid is dissolved in THF (1000ml), adjusts pH=1 with HCl-ethanol, stirring at room temperature 2 hours, process.Add strong aqua and adjust pH=9, add saturated aqueous common salt (2000ml) and ethyl acetate (1500ml), separatory, organic over anhydrous dried over mgso.Filter, filtrate reduced in volume, resistates silica gel column chromatography (eluent: ethyl acetate acetic acid ethyl ester/THF=5/1), collects qualified component, concentrated, obtains title compound: 20g, is 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-base) quinazoline-4-amine
Preparation method is with embodiment ten, and difference is that reaction raw materials changes embodiment 15 compound into by embodiment seven compound, is numbered compound 67.m/z(M+1)
+：566。
By the preparation method of embodiment ten, with embodiment 15 gained compound for starting raw material, react with reaction reagent, complete 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-base) quinazoline-4-amine
Preparation method is with embodiment 15, and difference is to change reaction raw materials into embodiment two compound by embodiment one compound, numbering compound 79.m/z(M+1)
+：551。
By the preparation method of embodiment ten, with embodiment 17 gained compound for starting raw material, react with reaction reagent, complete 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-base) quinazoline-4-amine
Method A: dimethyl sulfone (37.6g, 0.4mol) is dissolved in anhydrous THF (2000ml), is cooled to-20 DEG C under nitrogen protection, drips n-BuLi (0.3mol).Drip and finish, insulated and stirred 30min.Cooling reaction solution is to less than-80 DEG C, and insulation 5min, adds the solution of embodiment one compound (57.6g, 0.1mol) and anhydrous THF (200ml) fast, keeps Nei Wen less than-80 DEG C.Insulated and stirred 10min, process.By in reaction solution impouring saturated aqueous common salt 3000ml, add ethyl acetate 2000ml, separatory, organic layer saturated aqueous common salt 2000ml washes, anhydrous magnesium sulfate drying.Filter, filtrate reduced in volume obtains yellow solid 42g.
Upper step gained yellow solid is dissolved in THF (1000ml), adjusts pH=1 with HCl-ethanol, stirring at room temperature 2 hours, process.Add strong aqua and adjust pH=9, add saturated aqueous common salt (2000ml) and ethyl acetate (1500ml), separatory, organic over anhydrous dried over mgso.Filter, filtrate reduced in volume, resistates silica gel column chromatography (eluent: ethyl acetate--ethyl acetate/THF=5/1), collects qualified component, concentrated, obtains title compound: 20g, is numbered compound 92.
Method B: by the mixed solvent (7: 3 of embodiment nine or each 50g of embodiment 15 gained compound and methanol/water, 1000ml) put in reaction flask, after dissolving, gradation adds oxone (100g), continues at stirring at room temperature and react 2 hours after adding.Filter, the mixing solutions washing of filter cake methanol/water, filtrate adjusts pH=8 with saturated sodium bicarbonate solution, concentrating under reduced pressure, adds ethyl acetate (500ml × 2) and extracts, merge organic layer, then use anhydrous sodium sulfate drying.Filter, filtrate reduced in volume is done, column chromatography purification (eluent: chloroform/methanol=100: 1) obtain title compound: 40g, yellow solid.M/z (M+1)
+: 567; E.e value: 95.2% [(S): 97.6%, (R): 2.4%].
By the preparation method of embodiment ten, with embodiment 18 gained compound for starting raw material, react with reaction reagent, complete 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-base) quinazoline-4-amine
Method A: with embodiment ten method A from all directions, difference is to change starting raw material into embodiment two compound 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 method B from all directions, difference is that starting raw material changes embodiment 13 or embodiment 17 compound into by embodiment nine, embodiment 15 compound.
By the preparation method of embodiment ten, with embodiment 19 gained compound for starting raw material, react with reaction reagent, complete 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
Preparation method is with embodiment ten method A from all directions, and difference is to change reaction raw materials into embodiment three compound by embodiment one compound, is numbered compound 118.
M/z (M+1)
+: 584; E.e value: 91.4% [(S): 95.7%, (R): 4.3%].
By the method for embodiment ten, with embodiment 20 compound for starting raw material, react with reaction reagent, complete 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
Preparation method is with embodiment ten method A from all directions, and difference is to change reaction raw materials into embodiment four 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%].
By the method for embodiment ten, with embodiment 21 compound for starting raw material, react with reaction reagent, complete the preparation of following compound:
Embodiment 22
(S) preparation of-N-(1-(3-luorobenzyl)-1H-indazole-5-base)-6-(5-(1-(amino)-2-(methylsulfonyl) ethyl) furans-2-base) quinazoline-4-amine
Method A: preparation method is with embodiment ten method A from all directions, and difference is to change reaction raw materials into embodiment five compound 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: preparation method is with embodiment method A, and difference is to change reaction raw materials into embodiment 12 compound by embodiment nine, embodiment 15 compound.
By the method for embodiment ten, with embodiment 22 compound for starting raw material, react with reaction reagent, complete the preparation of following compound:
Embodiment 23
The preparation of formula (IX) compound
Add compound 97 (931.3g, 1.56mol) in reaction flask, THF (14L), add a hydration tosic acid (754.0g, 3.96mol) under stirring, stirred overnight at room temperature.Filter, forced air drying (60 DEG C, 6h) obtains formula (IX) compound (yellow solid, 1370.2g), and productive rate 147.2%, 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 evaluated
Test method: SRB
Cell strain: A431; MCF-7
Test design: cell and different concns compound incubation 72 hours, adopts the suppression degree of srb assay assessing compound on cell proliferation, calculates inhibiting rate, adopts 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 in table 1.
Table 1
Test example two
The pharmacokinetic trial of formula (IX) compound
Beasle dog and rat pharmacokinetics research display type (IX) compound oral absorption rate can rise because dosage raises.Enter after in body and metabolism can produce two active metabolite D1 and D2.This metabolism activation effect and positive drug lapatinibditosylate different.
After rat oral gavage administration, above-mentioned lot number be 20090219 medicine blood plasma peak time in rat body be about 1.33 ~ 5.50h, with dosage increase and extend.Plasma elimination half life is 1.32 ~ 2.72h, without dose-dependently.At the plasma concentration of each given low group metabolite D1 and D2 far above original shape medicine, and metabolite plasma concentration is 80% of original shape medicine in intravenously administrable group, point out these two kinds of N-to go alkyl metabolite to generate primarily of first pass metabolism.In 10 ~ 90mg/kg dosage range, above-mentioned lot number is that the medicine of 20090219 and the AUC0-t value of metabolite D1, D2 increase far above dosage increase ratio.After the continuous gastric infusion of rat, original shape medicine and metabolite are accumulated without obvious in rat body.Above-mentioned lot number be 20090219 medicine and metabolite D1, D2 plasma exposure amount in female rats higher than male rat (P 0.05).After dose modification, with the mean value calculation of the AUC0-t summation of original shape medicine and metabolite D1, D2, rat single oral gavage gives 10,30 and 90mg/kg formula (IX) compound after absolute bioavailability be respectively 6.02%, 23.3% and 67.0%.
After beasle dog oral administration, above-mentioned lot number be 20090219 medicine in vivo average blood plasma peak time be about 1.17 ~ 1.42h, plasma elimination half life is 0.89 ~ 2.01h.The plasma concentration of metabolite D1 and D2 is higher than original shape medicine, and metabolite plasma concentration is 22% of original shape medicine in intravenously administrable group, show that these two kinds of metabolites generate primarily of first pass metabolism.Above-mentioned lot number be 20090219 medicine and metabolite D1, D2 pharmacokinetics in beasle dog body show larger individual difference, in 8.0 ~ 32mg/kg dosage range, AUC0-t value increase a little more than dosage increase ratio.After dose modification, with the mean value calculation of the AUC0-t summation of original shape medicine and metabolite D1, D2, beasle dog single oral gavage gives 8.0,16 and the above-mentioned lot number of 32mg/kg be that the absolute bioavailability of the medicine of 20090219 is respectively 6.43%, 12.1% and 14.6%.
Above-mentioned lot number be 20090219 medicine, D1 and D2 and dog plasma protein binding rate are about 97.5% ~ 98.5%, are 98.1% ~ 98.4% with rat plasma protein binding rate.
It is after the medicine of 20090219 that rat oral gavage gives above-mentioned lot number, above-mentioned lot number be 20090219 the drug main tissue that will distribute have the tissue such as digestive tube, suprarenal gland, lung, liver; The tissue that metabolite D1 and D2 mainly distributes has the tissues such as liver, kidney, lung, suprarenal gland and spleen, and in great majority tissue, metabolite concentration is higher than original shape drug level.Above-mentioned lot number be 20090219 medicine and meta-bolites very low through hemato encephalic barrier degree.It is after the medicine of 20090219 that mice with tumor gavage gives above-mentioned lot number, and original shape medicine and the metabolite concentration in tumor tissues is higher than the concentration in each comfortable blood plasma, and in blood plasma, the AUC increase of original shape medicine and metabolite is directly proportional to dosage increase substantially.
Above-mentioned lot number be 20090219 the main metabolic pathway of medicine in rat body and in people, monkey, dog, rat and mouse hepatomicrosome hatching system is N-demethyl, N-removes two methyl and de-3-luorobenzyl, primarily of CYP 1A2,2C19,2D6,2E1,3A4 and 3A5 co-catalysis.
After gastric infusion, above-mentioned lot number be 20090219 drug main to discharge from excrement with the form of original shape medicine and metabolite.In excrement, the overall excretion of original shape medicine and metabolite accounts for 54.2% of dosage, in urine sample the not enough dosage of overall excretion 0.1%; In 0-24h, the overall excretion in bile accounts for 1.17% of dosage.
Above-mentioned lot number be 20090219 medicine to main CYP450 enzyme without obvious restraining effect, active in remarkable inducing action to rat CYP1A, CYP2C, CYP2D and CYP3A.According to above-mentioned lot number be 20090219 medicine in each kind liver microsomes incubation system metabolic stability test derivation obtain corresponding CLint value, show formula (IX) compound all belong in people, monkey, dog, rat and mouse body high definition remove medicine.
Test example 3
Formula (IX) compound is to the curative effect of people lung cancer Calu-3 Nude Mice
Experiment purpose
To evaluate and comparison expression (IX) compound, lapatinibditosylate (Lapatinib) is to the curative effect of people lung cancer Calu-3 Nude Mice.
Test medicine
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.
There is provided unit: Jiangsu Haosen Pharmaceutical Co., Ltd.
Compound method: HER-036, Lapatinib are all made into desired concn with the distilled water containing 0.1% tween-80.
Laboratory animal
BALB/cA-nude nude mouse, in 6-7 week, ♀, purchased 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, by animal random packet (d0).Dosage and dosage regimen are in table 2.Survey 2-3 knurl volume weekly, claim mouse 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 lung cancer Calu-3; No matter compare from tumour inhibiting rate or tumor regression rate, the curative effect of HER-036 to Calu-3 is all better than Lapatinib.
Claims (5)
1. structure is such as formula the compound shown in (IX):
Wherein, band * carbon atom is chiral carbon atom, exists with S configurational isomers.
2. compound according to claim 1, is characterized in that its structure is such as formula shown in (IX):
Wherein, band * carbon atom is chiral carbon atom, exists to be rich in S configurational isomers.
3. a medicinal compositions, said composition contains the compound as described in claim 1-2 any one for the treatment of effective dose and pharmaceutically acceptable carrier.
4. the compound as described in claim 1-2 any one or medicinal compositions as claimed in claim 3 regulate the purposes in the medicine of c-erbB-2 and/or EGF-R protein tyrosine kinase activity relative disease in preparation treatment.
5. purposes according to claim 4, is characterized in that described disease is malignant tumour or psoriasis.
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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. |