CN102344444B - Optically pure quinazoline compounds - Google Patents

Optically pure quinazoline compounds Download PDF

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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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compound
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quinazolin
furan
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CN102344444A (en
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岑均达
唐家邓
吴雪松
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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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

Optically pure quinazoline compound
Technical Field
The invention relates to an optically pure quinazoline compound, a medicinal composition containing a therapeutically effective amount of the compound, and application of the compound in preparing medicaments for treating and regulating diseases related to c-erbB-2 and/or EGF-R protein tyrosine kinase activity.
Background
Protein tyrosine kinases catalyze the phosphorylation of specific tyrosine residues in a variety of proteins involved in the regulation of cell growth and differentiation. Protein tyrosine kinases can be broadly classified as receptor (e.g., EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) or non-receptor (e.g., c-src, lck, zap70) kinases. Inappropriate or uncontrolled activation of many of these kinases has been shown, i.e. aberrant protein tyrosine kinase activity, for example due to overexpression or mutation, can lead to uncontrolled cellular production.
Abnormal activity of protein tyrosine kinases such as c-erbB-2, c-src, c-met, EGFr, PDGFr is associated with human malignancies. For example, increased EGFr activity has been associated with non-small cell lung cancer, bladder cancer, and head and neck cancer, and increased c-erbB-2 activity has been associated with cancers of the breast, ovary, stomach, and pancreas. Therefore, inhibition of protein tyrosine kinases should provide a treatment for the above-mentioned tumors.
Abnormal protein tyrosine kinase activity has also been implicated in various other diseases: such as psoriasis, fibrosis, atherosclerosis, restenosis, autoimmune diseases, allergy, asthma, etc., have been shown to be controlled by the action of certain receptor tyrosine kinases.
Chinese patent 99803887.3 discloses a series of compounds reported to have protein tyrosine kinase inhibitory activity; chinese patent 20081000815 also discloses a series of novel quinazoline compounds, but they were developed in racemic form and no optically pure isomers were studied.
Disclosure of Invention
The invention aims to provide an optically pure quinazoline compound shown in a general formula (I) and application thereof.
The invention also aims to provide a pharmaceutical composition containing an effective dose of the optically pure quinazoline compound shown in the general formula (I) and application of the pharmaceutical composition in treating diseases such as cancer, malignant tumor, psoriasis and the like;
the invention discloses a compound of general formula (I):
wherein
R1To representWherein Ar is furan or thiazole optionally substituted by 1 or 2 substituents selected from halogen atoms, C1-4Alkyl or C1-4An alkoxy group;
R2、R3independently of one another, from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, or cycloalkylalkyl;
y is optionally substituted by R4、R5Substituted phenyl or 1H-indazolyl; wherein R is4Selected from benzyl, halo-, dihalo-or trihalobenzyl, benzyloxy, halo-, dihalo-or trihalobenzyloxy; r5Selected from hydrogen, hydroxy, halogen atoms, C1-4Alkyl radical, C1-4Alkoxy, amino, cyano or trifluoromethyl;
with carbon atoms as chiral carbon atoms, in the form of (S) single enantiomers or enriched in (S) single enantiomers;
b is selected from tartaric acid, lactic acid, phosphoric acid, citric acid, acetic acid, trifluoroacetic acid, malic acid, nitric acid, hydrochloric acid, sulfuric acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid or p-toluenesulfonic acid.
In a preferred embodiment of the invention, Ar is selected from unsubstituted furan or thiazole, more preferably unsubstituted furan.
In a preferred embodiment of the invention, R2、R3Independently of one another, from hydrogen, C1-4Alkyl radical, C2-5Alkenyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl radical, C3-8Cycloalkyl, or C3-8cycloalkyl-C1-4An alkyl group.
In a preferred embodiment of the invention, R4Selected from benzyl, halo-benzyloxy, preferably halo-benzyl, halo-benzyloxy; r5Selected from hydrogen, halogen atoms, C1-4Alkyl or C1-4An alkoxy group.
In a preferred embodiment of the invention, the carbon atoms are present in the form of a single enantiomer (S) or in the form enriched in (S), preferably with a content of (S) configuration of > 90%.
In the scheme of the present invention, preferred compounds include p-toluenesulfonate salt of the following compounds:
(S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (amino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 92)
(S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (methylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 93)
(S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (ethylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 94)
(S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (propylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 95)
(S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (cyclopropylmethylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 96)
(S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (N, N-dimethylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 97)
(S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (N, N-diethylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 98)
(S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (N, N-dipropylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 99)
(S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (N-methyl, N-ethylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 100)
(S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (allylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 101)
(S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (propargylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 102)
(S) -N- (1- (3-fluorobenzyl) -1H-indazol-5-yl) -6- (5- (1- (amino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 144)
(S) -N- (1- (3-fluorobenzyl) -1H-indazol-5-yl) -6- (5- (1- (methylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 145)
(S) -N- (1- (3-fluorobenzyl) -1H-indazol-5-yl) -6- (5- (1- (ethylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 146)
(S) -N- (1- (3-fluorobenzyl) -1H-indazol-5-yl) -6- (5- (1- (propylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 147)
(S) -N- (1- (3-fluorobenzyl) -1H-indazol-5-yl) -6- (5- (1- (N, N-dimethylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 149)
(S) -N- (1- (3-fluorobenzyl) -1H-indazol-5-yl) -6- (5- (1- (cyclopropylmethylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 148)
(S) -N- (1- (3-fluorobenzyl) -1H-indazol-5-yl) -6- (5- (1- (allylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine; (Compound 153)
(S) -N- (1- (3-fluorobenzyl) -1H-indazol-5-yl) -6- (5- (1- (propargylamino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine. (Compound 154)
In the scheme of the invention, more preferred compounds are represented by formula (IX):
in the present invention:
"enriched in one enantiomer" means that the content of one enantiomer (S) configuration is more than or equal to 60%;
"alkyl" refers to a branched or straight chain saturated aliphatic hydrocarbon group; preferably a branched or straight chain saturated aliphatic alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, etc.;
"alkenyl" means a branched, straight chain or cyclic nonaromatic hydrocarbon group containing at least one carbon-carbon double bond, such as ethenyl, propenyl, allyl, butenyl, cyclohexene and the like;
"alkynyl" means a branched, straight chain or cyclic hydrocarbon group containing at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, 3-methylbutynyl, propargyl, and the like.
"cycloalkyl" means a cycloalkyl group containing a single ring of saturated aliphatic hydrocarbon groups, preferably 3 to 8 carbon atoms, such as cyclopropyl, methyl-cyclopropyl, 2-dimethyl-cyclobutyl, ethyl-cyclopentyl, cyclohexyl, etc.;
"alkoxy" means a group in which a straight-chain or branched alkyl group is bonded to an oxygen atom, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.;
"halogen atom" means fluorine, chlorine, bromine, iodine atom.
A process for preparing a compound of formula (I) comprising the steps of:
1) reacting the compound of the general formula (II) with tert-butyl sulfenamide to obtain a compound of the general formula (III);
2) reacting the compound of the general formula (III) with the compound of the general formula (IV) to obtain a compound of a general formula (V);
3) reacting the compound of the general formula (V) under an acidic condition to obtain a compound of a general formula (VI);
4) compounds of the general formula (VI) and reagents R2-L or R3-L to obtain a compound of formula (VII);
5) reacting a compound with a general formula (VII) with an oxidant to obtain a compound with a general formula (VIII);
6) reacting the compound of the general formula (VIII) with acid to obtain a compound of a general formula (I);
wherein,
R1、Y、Ar、R2、R3the carbon atoms and the acid are as defined in formula (I);
t is a sulfur atom or a sulfinyl group;
the tert-butyl sulfenamide is optically pure and exists in the form of (S) single enantiomer or enriched in the form of (S) single enantiomer;
l is a leaving group selected from a halogen atom or a sulfonyloxy group.
In the preparation of the compounds of the general formula (III), the reaction is carried out in the presence of a metal reagent. The metal agent includes tetraethoxy titanium, tetraisopropoxy titanium, etc., preferably tetraisopropoxy titanium; the reaction temperature is controlled at 0-100 deg.C, preferably 0-50 deg.C.
In the preparation of the compounds of the general formula (VI), the reaction is carried out under acidic conditions, the acid used being selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid or a mixture of the above acids, preferably hydrochloric acid.
In the preparation of the compounds of the general formula (I), the reaction of the sulfur atom or sulfinyl oxide to the sulfonyl group is well known to the person skilled in the art and the oxidizing agent used is chosen from: m-chloroperoxybenzoic acid, peracetic acid, hydrogen peroxide, oxone, and the like, but oxone is preferable.
Another process for preparing compounds of formula (I) comprises the steps of:
1) reacting the compound of the general formula (II) with tert-butyl sulfenamide to obtain a compound of the general formula (III);
2) reacting a compound in a general formula (III) with a compound in a general formula (A) to obtain a compound in a general formula (B);
3) reacting the compound of the general formula (B) under an acidic condition to obtain a compound of a general formula (C);
4) compounds of the general formula (C) and reagents R2-L or R3-L to obtain a compound of formula (VIII);
5) reacting the compound of the general formula (VIII) with acid to obtain a compound of a general formula (I);
wherein,
R1y, Ar, the carbon atom with the mark is defined by the general formula (I);
tert-butylsulfinamide, L is as defined above;
m is an alkali metal ion or a halo-alkaline earth metal ion selected from Li+、Na+、K+、[MgCl]+Or [ MgBr ]]+。
In the preparation of the compounds of formula (I), L represents a leaving group well known to those skilled in the art, such as a halogen atom (e.g. fluorine, chlorine, bromine, iodine atom), preferably bromine, iodine atom; sulfonyloxy (e.g., methanesulfonyloxy, p-toluenesulfonyloxy), etc.;
in the preparation of the compound of the general formula (C), the reaction is carried out under acidic conditions, and the acid used is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid or a mixed acid of the above acids, preferably hydrochloric acid.
The step 4) of the reaction is carried out under alkaline conditions, and the base is selected from inorganic bases (such as sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like) or organic bases (such as ethylamine, triethylamine, diisopropylethylamine and the like).
It is still another object of the present invention to provide a pharmaceutical composition comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.
The invention also provides the use of a compound of formula (I) or a pharmaceutical composition containing the compound in the preparation of a medicament for treating diseases related to the regulation of c-erbB-2 and/or EGF-R protein tyrosine kinase activity.
It is a further object of the present invention to provide the use of a compound of formula (I) or a pharmaceutical composition comprising the compound in the preparation of a medicament for the treatment of cancer and malignancies.
It is a further object of the present invention to provide the use of a compound of formula (I) or a pharmaceutical composition comprising the compound in the manufacture of a medicament for the treatment of psoriasis.
The compound provided by the invention has excellent in-vitro anti-tumor activity, curative effect and pharmacokinetic property.
The pharmaceutical formulations of the present invention may be presented in unit dosage form containing a predetermined amount of the active ingredient per unit dose. Such units may contain, for example, 0.5mg to 1g, the particular amount depending on the disease to be treated, the route of administration and the age, weight, condition of the patient, among other factors.
The pharmaceutical formulations may be administered by any suitable route, for example orally, rectally, nasally, topically or parenterally (including subcutaneously, intramuscularly, intravenously or transdermally). The various formulations described above may be prepared by any method known in the art of pharmacy, for example, by mixing the active ingredient with a carrier or excipient.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be administered alone or in combination with other therapeutic agents for the treatment of the above-mentioned diseases. In particular, in the treatment of tumors, combination with other chemotherapeutic agents, hormones or antibody drugs is contemplated.
Detailed Description
In order to illustrate the present invention in more detail, the following examples are given. The scope of the invention is not limited thereto.
Enantiomeric excess values (e.e) in the following examples refer to the relative amounts of each enantiomer. This value is defined as the difference between the relative percentages of the two enantiomers. Thus, for example, when the percentage content of the (R) enantiomer is 90%, (S) enantiomer is 10%, (R) enantiomeric excess is 80%, i.e. the e.e value is: 80 percent.
The composition of the enantiomers of each compound was determined by chiral HPLC under the following conditions:
column: AD column from DAICEL;
mobile phase: n-hexane-ethanol-diethylamine (50: 0.1).
PREPARATION EXAMPLE 1 preparation of N- (4- (3-Fluorobenzyloxy) -3-chlorophenyl) -6-iodoquinazolin-4-amine
6-iodo-3H-quinazolin-4-one (100g) was added to a 2000mL flask, dissolved in a mixed solvent of thionyl chloride (1000mL) and N, N-dimethylformamide (20mL), and heated under reflux until the reaction solution was clear and transparent. Thionyl chloride was evaporated and taken up twice with toluene for further use.
The intermediate was dissolved in isopropanol (2000ml) and 3-chloro-4- (3-fluoro-benzyloxy) -aniline hydrochloride (70g) was added and anhydrous K was added with mechanical stirring2CO3(150g) And heated to reflux overnight. Cooling the reaction solution to room temperature the next day, filtering under reduced pressure, pulping the filter cake with water to remove K2CO3To neutrality, suction filtered under reduced pressure, dried in vacuo to give the title product: 95g, off-white solid.
m/z(M+1)+：506。
Preparation example 2 preparation of N- (1- (3-fluorobenzyl) -1H-indazol-5-yl) -6-iodoquinazolin-4-amine
The procedure is as in preparation 1, except that 3-chloro-4- (3-fluoro-benzyloxy) -aniline hydrochloride is changed to 1- (3-fluorobenzyl) -1H-indazol-5-amine hydrochloride.
m/z(M+1)+：496。
Preparation example preparation 35- (4- (4- (3-fluorobenzyloxy) -3-chlorophenylamino) quinazolin-6-yl) furan-2-al
The compound of preparation example 1 (50g), 5-boronic acid-2-furfural (21g), Pd (PPh)3)2Cl2(6.2g), triethylamine (62ml) and methanol (1000ml) were put into a reaction flask and reacted under reflux for 2 hours. Cooling to room temperature, filtering, washing the filter cake with a small amount of methanol, and then drying at 50 ℃ to obtain the title compound: 40g of yellow solid.
m/z(M+1)+：473。
Preparation example 45 preparation of 4- (1- (3-fluorobenzyl) -1H-indazol-5-ylamino) quinazolin-6-yl) furan-2-al
The procedure is as in preparation 3, except that the starting material is changed from the compound of preparation 1 to the compound of preparation 2. M/z (M +1)+：464。
Preparation 52- (4- (4- (3-fluorobenzyloxy) -3-chlorophenylamino) quinazolin-6-yl) thiazol-5-al preparation
The compound of preparation 1 (50g), 2-boronic acid-5-thiazolealdehyde (21g), Pd (PPh)3)2Cl2(6.2g), triethylamine (62ml) and methanol (1000ml) were put into a reaction flask and reacted under reflux for 2 hours. Cooling to room temperature, filtering, washing the filter cake with a small amount of methanol, and then drying at 50 ℃ to obtain the title compound: 30 g.
m/z(M+1)+：490。
Preparation example preparation of 62- (4- (1- (3-fluorobenzyl) -1H-indazol-5-ylamino) quinazolin-6-yl) thiazol-5-al
The procedure was as in preparation 5, except that the starting material was changed from the compound of preparation 1 to the compound of preparation 2.
m/z(M+1)+：480。
Example one
Preparation of (S) -N- ((5- (4- (4- (3-fluorobenzyloxy) -3-chlorophenylamino) quinazolin-6-yl) furan-2-yl) methylene) -2-methylpropane-2-sulfinamide
The compound of preparation 3 (47.3g, 0.1mol), S-tert-butylsulfinamide (14.5g, 0.12mol), titanium tetraisopropoxide (85g, 0.3mol) and anhydrous THF (1000ml) were put into a reaction flask and reacted at room temperature overnight. The next day, treatment: water (50ml) and ethyl acetate (500ml) were added, stirred for 10min, filtered and the filter cake washed 3 times with THF. The filtrate was dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate under reduced pressure gave the title compound: 50 g. M/z (M +1)+：577。
Example two
Preparation of (R) -N- ((5- (4- (4- (3-fluorobenzyloxy) -3-chlorophenylamino) quinazolin-6-yl) furan-2-yl) methylene) -2-methylpropane-2-sulfinamide
The preparation method is the same as that of the first example, except that the reaction raw material is changed from S-tertiary butyl sulfinamide to R-tertiary butyl sulfinamide. M/z (M +1)+：577。
EXAMPLE III
Preparation of (S) -N- ((2- (4- (4- (3-fluorobenzyloxy) -3-chlorophenylamino) quinazolin-6-yl) thiazol-5-yl) methylene) -2-methylpropane-2-sulfinamide
The preparation method is the same as the first example, except that the reaction raw material is changed from the compound of the preparation example 3 to the compound of the preparation example 5. M/z (M +1)+：594。
Example four
Preparation of (R) -N- ((2- (4- (4- (3-fluorobenzyloxy) -3-chlorophenylamino) quinazolin-6-yl) thiazol-5-yl) methylene) -2-methylpropane-2-sulfinamide
The preparation method is the same as that of example III, except that the reaction raw material is changed from S-tertiary butyl sulfinamide to R-tertiary butyl sulfinamide. M/z (M +1)+：594。
EXAMPLE five
Preparation of (S) -N- ((5- (4- (1- (3-fluorobenzyl) -1H-indazol-5-ylamino) quinazolin-6-yl) furan-2-yl) methylene) -2-methylpropane-2-sulfinamide
The preparation method is the same as the first example, except that the reaction raw material is changed from the compound of the preparation example 3 to the compound of the preparation example 4. M/z (M +1)+：567。
EXAMPLE six
Preparation of (R) -N- ((5- (4- (1- (3-fluorobenzyl) -1H-indazol-5-ylamino) quinazolin-6-yl) furan-2-yl) methylene) -2-methylpropane-2-sulfinamide
The preparation method is the same as example two, except that the reaction raw material is changed from the compound of preparation 3 to the compound of preparation 4. M/z (M +1)+：567。
EXAMPLE seven
Preparation of (S) -N- ((2- (4- (1- (3-fluorobenzyl) -1H-indazol-5-ylamino) quinazolin-6-yl) thiazol-5-yl) methylene) -2-methylpropane-2-sulfinamide
The preparation method is the same as the first example, except that the reaction raw material is changed from the compound of the preparation example 3 to the compound of the preparation example 6. M/z (M +1)+：584。
Example eight
Preparation of (R) -N- ((2- (4- (1- (3-fluorobenzyl) -1H-indazol-5-ylamino) quinazolin-6-yl) thiazol-5-yl) methylene) -2-methylpropane-2-sulfinamide
The preparation method is the same as the first example, except that the reaction raw material is changed from the compound of the preparation example 3 to the compound of the preparation example 6. M/z (M +1)+：584。
Example nine
Preparation of (S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (amino) -2- (methylthio) ethyl) furan-2-yl) quinazolin-4-amine
A methylthiomethyl magnesium chloride/THF solution (0.3mol) was charged into a reaction flask, the reaction solution was cooled to-80 ℃ or lower, and the temperature was maintained for 5min, and a solution of the compound of example (57.6g, 0.1mol) and anhydrous THF (200ml) was rapidly added thereto, and the internal temperature was maintained at-80 ℃ or lower. Stirring for 10min under heat preservation, and processing. The reaction mixture was poured into saturated saline (3000ml), ethyl acetate (2000ml) was added thereto, the layers were separated, and the organic layer was washed with saturated saline (2000ml) and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 50g of a yellow solid.
The yellow solid obtained in the above step was dissolved in THF (1000ml), adjusted to pH 1 with HCl-ethanol, stirred at room temperature for 2 hours, and worked up. The pH was adjusted to 9 with concentrated aqueous ammonia, and saturated brine (2000ml) and ethyl acetate (1500ml) were added to separate the layers, and the organic layer was dried over anhydrous magnesium sulfate. Filtration, concentration of the filtrate under reduced pressure, chromatography of the residue on a silica gel column (eluent: ethyl acetate-ethyl acetate/THF-10/1), collection of the qualified fractions, and concentration to give the title compound: 30g, numbered Compound 1. M/z (M +1)+：535。
Example ten
Preparation of (S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (methylamino) -2- (methylthio) ethyl) furan-2-yl) quinazolin-4-amine
The method A comprises the following steps: the compound (2.0g) obtained in example nine, methyl iodide (0.5g) and triethylamine (0.7g) were dissolved in THF (150ml), and the mixture was heated to reflux for 2 hours. After the heating was stopped, saturated brine was added to the reaction mixture, followed by extraction with ethyl acetate, and the organic phase was washed twice with saturated brine and dried over anhydrous magnesium sulfate. Filtration, concentration of the filtrate under reduced pressure and column chromatography purification of the residue (chloroform/methanol 100: 1) gave title compound 1.5g, numbered compound 2.
The method B comprises the following steps: the compound of example nine (5.4g) was dissolved in DMSO (50ml), and formaldehyde (6ml) and formic acid (3ml) were added to stir the reaction at room temperature overnight. The reaction solution was flushed into ice water (500ml), filtered, drained, the filter cake was dissolved in THF, silica gel was made into sand, and column chromatography was performed to purify the title compound: 4.2g, numbered Compound 2. M/z (M +1)+：549。
The following compounds were prepared by the method of example ten starting with the compound obtained in example nine and reacting with the reactants:
EXAMPLE eleven
Preparation of (S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (amino) -2- (methylthio) ethyl) thiazol-2-yl) quinazolin-4-amine
The preparation method is the same as that of the ninth embodiment, except that the reaction raw materials are changed from the compound in the first embodiment to the compound in the third embodiment, and the method is compiledCompound No. 14. M/z (M +1)+：552。
The following compounds were prepared by the method of example ten starting with the compound of example eleven and reacting with the reactants:
example twelve
Preparation of (S) -N- (1- (3-fluorobenzyl) -1H-indazol-5-yl) -6- (5- (1- (amino) -2- (methylthio) ethyl) furan-2-yl) quinazolin-4-amine
The preparation method is the same as that of example nine, except that the reaction raw material is changed from the compound in example one to the compound in example five, and the number is compound 27. M/z (M +1)+：525。
The following compounds were prepared by the method of example ten starting with the compound of example twelve as the starting material and reacting with the reactants:
EXAMPLE thirteen
Preparation of (R) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (amino) -2- (methylthio) ethyl) furan-2-yl) quinazolin-4-amine
The preparation method is the same as that of the ninth embodiment, except that the reaction raw materials are changed from the compound in the embodiment to the compound in the embodiment, and the number of the reaction raw materials is the compound 40. M/z (M +1)+：535。
The following compounds were prepared by the method of example ten starting with the compound obtained in example thirteen and reacting with the reactants:
example fourteen
Preparation of (R) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (amino) -2- (methylthio) ethyl) thiazol-2-yl) quinazolin-4-amine
The preparation method is the same as that of the ninth example, except that the reaction raw material is changed from the compound in the first example to the compound in the fourth example, which is numbered as compound 53. M/z (M +1)+：552。
The following compounds were prepared by the method of example ten starting from the compound of example fourteen and reacting with the reactants:
example fifteen
Preparation of (S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (amino) -2- (methylsulfinyl) ethyl) furan-2-yl) quinazolin-4-amine
Dimethyl sulfoxide (0.4mol) was dissolved in anhydrous THF (2000ml), cooled to-20 ℃ under nitrogen protection, and n-BuLi (0.3mol) was added dropwise. After dripping, stirring for 30min under heat preservation. The reaction was cooled to below-80 ℃ and the temperature was maintained for 5min, a solution of the compound of example (57.6g, 0.1mol) and anhydrous THF (200ml) was added rapidly, and the internal temperature was maintained below-80 ℃. Stirring for 10min under heat preservation, and processing. The reaction mixture was poured into 3000ml of saturated saline solution, 2000ml of ethyl acetate was added thereto, the mixture was separated, and the organic layer was washed with 2000ml of saturated saline solution and dried over anhydrous magnesium sulfate. The filtrate was filtered and concentrated under reduced pressure to give 42g of a yellow solid.
The yellow solid obtained in the above step was dissolved in THF (1000ml), adjusted to pH 1 with HCl-ethanol, stirred at room temperature for 2 hours, and worked up. The pH was adjusted to 9 with concentrated aqueous ammonia, and saturated brine (2000ml) and ethyl acetate (1500ml) were added to separate the layers, and the organic layer was dried over anhydrous magnesium sulfate. Filtration, concentration of the filtrate under reduced pressure, chromatography of the residue on a silica gel column (eluent: ethyl acetate-ethyl acetate/THF-5/1), collection of the qualified fractions, and concentration to give the title compound: 20g, numbered Compound 66. M/z (M +1)+：551。
Example sixteen
Preparation of (S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (methylamino) -2- (methylsulfinyl) ethyl) furan-2-yl) quinazolin-4-amine
The preparation method is the same as that in the tenth example, except that the reaction raw material is changed from the compound in the seventh example to the compound in the fifteenth example, which is numbered as compound 67. M/z (M +1)+：566。
The following compounds were prepared by the method of example ten starting with the compound obtained in example fifteen and reacting with the reactants:
example seventeen
Preparation of (R) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (amino) -2- (methylsulfinyl) ethyl) furan-2-yl) quinazolin-4-amine
The preparation method is the same as that of example fifteen, except that the reaction raw material is changed from the compound in example one to the compound in example two, and the compound is numbered 79. M/z (M +1)+：551。
The following compounds were prepared by the method of example ten starting with the compound obtained in example seventeen and reacting with the reactants:
EXAMPLE eighteen
Preparation of (S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (amino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine
The method A comprises the following steps: dimethyl sulfone (37.6g, 0.4mol) was dissolved in anhydrous THF (2000ml), cooled to-20 ℃ under nitrogen and n-BuLi (0.3mol) was added dropwise. After dripping, stirring for 30min under heat preservation. The reaction was cooled to below-80 ℃ and the temperature was maintained for 5min, a solution of the compound of example (57.6g, 0.1mol) and anhydrous THF (200ml) was added rapidly, and the internal temperature was maintained below-80 ℃. Stirring for 10min under heat preservation, and processing. The reaction mixture was poured into 3000ml of saturated saline solution, 2000ml of ethyl acetate was added thereto, the mixture was separated, and the organic layer was washed with 2000ml of saturated saline solution and dried over anhydrous magnesium sulfate. The filtrate was filtered and concentrated under reduced pressure to give 42g of a yellow solid.
The yellow solid obtained in the above step was dissolved in THF (1000ml), adjusted to pH 1 with HCl-ethanol, stirred at room temperature for 2 hours, and worked up. The pH was adjusted to 9 with concentrated aqueous ammonia, and saturated brine (2000ml) and ethyl acetate (1500ml) were added to separate the layers, and the organic layer was dried over anhydrous magnesium sulfate. Filtration, concentration of the filtrate under reduced pressure, chromatography of the residue on a silica gel column (eluent: ethyl acetate-ethyl acetate/THF-5/1), collection of the qualified fractions, and concentration to give the title compound: 20g, numbered Compound 92.
The method B comprises the following steps: 50g of each of the compounds obtained in example nine or example fifteen and a mixed solvent of methanol/water (7: 3, 1000ml) were put into a reaction flask, and after dissolution, oxone (100g) was added in portions, and after completion of the addition, the reaction was continued with stirring at room temperature for 2 hours. Filtering, washing the filter cake with mixed solution of methanol/water, and filtering with saturated bicarbonateThe pH of the sodium solution was adjusted to 8, the mixture was concentrated under reduced pressure, ethyl acetate (500ml × 2) was added to the concentrated solution to extract the mixture, and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure to dryness and purification by column chromatography (eluent: chloroform/methanol 100: 1) gave the title compound: 40g of yellow solid. M/z (M +1)+: 567. a first step of mixing; e.e value: 95.2% [ (S): 97.6%, (R): 2.4 percent of]。
The following compounds were prepared by the method of example ten starting with the compound obtained in example eighteen and reacting with the reactants:
example nineteen
Preparation of (R) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (amino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine
The method A comprises the following steps: the method A is the same as the eighteen embodiment except that the starting material is changed from the compound in the embodiment into the compound in the embodiment with the number of 105; m/z (M +1)+: 567. a first step of mixing; e.e value: 95.8% [ (R): 97.9%, (S): 2.1 percent of]。
The method B comprises the following steps: the difference from the eighteen embodiment and the eighteen embodiment is that the starting materials are changed from the nine and fifteen embodiments compounds to the thirteen or seventeen embodiment compounds.
The following compounds were prepared by the method of example ten starting with the compound obtained in example nineteen and reacting with the reactants:
example twenty
Preparation of (S) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (amino) -2- (methylsulfonyl) ethyl) thiazol-2-yl) quinazolin-4-amine
The preparation method is the same as the eighteen method A in the example, except that the reaction raw material is changed from the compound in the example one to the compound in the example three, and the number is the compound 118.
m/z(M+1)+: 584; e.e value: 91.4% [ (S): 95.7%, (R): 4.3 percent of]。
The following compounds were prepared by the method of example ten starting with the compound of example twenty and reacting with the reactants:
example twenty one
Preparation of (R) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- (1- (amino) -2- (methylsulfonyl) ethyl) thiazol-2-yl) quinazolin-4-amine
The preparation method is the same as the eighteen method A in the example, except that the reaction raw material is changed from the compound in the example one to the compound in the example four, which is numbered as the compound 131.
m/z(M+1)+: 584; e.e value: 92.2% [ (R): 96.1%, (S): 3.9 percent]。
The following compounds were prepared by the method of example ten starting with the compound of example twenty-one and reacting with the reactants:
example twenty two
Preparation of (S) -N- (1- (3-fluorobenzyl) -1H-indazol-5-yl) -6- (5- (1- (amino) -2- (methylsulfonyl) ethyl) furan-2-yl) quinazolin-4-amine
The method A comprises the following steps: the preparation method is the same as the eighteen embodiment method A, except that the reaction raw material is changed from the compound in the embodiment one to the compound in the embodiment five, and the number is the compound 144.
m/z(M+1)+: 557; e.e value: 93.0% [ (S): 96.5%, (R): 3.5 percent]。
The method B comprises the following steps: the preparation method is the same as the method A of the embodiment except that the reaction raw materials are changed from the nine compounds and the fifteen compounds of the embodiment into the twelve compounds of the embodiment.
The following compounds were prepared by the method of example ten, starting with the compound of example twenty-two, and reacting with the reactants:
example twenty three
Preparation of the Compound of formula (IX)
Compound 97(931.3g, 1.56mol), THF (14L) was added to the flask, p-toluenesulfonic acid monohydrate (754.0g, 3.96mol) was added with stirring, and the mixture was stirred at room temperature overnight. Filtration and forced air drying (60 ℃, 6h) gave the compound of formula (IX) (yellow solid, 1370.2g) in 147.2% yield and an e.e value of 95.2.
1HNMR(DMSO-D6，400M)：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 1
Evaluation of antitumor Activity in vitro
The test method comprises the following steps: SRB
Cell lines: a431; MCF-7
And (3) experimental design: incubating cells with compounds with different concentrations for 72 hours, evaluating the inhibition degree of the compounds on cell proliferation by adopting an SRB method, calculating the inhibition rate, and calculating IC by adopting a Logit method according to the inhibition rate50In vitro antitumor activity of the compounds was compared.
The inhibition rate calculation method comprises the following steps: the inhibition ratio (%) is (control group OD value-use group OD value)/control group OD value x 100%
The test results are shown in Table 1.
TABLE 1
Test example two
Pharmacokinetic testing of Compounds of formula (IX)
Pharmacological studies in beagle dogs and rats have shown that the oral absorption of the compound of formula (IX) may be increased by an increase in dosage. After entering the body, the two active metabolites D1 and D2 can be metabolized. This metabolic activation is different from the positive drug lapatinib.
After the gastric lavage of rats, the plasma peak time of the drug with the lot number of 20090219 in the rats is about 1.33-5.50 h, which is prolonged along with the increase of the dose. The half-life period of plasma elimination is 1.32-2.72 h, and dose dependence is avoided. Plasma concentrations of metabolites D1 and D2 were much higher than the prototype drug in each gavage dose group, while plasma concentrations of metabolites were 80% of the prototype drug in the intravenous group, suggesting that the two N-dealkylated metabolites are mainly produced by first pass metabolism. The AUC0-t value increase of the drug and metabolites D1, D2 of lot No. 20090219 was much higher than the dose increase rate in the dose range of 10-90 mg/kg. After continuous gavage administration of rats, the prototype drug and metabolite do not accumulate in the body of rats obviously. The drug and metabolites D1, D2 of lot 20090219 exhibited higher plasma exposure in female rats than in male rats (P0.05). After dose correction, the absolute bioavailability after a single gavage administration of 10, 30 and 90mg/kg of the compound of formula (IX) in rats was 6.02%, 23.3% and 67.0%, respectively, calculated as the mean of the sum of AUC0-t for the pro-drug and the metabolites D1, D2.
After oral administration of beagle dogs, the mean plasma peak time of the drug with the batch number of 20090219 in vivo is about 1.17-1.42 h, and the plasma elimination half-life period is 0.89-2.01 h. Plasma concentrations of metabolites D1 and D2 were higher than the prototype drug, while plasma concentrations of the metabolites were 22% of the prototype drug in the intravenously administered group, indicating that the two metabolites are mainly produced by first pass metabolism. The pharmacokinetic properties of the 20090219 lot drug and metabolites D1 and D2 in beagle dogs show larger individual differences, and the AUC0-t value is slightly higher than the dose increase ratio within the dose range of 8.0-32 mg/kg. After dose correction, the absolute bioavailability of 8.0, 16 and 32mg/kg of the aforementioned lot 20090219 drug administered by single gavage in beagle dogs was 6.43%, 12.1% and 14.6%, respectively, as calculated from the average of the sum of AUC0-t of the prototype drug and metabolites D1, D2.
The drug of lot 20090219, D1 and D2, had a binding rate of about 97.5% to 98.5% to canine plasma protein and a binding rate of 98.1% to 98.4% to rat plasma protein.
After the drug with the lot number of 20090219 is administered to rats by gavage, the tissues mainly distributed by the drug with the lot number of 20090219 comprise tissues such as digestive tract, adrenal gland, lung, liver and the like; the metabolites D1 and D2 were mainly distributed in the liver, kidney, lung, adrenal gland and spleen, and in most tissues, the metabolite concentration was higher than the original drug concentration. The drug and metabolite of lot 20090219 penetrated the blood brain barrier to a very low degree. After intragastric administration of the drug of lot 20090219, the concentrations of the pro-drug and the metabolite in the tumor tissue were higher than the respective concentrations in plasma in tumor-bearing mice, and the increase in AUC of the pro-drug and the metabolite in plasma was substantially proportional to the dose increase.
The major metabolic pathways of the drug of lot 20090219 in rat and in the human, monkey, dog, rat and mouse liver microsome hatching system were N-demethyl, N-demethyl and 3-fluorobenzyl, and were mainly catalyzed by CYP1A 2, 2C19, 2D6, 2E1, 3A4 and 3A 5.
After intragastric administration, the drug of lot 20090219 was excreted from the feces mainly as a crude drug and metabolite. The total excretion of the orthodox drugs and metabolites in the feces accounts for 54.2 percent of the administration dosage, and the total excretion in the urine sample is less than 0.1 percent of the administration dosage; the total excretion amount in bile is 1.17% of the administration dosage within 0-24 h.
The drug of lot 20090219 had no significant inhibitory effect on the major CYP450 enzymes, and no significant induction effect on the activity of rat CYP1A, CYP2C, CYP2D and CYP 3A. Corresponding CLint values were derived from metabolic stability tests of the drug of lot 20090219 in liver microsome incubation systems of various genera, indicating that the compound of formula (IX) is a high clearance drug in humans, monkeys, dogs, rats and mice.
Test example 3
The curative effect of the compound of formula (IX) on human lung cancer Calu-3 nude mouse transplantation tumor
Purpose of experiment
The efficacy of the compound of formula (IX), Lapatinib (Lapatinib), on human lung carcinoma Calu-3 nude mouse transplantable tumors was evaluated and compared.
Test drug
Drug name and lot number: compound of formula (IX) (HER-036 for short), light yellow powder, content 99.5%, batch No.: 20090201, respectively; lapatinib ditosylate, Lapatinib ditosylate for short, khaki powder, lot number: 20090105.
providing a unit: jiangsu Haofen pharmaceuticals, Inc.
The preparation method comprises the following steps: HER-036 and Lapatinib are prepared into required concentrations by using distilled water containing 0.1 percent of Tween-80.
Laboratory animal
BALB/cA-nude mice, 6-7 weeks old, purchased from Shanghai Spiker laboratory animals, Inc. Certificate number: SCXK (Shanghai) 2007 & 0005. A breeding environment: SPF grade.
Experimental procedure
Inoculating human lung cancer Calu-3 cells subcutaneously to nude mice until tumor grows to 60-150mm3Thereafter, the animals were randomly assigned (d 0). The dosage and schedule of administration are shown in table 2. Tumor volumes were measured 2-3 times a week, mice weighed, and data recorded. Tumor volume (V) was calculated as: v is 1/2 × a × b2, where a and b represent length and width, respectively.
Conclusion
HER-036 and Lapatinib both obviously inhibit the growth of human lung cancer Calu-3; compared with the tumor inhibition rate and the tumor regression rate, the curative effect of HER-036 on Calu-3 is better than that of Lapatinib.

Claims (5)

1. A compound having the structure of formula (IX):
wherein, the carbon atom with the star is chiral carbon atom and exists in the form of S configuration isomer.
2. The compound of claim 1, having the structure of formula (IX):
wherein, the carbon atom with the star is chiral carbon atom and exists in the form of S-enriched isomer.
3. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-2 and a pharmaceutically acceptable carrier.
4. Use of a compound according to any one of claims 1 to 2 or a pharmaceutical composition according to claim 3 in the manufacture of a medicament for the treatment of a disease associated with modulation of c-erbB-2 and/or EGF-R protein tyrosine kinase activity.
5. Use according to claim 4, characterized in that the disease is a malignancy or psoriasis.
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