WO2008015794A1 - Boronated quinazoline derivative - Google Patents

Abstract

Disclosed is a compound having an inhibitory activity against a tyrosine kinase such as EGFR and VEGFR2 and therefore is useful as an anti-tumor agent. Specifically, disclosed is a boronated quinazoline derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof. (1) wherein R1 and R2 independently represent a hydrogen atom, an alkoxy group, -O-(CH2)n-OCH3 (n represents an integer ranging from 1 to 10), –X-B-(OR6)(OR7) or the like; R3 and R4 independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group or a halogen atom; R5 represents a hydrogen atom or –B(OR8)(OR9); and D represents -O- or –NH-, provided that, when R5 represents a hydrogen atom, at least one of R1 and R2 represents –B(OR6)(OR7), and when R5 represents –B(OR8)(OR9), R5 binds in a meta- or para-position relative to a linking group D.

Description

 Specification

 Boron-containing quinazoline derivatives

 Technical field

 [0001] The present invention relates to a novel quinazoline derivative, and more particularly to a boron-containing quinazoline derivative useful as an antitumor agent.

 Background art

 [0002] The expression level and frequency of the epidermal growth factor receptor (EG FR), a member of the receptor tyrosine kinase family, are higher in tumor cells than in normal cells. Head and neck cancer, breast cancer, colon cancer, It is known to be overexpressed in many solid cancers such as prostate cancer, kidney cancer, uterine cancer, ovarian cancer, and bladder cancer, and these are often closely related to the prognosis of cancer. (Non-Patent Document 1). Proliferation signal transduction activated by ligand binding to EG FR is known to be deeply involved in tumor immortalization, angiogenesis, invasion, and metastasis. Is considered as one of the new target molecules in cancer treatment. For example, a compound having 4-anilinoquinazoline as a mother nucleus is known to have an EG FR inhibitory action and a tumor growth inhibitory action (Non-Patent Document 2, etc.).

[0003] On the other hand, in order for cancer to increase, cancer neovascularization that carries oxygen and nutrients is necessary. First, growth hormones such as vascular endothelial growth factor (VEG F) and basic fibroblast growth factor (b FG F) are produced from cancer cells, and the stimulated vascular endothelium is the matrix meta-proteal membrane. ZE (MMPs) produces urokinase-type plasminogen activator (uPA), which degrades the basement membrane lining the blood vessels. Vascular endothelial cells that have migrated to the stroma form lumens and build new blood vessels. This new blood vessel replenishes cancer cells with oxygen and nutrients and promotes cancer invasion. V EG F is known not only to be a powerful vascular endothelial migration factor, but also to be involved in endothelial cell proliferation and lumen formation (Non-patent Document 3), VEG F receptor (VEG FR) The search for drugs targeting the drug is also underway (Non-Patent Document 4) ~ 5 etc.).

 [0004] Drugs targeting these receptors are being actively searched, and development of drugs having high selectivity and excellent effects is awaited.

 Non-Patent Document 1: I n v e s t. N e w D rug s, 1 7, 259—269, 1 999

 Non-Patent Document 2: Bui I C anc cer, 87 (1 2), 873— 876, 2 000

 Non-Patent Document 3: J. C el I B i o l., 1 29, 895— 898, 1 99 5

 Non-Patent Document 4: J. Me d. C hem., 45, 1 300- 1 3 1 2, 200 2

 Non-Patent Document 5: J. Me d. C hem., 48, 1 359-1 366, 200 5

 Disclosure of the invention

 Problems to be solved by the invention

 [0005] An object of the present invention is to provide an antitumor agent having a high selectivity and a tyrosine kinase inhibitory ability.

 Means for solving the problem

 [0006] Thus, the present inventors have synthesized various compounds and searched for the inhibition of tyrosine kinase activity as an index. As a result, the boron-containing quinazoline derivative represented by the following formula (1) has excellent tyrosine kinase activity. It was found that it has an inhibitory action and is useful as an antitumor agent, and the present invention was completed.

That is, the present invention provides the following formula (1)

[0008] [Chemical 1]

[0009] [式中、 R¹および R²はそれぞれ独立して水素原子、 アルコキシ基、 _0 (CH₂) _n-OCH₃ ( nは 1〜 1 0の整数を示す） 、

[Wherein, R ¹ and R ² are each independently a hydrogen atom, an alkoxy group, _0 (CH ₂ ) _n —OCH ₃ (n represents an integer of 1 to 10),

[0010] [Chemical 2]

 [0011] (m represents an integer of 1 to 1 0)

[0012] [Chemical 3]

-0— (CH ₂ ) _p --Ν Ο

 \ _ /

 [0013] (ρ represents an integer of 1 to 10)

Or _X_B_ (OR ⁶ ) (OR ⁷ ) (where X is a single bond, _OCH ₂ _,-

OCH ₂ CH = CH_ or

[0014] [Chemical 4]

[0015] R ⁶ and R ⁷ represent a hydrogen atom, or OR ⁶ and OR ⁷ are connected to each other, and a boron-containing heterocyclic group which may have a substituent together with an adjacent boron atom Forming);

R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group or a halogen atom;

R ⁵ represents a hydrogen atom or —B (OR ⁸ ) (OR ⁹ ) (wherein R ⁸ and R ⁹ each independently represent a hydrogen atom or an alkyl group, or OR ⁸ and OR ⁹ And a boron-containing heterocyclic group which may have a substituent together with an adjacent boron atom is formed, and D represents —O— or —N H —. Provided that when R ⁵ represents a hydrogen atom, R ¹ or R ² is an alkoxy group, _0_ (CH ₂ ) _n _OCH ₃ (n is as defined above),

[0016] [Chemical 5] [0017] (m is the same as defined above)

[0018] [Chemical 6]

 [0019] (p is as defined above)

Or B_ (OR ⁶ ) (OR ⁷ ) (wherein R ⁶ and R 7 are the same as defined above). When R ⁵ represents _B (OH) ₂ and D represents _NH—, neither R ¹ nor R ² represents a methoxy group.

When R ⁵ represents a hydrogen atom, at least one of R ¹ and R ² represents -B (OR ⁶ ) (OR ⁷ ), and R ⁵ represents _ B (OR ⁸ ) (OR ⁹ ) Is attached to the linking group D at the meta or para position.

]

 Or a pharmaceutically acceptable salt thereof.

[0020] Further, the present invention provides the following formula (1a),

[0021] [Chemical 7]

[Wherein R ¹ and R ² are each independently a hydrogen atom, an alkoxy group, _0_

(CH ₂ ) _n -OCH ₃ (n represents an integer of 1 to 10),

[0023] [Chemical 8]

[0024] (m represents an integer of 1 to 10) [0025] [Chemical 9]

[0026] (p represents an integer of 1 to 1 0)

Or _X_B_ (OR ⁶ ) (OR ⁷ ) (where X is a single bond, _OCH ₂ _,-

OCH ₂ CH = CH_ or

[0027] [Chemical 10]

[0028] R ⁶ and R ^{7 each} represents a hydrogen atom, or OR ⁶ and OR ⁷ are connected to each other, and a boron-containing heterocyclic group which may have a substituent together with an adjacent boron atom Form)

R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group or a halogen atom,

R ⁵ represents a hydrogen atom or —B (OR ⁸ ) (OR ⁹ ) (wherein R ⁸ and R ⁹ each independently represent a hydrogen atom or an alkyl group, or OR ⁸ and OR ⁹ And a boron-containing heterocyclic group which may have a substituent together with the adjacent boron atom, and D represents —O— or —N H —. However, when R ⁵ represents a hydrogen atom, ¹ or ² is _ 乂 '-B- (OR ⁶ ) (OR ⁷ ) (where X' is _OCH ₂ _, _OCH ₂ CH = CH_ or

[0029] [Chemical 11]

[0030] R ⁶ and R ⁷ are the same as defined above.

When R ⁵ represents a hydrogen atom, at least one of R ¹ and R ² represents -B (OR ⁶ ) (OR ⁷ ), and R ⁵ represents _B (OR ⁸ ) (OR ⁹ ) When it is shown, it shall be bonded to the linking group D at the meta position or the para position.

] And a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

 [0031] Further, the present invention provides the above formula (1a),

 [0032] The present invention provides an antitumor agent comprising a boron-containing quinazoline derivative represented by the formula: or a pharmaceutically acceptable salt thereof as an active ingredient.

[0033] The present invention also provides the use of a boron-containing quinazoline derivative represented by the above formula (1a) or a pharmaceutically acceptable salt thereof for the production of an antitumor agent. .

 [0034] Further, the present invention provides a method for treating a tumor, characterized by administering an effective amount of a boron-containing quinazoline derivative represented by the above formula (1a) or a pharmaceutically acceptable salt thereof. To do.

 The invention's effect

 [0035] The boron-containing quinazoline derivative of the present invention or a pharmaceutically acceptable salt thereof has an excellent tyrosine kinase activity inhibitory action and is useful as an antitumor agent against various cancers.

 BEST MODE FOR CARRYING OUT THE INVENTION

 [0036] The boron-containing quinazoline derivative according to the present invention is represented by the formula (1) or (1a).

The alkoxy group represented by R \ RR ³ and R ^4, main butoxy group, an ethoxy group, n- propoxy group, i - propoxy group, n- butoxy group, i _ butoxy group, t _ butoxy group, n _ Penchiruokishi Group, an alkoxy group having 1 to 10 carbon atoms such as n_hexyloxy group, n_heptyloxy group and the like, more preferably an alkoxy group having 1 to 5 carbon atoms. Examples of the halogen atom represented by R ³ and R ⁴ include a fluorine atom, a chlorine atom, and a bromine atom. Examples of the alkyl group represented by R ³ , RR ⁸ and R ⁹ include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n_butyl group, an i_butyl group, a t_butyl group, and an n_pentyl group. Group, n_hexyl group, n_heptyl group, etc. An alkyl group having ˜10, and more preferably an alkyl group having 1 to 5 carbon atoms. Examples of the haloalkyl group represented by R ³ or R ⁴ include a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a trifluoromethyl group, a 1, 1, 1-tolufluoroethyl group, etc. And more preferably a haloalkyl group having a fluorine atom.

In addition, examples of the heterocyclic group that can be formed together with an adjacent boron atom when OR ⁶ and OR ⁷ or OR ⁸ and OR ⁹ are connected to each other include the following.

[0038] [Chemical 12]

[0039] On these rings may have 1-4 alkyl groups of 1-5 carbon atoms, hydroxyl groups, hydroxy one C ₁ _C ₅ substituent such as an alkyl group. Here, preferable examples of the substituent include 1 to 4 methyl, ethyl, n-propyl, i-propyl, hydroxyl, hydroxymethyl, and hydroxyethyl groups.

 [0040] n represents an integer of 1 to 10, more preferably 1 to 6, and particularly preferably 1 to 4. m represents an integer of 1 to 10, preferably 1 to 6, particularly 1 to 4. p represents an integer of 1 to 10, more preferably 1 to 6, and particularly preferably 1 to 4. D is particularly preferably NH. X is particularly preferably a single bond.

[0041] Formula (1) or in (1 a), R ¹ and R ² is a hydrogen atom, an alkoxy _{group, -0- (CH 2) n -OCH} 3 (n is as defined above),

[0042] [Chemical 13]

 [0043] (m is the same as defined above)

 Or

[0044] [Chemical 14]

 [0045] (p is as defined above)

Wherein ⁵ is _ が (OR ⁸ ) (OR ⁹ ).

At this time, one B (OR ⁸ ) (OR ⁹ ) which is R ⁵ is bonded to the linking group D at the meta position or the para position, and particularly preferably bonded at the para position. When R ⁵ is _B (OR ⁸ ) (OR ⁹ ), R ¹ and R ² are both alkoxy groups having 1 to 5 carbon atoms or _0_ (CH ₂ ) _n _0_CH ₃ (η ′ is 1 to 4 represents an integer). Further, at this time, R ⁵ is particularly preferably _B (OH) ₂ .

[0046] In the formula (1), at least one of R ¹ and R ² is _B_ (OR ⁶ ) (OR ⁷ ) (wherein R ⁶ and R 7 are the same as defined above), and R ³ And a compound in which at least one of R ⁴ is a halogen atom is preferred.

[0047] R ¹ is one B_ (OR ⁶ ) (OR ⁷ ) (wherein R ⁶ and R 7 are the same as defined above), R ² is an alkoxy group, _0_ (CH ₂ ) _n -OCH ₃ (n is as defined above),

[0048] [Chemical 15]

 [0049] (m is as defined above)

 Or

[0050] [Chemical 16]

— Ο— (CH ₂ ) 厂 Ν ^

[0051] (ρ is as defined above)

 Also preferred are compounds that are

 [0052] In the above formula (1) or (1a), 4_ (6,7_bis (2-methoxyethoxy) quinazoline_4-ylamino) phenylboric acid, and pharmaceutically acceptable thereof Particularly preferred are salts.

 [0053] The pharmaceutically acceptable salt of the compound of the formula (1) or (1a) is not particularly limited, and examples thereof include hydrochloride, hydrobromide, sulfate, phosphate, and acetate. Acid addition salts such as tartrate, gluconate, lactate, malate, oxalate, maleate, fumarate, citrate, benzoate, benzenesulfonate, methanesulfonate; Metal salts such as sodium salt, strong salt, magnesium salt, calcium salt, aluminum salt and zinc salt; ammonium salt such as ammonium salt and tetramethylammonium salt; organic amine addition such as morpholine salt and piperidine salt Salt; lysine salt, glycine salt, phenylalanine salt, aspartate, glutamate and other amino acid salts.

 [0054] The boron-containing quinazoline derivative (1) or (1a) of the present invention can be produced, for example, by the following method.

[0055]

[Chemical 17]

 Manufacturing method 1

 In the solvent such as isopropyl alcohol, ethanol, butyl alcohol, dioxane, tetrahydrofuran, dimethylformamide, etc. By reacting with an aniline derivative represented by the formula (3) for about 5 minutes to 72 hours at a temperature of about C, an anilinoquinazoline derivative represented by the formula (4) is obtained.

 Next, in the presence of an inert gas, in a solvent such as dioxane, tetrahydrofuran, dimethylformamide, and acetonitrile, a palladium complex alone, or a zerovalent palladium complex such as tetrakistriphenylphosphine palladium, dibenzyldenacetone palladium, or Divalent palladium salts such as palladium chloride and palladium acetate and phosphine ligands (triphenylphosphine, tricyclohexylphosphine, tributylphosphine, diphenylphosphinophlocene, diphenylphosphinoethane, diphenylphosphinopropane, diphf Together with a catalyst such as in combination with enilphosphinobutane, etc.

1) An anilinoquinazoline borate ester compound represented by the formula (6) by reacting with a diplonone ester represented by the formula (5) at a temperature of about 50 ° C. for about 5 minutes to 72 hours. Get. [0058] Next, in the presence of a solvent such as methanol, ethanol, propanol, isopropyl alcohol, butyl alcohol, dioxane, tetrahydrofuran or dimethylformamide, an aqueous solution of potassium hydrogen fluoride or an acid such as acetic acid, hydrochloric acid, sulfuric acid or nitric acid is added. In addition, the reaction is carried out at a temperature of about 10-50 ° C for about 5 minutes to 72 hours. By adding a boric acid compound such as phenylboric acid, isobutyl boric acid, and aryl boric acid to this, and reacting at a temperature of about 10 to 50 ° C for about 5 minutes to 72 hours, it is expressed by the formula (7). Can be obtained. At this time, if necessary, by using an alkane solvent such as pentane, hexane, heptane, and octane, the boric acid ester compound produced by the transesterification reaction is extracted and removed, so that The compound represented can be obtained.

 [0059] It should be noted that 4 _ black mouth 6 _ single quinazoline represented by the formula (2) is the one described in B ioor g. Med. Chem. Lett., 1 3, 637, 2003 Can be synthesized by the method.

 [0060] [Chemical 18]

 Production method 2

(12) (13) In the above reaction formula, R ^{2 to} R ⁷ are the same as defined above.

 The 6-acetoxy 4_chloroquinazoline derivative represented by the formula (8) is dissolved in a solvent such as isopropyl alcohol, ethanol, butyl alcohol, dioxane, tetrahydrofuran, dimethylformamide, _10 to 50 ° C. By reacting with an aniline derivative represented by the formula (3) at a temperature of about 5 minutes to 72 hours, an anilinoquinazoline derivative represented by the formula (9) is obtained.

 [0062] Next, this was dissolved in a solvent such as methanol, ethanol, butyl alcohol, dioxane, tetrahydrofuran, dimethylformamide, ammonia water, sodium metoxide, sodium metoxide, sodium hydroxide aqueous solution, hydroxy acid. It is expressed by the formula (1 0) by reacting with a basic substance such as an aqueous solution of rhodium or an acidic substance such as hydrochloric acid or sulfuric acid at a temperature of about 0 to 1550 ° C. for about 5 minutes to 72 hours. 6-hydroxy dilinoquinazoline derivative is obtained.

 [0063] Next, in the presence of an inert gas, together with a base such as pyridine, triethylamine, sodium carbonate, sodium hydrogen carbonate, dimethylaminopyridine, 2,6-lutidine, etc., _50 to 100 ° C Reaction with anhydrous triflate at a temperature of about 5 minutes to 72 hours to obtain an anilinoquinazoline triflate compound represented by the formula (1 1).

[0064] Next, in the presence of an inert gas, in a solvent such as dioxane, tetrahydrofuran, dimethylformamide, and acetonitrile, the palladium complex alone, or tetravalent triphenylphosphine palladium, dibenzyldenaceton palladium, etc. Palladium complexes or divalent palladium salts such as palladium chloride and palladium acetate and phosphine ligands (triphenylphosphine, tricyclohexylphosphine, tributylphosphine, diphenylphosphinophenocene, diphenylphosphinoethane, diphenylphosphinopro Together with a catalyst such as a combination with bread, diphenylphosphinobutane, etc., at a temperature of about 0 to 150 ° C. for about 5 minutes to about 72 hours with a dipolone ester represented by the formula (5) And expressed by the formula (1 2) An aniline quinazoline borate compound is obtained. [0065] Next, in the presence of a solvent such as methanol, ethanol, propanol, isopropyl alcohol, butyl alcohol, dioxane, tetrahydrofuran, dimethylformamide, potassium hydrogen fluoride aqueous solution, or acetic acid, hydrochloric acid, sulfuric acid, nitric acid, etc. Add acid and react at _10 ~ 50 ° C for 5 minutes to 72 hours. To this, a boric acid compound such as phenylboric acid, isobutylboric acid, and arylboronic acid is added and reacted at a temperature of about -10 to 50 ° C. for about 5 minutes to 72 hours. Can be obtained. At this time, if necessary, by using an alkane solvent such as pentane, hexane, heptane, and octane, the boric acid ester compound produced by the transesterification reaction is extracted and removed, so that the formula (1 3 ) Can be obtained.

 [0066] It should be noted that the 6-acetoxy 4-chloroquinazoline derivative represented by the formula (8) is represented by B ioor g. Med. C hem. Lett., 1 1, 1 9 1 1, 200 1 It can be synthesized by the method described or a method analogous thereto.

[0067]

[Chemical 19]

上記反応式中、 R¹、 R²、 R R⁹は前記定義と同じである, 式 （1 4) で表される 4 _クロ口キナゾリン誘導体を、 イソプロピルアル コール、 エタノール、 ブチルアルコール、 ジォキサン、 テトラヒドロフラン 、 ジメチルホルムアミ ド等の溶媒中、 0〜 1 50°C程度の温度で、 5分間〜 72時間程度、 式 （1 5) で表されるァニリンのホウ酸エステル化合物と反 応させて、 式 （1 6) で表されるァニリノキナゾリンのホウ酸エステル化合 物を得る。

In the above reaction formula, R ¹ , R ² and RR ⁹ are the same as defined above, The 4-chloroquinazoline derivative represented by the formula (14) is dissolved in a solvent such as isopropyl alcohol, ethanol, butyl alcohol, dioxane, tetrahydrofuran, dimethylformamide at a temperature of about 0 to 150 ° C. By reacting with the boric acid ester compound of aniline represented by the formula (15) for about 5 minutes to 72 hours, the boric acid ester compound of anilinoquinazoline represented by the formula (16) is obtained.

 [0069] Next, in the presence of a solvent such as methanol, ethanol, propanol, isopropyl alcohol, butyl alcohol, dioxane, tetrahydrofuran, dimethylformamide, potassium hydrogen fluoride aqueous solution, or acetic acid, hydrochloric acid, sulfuric acid, nitric acid, etc. A compound represented by the formula (17) can be obtained by adding an acid and reacting at a temperature of about 10 to 50 ° C. for about 5 minutes to 72 hours.

 [0070] In addition, a 4_cloquinoquinoline derivative represented by the formula (14) is mixed with a solvent such as isopropyl alcohol, ethanol, butyl alcohol, dioxane, tetrahydrofuran, dimethylformamide, potassium carbonate, sodium carbonate, Sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, potassium tert —Butoxide, sodium hydride, hydrogenated hydrogen, calcium hydride and other catalysts at a temperature of about 0 to 150 ° C for about 5 minutes to 72 hours The compound represented by the formula (19) can be obtained by reacting with 3-hydroxyphenylboric acid represented by the formula (18).

 [0071] Further, the 4-chloroquinazoline derivative represented by the formula (14) is mixed with a solvent such as isopropyl alcohol, ethanol, butyl alcohol, dioxane, tetrahydrofuran, dimethylformamide, concentrated hydrochloric acid, concentrated sulfuric acid, It is reacted with 3-aminophenylboric acid represented by the formula (20) at a temperature of about _50 to 100 ° C for about 5 minutes to 72 hours with a catalyst such as concentrated nitric acid, and the formula (2 1 ) Can be obtained.

In addition, the 4_black quinazoline derivative represented by the formula (1 4) is a method described in T etrahedron Letters, 47, 2539, 2006 or Can be synthesized by a method analogous thereto.

 [Chemical 20]

 Manufacturing method 4

 (twenty two)

 (twenty four)

 [0073] In the formula, n is as defined above.

 The 4_black quinazoline derivative represented by the formula (22) is mixed with a catalyst such as concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid in a solvent such as isopropyl alcohol, ethanol, butyl alcohol, dioxane, tetrahydrofuran, and dimethylformamide. At the same time, the compound represented by the formula (24) is reacted with the aminophenylboric acid represented by the formula (23) at a temperature of about _50 to 100 ° C for about 5 minutes to 72 hours. Obtainable.

 [0074] Further, at this time, the 4_black quinazoline derivative represented by the formula (22) is reacted with the boric acid ester compound of aniline represented by the formula (15) to obtain boric acid of anilinoquinazoline. An ester compound can be obtained, and a compound represented by the formula (24) can be derived in the same manner as in the production method 3 described above.

 [0075] The 4-chloroquinazoline derivative represented by the formula (22) can be synthesized by the method described in Tetrafandrontter., 47, 2539, 2006 or a method analogous thereto.

 [0076] In each of the above production methods, the intermediate of the reaction and the target compound of the present invention are separated and purified commonly used in the field of synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, It can be isolated and purified by using various means such as chromatography. The intermediate can be subjected to the next reaction without isolation and purification.

[0077] Among the compounds of the present invention, there may exist stereoisomers such as positional isomers, geometric isomers, optical isomers, tautomers, etc., but the present invention includes all these isomers. And mixtures thereof.

 [0078] When obtaining a salt of the compound of the present invention, it may be purified as it is when the compound is obtained in the form of a salt, and when obtained in a free form, the compound is dissolved or dissolved in an appropriate solvent. It can be isolated and purified by forming a salt by suspending and adding acid or base.

 [0079] The compound of the formula (1) or (1a) and a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents. Included in the compound.

 [0080] The compound of the formula (1) or (1a) or a pharmaceutically acceptable salt thereof according to the present invention is useful for the treatment of a disease mediated by a receptor tyrosine kinase. Examples of related diseases include malignant tumors, specifically non-solid tumors such as leukemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain / CNS, breast, colorectal, intrauterine Solid tumors typified by cancer such as membrane, stomach, head and neck, liver, lung, nerve cell, esophagus, ovary, kidney, prostate, kidney, skin, testis, thyroid, uterus, vagina.

 [0081] The compound of the formula (1) or (1a) according to the present invention or a pharmaceutically acceptable salt thereof can be administered as it is, but it is usually used as various pharmaceutical preparations for animals. It is desirable to provide it for use in particular for humans. Such a pharmaceutical preparation is prepared by mixing a compound represented by the formula (1) or (1a) or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers. As a product, it is manufactured by a conventional method.

 [0082] As the administration route, it is preferable to use one that is most effective in the treatment, and examples thereof include oral administration and parenteral administration such as intravenous administration.

 [0083] Examples of the dosage form include tablets, injections and the like.

 For oral administration, for example, tablets can be manufactured using excipients such as lactose, disintegrants such as Zenpun, lubricants such as magnesium stearate, binders such as hydroxypropyl methylcellulose, and the like. .

For parenteral administration, for example, in the case of injections, salt solution, glucose solution It can be produced using a mixed solution of saline and glucose solution.

 The dose and frequency of administration of the compound of formula (1) or (1a) or a pharmaceutically acceptable salt thereof will vary depending on the mode of administration, patient age, body weight, nature or severity of the condition to be treated, etc. However, in the case of oral administration, it is administered once or several times a day in the range of 0.01-1, 00 Omg, preferably 0.05-500 mg per adult per adult. In the case of parenteral administration such as intravenous administration, usually 0.00 1 to 1, 000 Omg, preferably 0.0 1 to 300 mg per adult is administered once to several times a day.

 Example

 Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples as long as the gist thereof is not exceeded.

[0085] [Chemical 21]

 6a

 6b

 [0086] (Synthesis Example 1) Synthesis of 4-anilino-6_monoquinazoline 4a

 4—Black mouth 6-yodoquinazoline (5.44 g, 18.8 mmol, G au I, M,. D. et. A and B ioor g. Med. C he m. L ett. The compound reported in 2003, 1 3, 637 was dissolved in isopropyl alcohol (15 OmL), 3-chloroaniline (2.01 mL, 19 Ommo I) was added and stirred. After 24 hours, the precipitated solid was filtered and washed with isopropyl alcohol. The obtained solid was dried with a vacuum pump to obtain dilinoquinazoline 4a (4.93 g, 12.9 mm o I, 69%).

[0087] (3_black) 1 (6--doquinazoline 1__) Amine (4 a).

H-NMR (400 MHz; CD ₃ OD) δ: 8. 9 9 (s, 1 H), 8. 7 7 (s, 1 H), 8. 3 2 (d, J = 9.2 H z, 1 H), 7.8 0 (s, 1 H), 7.5 4-7. 5 8 (m, 2 H), 7. 3 9 (t, J = 8. OH z, 1 H ), 7. 2 9 (d, J = 8. 0 H z, 1 H)

[0088] (Synthesis Example 2) Synthesis of 4-anilino 6_-doquinazoline 4b

 Anthropinoquinazoline 4 _Chromatic mouth _ 6 _Chodoquinazoline (6 4 3 mg, 2.20 mm ol), 3-Black mouth 4-Fluoroa dilin (3 0 6 mg, 2.1 mm o I) and isopropyl alcohol (20 mL) were used to obtain anilinoquinazoline 4 b (76 3 mg, 1.9 1 mm o I, 87%) .

 [0089] (3 _ black mouth 4 _ fluorophenyl) 1 (6-yodoquinazoline _ 4-yl) Amine (4 b).

¹ H _ NMR (300 MHz; CD ₃ OD) δ: 8.95 (d, J = 3. OH z, 1 H), 8. 74 (s, 1 H), 8. 30 (dd, J = 3.0 Hz, 9.0 Hz, 1 H), 7.90 (dd, J = 3.0 Hz, 6.0 Hz, 1 H), 7.57 -7. 6 2 (m, 1 H), 7.5 5 (d, J = 9. OH z, 1 H), 7. 2 8 (t, J = 9. OH z, 1 H)

[Synthesis Example 3] Synthesis of borate ester 5a

Under an argon atmosphere, anilinoquinazoline 4a (45Omg, 1.18mmoI), bispinacolatodipolone (33,1mg, 1.3OmmoI), palladium chloride (21mg) , O. 1 2 mm o I), diphenylphosphinophenocene (6 6 mg, 0.12 mm o I), potassium acetate (3 4 7 mg, 3.5 4 mm o I) in dimethylform The mixture was stirred at 80 ° C. in amide (20 mL). After 2 hours, the mixture was allowed to stand at room temperature, water was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. Remove the residue obtained by removing the solvent. Purification by layer chromatography (hexane: ethyl acetate = 4: 1) gave boric acid ester 5a (144 mg, 0.38 mm o I, 32%).

[0091] (3—Black mouth phenyl) One [6— (4,4,5,5-Tetramethylone [1,3,2] Dioxapoloranone 2 _yl) Quinazoline 1 4 _il] Amine (5 a).

^{1 H _ NMR (3 0 0} MH z; CDCI 3) (5: 8. 8 2 (s, 1 Η), 8. 3 4 (s, 1 Η), 8. 2 0 (dd, J = 3. Ο Η ζ, 6. Ο Η ζ, 1 Η), 7. 9 9 (t, J = 3. Ο Η ζ, 1 Η), 7. 90 (d, J = 6. Ο Η ζ, 1 Η ), 7. 6 2-7. 6 5 (m, 2 Η), 7. 3 5 (t, J = 6. OH ζ, 1 Η), 7. 16 (dd, J = 3. Ο Ο ζ , 6. Ο ζ ζ, 1 Η), 1.4 1 (s, 1 2 Η)

[Synthesis Example 4] Synthesis of borate ester 5b

 An anilinoquinazoline 4b (4 1 1 mg, 1.0 3 mm ol), bispinacola todipolone (2 8 9 mg, 1.1 4 mm o I), Palladium chloride (18 mg, 0.10 mm ol), diphenylphosphinophenol (55 mg, O.1 Ommo I), acetic acid rhodium (300 mg, 3.15) Boric acid ester 5b (17 4 mg, 0.44 mm o I, 4 2%) was obtained using mm o I) and dimethylformamide (2 O mL).

 [0093] (3-Chrono-one 4-Fluorophenyl) One [6- (4, 4, 5, 5, 5-Tetramethylone [1,3,2] Dioxapoloran 2-I) Quinazoline _4- Amin (5 b).

¹ H _ NMR (4 00 MHz; CDCI ₃ ) (5: 8. 80 (s, 1 Η), 8. 3 3 (s, 1 Η), 8. 20 (d, J = 8. 4 Η ζ, 1 Η), 8. 0 1 (dd, J = 2.4 Η ζ, 6. Ο Η ζ, 1 Η), 7. 90 (d, J = 8.4 ζ ζ, 1 Η ), 7.5 6-7. 6 1 (m, 2 Η), 7.20 (t, J = 8.8 ζ ζ, 1 Η), 1.4 1 (s, 1 2 Η)

 [Synthesis Example 5] Synthesis of boric acid compound 6a

 Boric acid ester 5 a (1 4 4 mg, 0. 3 8 mm o I) dissolved in methanol (1 O ml) and potassium hydrogen fluoride (2 0 6 mg, 2. 6 4 mm o I) in water ( 1 O m L) was added. 1 After stirring for 2 hours, the solvent was removed with a mouth-to-mouth evaporator. Phenylboric acid (1 39 mg, 1.14 mmol), acetonitrile and hexane were added, and the mixture was stirred for 1 hour, and then the hexane layer was removed. The remaining acetonitrile layer was removed with a single evaporator and purified by thin layer chromatography (dichloromethane: methanol = 20: 1). Compound 6a (54 mg, 0.18 mm o I 7%).

 [0095] 4-(3_Black mouth phenylamino) Quinazoline _ 6-ylpolonic acid (6a)

¹ H _ NMR (300 MHz; CD ₃ OD) δ: 8. 6 2 (s, 1 Η), 8.4 9 (s, 1 Η), 8.0 6 (d, J = 9. Ο ζ ζ, 1 Η), 7. 8 9 (s, 1 Η), 7.5 9-7. 66 6 (m, 2 Η), 7. 2 7 (t, J = 9. OH ζ, 1 Η), 7. 0 7 (d, J = 9.0 Η ζ, 1 Η)

MS (ESI) m / z 3 0 0 ([C _{1 4} H ₉ CIN ₃ B (OH) ₂ + H] +), 3 1 4 ((C _{1 4} H ₉ CIN a B (OH) (OM e) + H] +)

[Synthesis Example 6] Synthesis of boric acid compound 6b

 In the same manner as the synthesis of boric acid compound 6a, boric acid ester 5b (35 mg, 0.09 mm o I), methanol (3 mL), hydrofluoric acid rhodium (48 mg, 0. 6 1 mm ol), water (3 mL), phenylboric acid (3 2 mg, 0.26 mm o I) and boric acid compound 6 b (9 mg, 0.0 3 mm o I, 3 2 %).

 [0097] 4-(3-black mouth 4 _ fluorophenylamino) quinazoline _ 6-ylboronic acid (6 b).

H-NMR (400 MHz; CD ₃ OD) δ: 8.85 (s, 1 H), 8.68 (s, 1 H), 8.30 (d, J = 8.4) H z, 1 H), 7. 8 2 (d d, J = 2.4 H z, 6.8 H z, 1 H), 7.70 (d, J = 8.4 H z, 1 H), 7. 53-7. 57 (m, 1 H ), 7. 25 (t, J = 8.8 H z, 1 H)

MS (ES I) m / z 31 8 ([C ₁₄ H ₉ CI FN ₃ B (OH) ₂ + H] +), 332 ([C ₁₄ H ₉ CIFN a B (OH) (OMe) + H] + )

[Chemical 22]

(Synthesis Example 7) Synthesis of triflate 7a

 6-acetoxy _ 4 _ black mouth _ 7- methoxyquinazoline (504 mg, 1 99 mmol, Barker, A. J. eta I. B ioor g. Med. C chem. L ett. 2001, 1 1, 1 91 1.) 3_chloroaniline (0.23 m 2. 19 mm o I) was heated to reflux in isopropyl alcohol (15 mL) for 2 hours. After leaving to room temperature, the precipitated solid was filtered and washed with isopropyl alcohol.

 The obtained solid was dissolved in methanol (1 OmL), 25% aqueous ammonia (2 mL) was added, and the mixture was stirred at room temperature for 8 hr. The solvent was removed with a mouth-to-mouth evaporator, dichloromethane was added and filtered, and the resulting solid was dried with a vacuum pump.

Under an argon atmosphere, pyridine (5 mL) was added to the solid, cooled to 0 ° C. with an ice bath, and anhydrous triflate was gradually added. After returning to room temperature and stirring for 7 hours, the solvent was removed with a mouth-tallow evaporator and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1) to obtain compound 7a (1 33 mg, 0. 3 1 mm o I, 3 steps 15%).

[0100] Trifluoromethanesulfonic acid 4 _ (3-chloro-phenylamino) _ 7 _ methoxyquinazoline _ 6-yl ester (7 a).

H-NMR (400 MHz; CDCI ₃ ) δ: 8. 7 7 (s, 1 H), 7.

8 9 (s, 1 H), 7. 7 3 (s, 1 H), 7.5 5 (d, J = 8.4 H z, 1 H), 7. 4 2 (s, 1 H), 7. 3 6 (t, J = 8.4 H z, 1 H)

, 7. 1 9 (d, J = 9.2 H z, 1 H), 4.0 7 (s, 3 H)

 [0101] (Synthesis Example 8) Synthesis of triflate 7b

 6-acetoxy _ 4 _ black mouth _ 7-methoxyquinazoline (4 8 8 mg, 1.9 3 mm ol), 3 _ n n_ 4 — Fluoroarin (30 mg, 2.1 2 mm o I), isopropyl alcohol (28 mL), 25% aqueous ammonia (2 mL), methanol (1 O mL), Finally, triflate 7 b (5 7 5 mg, 1.2 7 mm o I, 6 by pyridine (1 O mL), anhydrous triflate (0.64 mL, 3.86 mmol) 6%).

 [0102] Trifluoromethanesulfonic acid 4 _ (3-chloro-phenyl 4-fluorophenylamino) _ 7-methoxyquinazoline _ 6-yl ester (7 b).

1 H _ NMR (4 00 MHz; CDCI ₃ ) (5: 8. 7 4 (s, 1 Η), 7.

9 0 (d d, J = 2.8 Η, 6.4 Η ζ, 1 Η), 7. 7 3 (s, 1 Η)

, 7. 4 9-7.5 3 (m, 1 Η), 7. 4 2 (s, 1 Η), 7. 2 1 (t, J = 8.8 ζ ζ, 1 Η), 4.0 7 (s, 3 Η)

Example 1 Synthesis of borate ester 8a

Borate ester 5a In the same manner, triflate 7a (4Omg, O.09mmoI), bispinacolatodipolone (35mg, O.14mmol), palladium chloride (2mg, O.O 1 mm o I), diphenylphosphinophene (6 mg, 0.01 mm o I), potassium acetate (2 7 mg, 0.28 mm o I), dimethylformamide ( 2 ml) using 8 a (22 mg, 0 0 5 mm o I, 5 8%).

[0104] (3—Clorophenyl) 1 [7-Methoxy 1-6— (4,4,5,5—Tetramethyl 1 [1,3,2] Dioxapoloran 2 _yl) Quinazoline _ 4— Le] Amin (8a).

H-NMR (400 MHz; CDCI ₃ ) δ: 8.73 (s, 1 H), 8.

3 2 (s, 1 H), 7. 9 2 (s, 1 H), 7. 8 5 (b s, 1 H), 7.

5 9 (d, J = 8. O H z, 1 H), 7. 30 (t, J = 8. O H z, 1 H

), 7. 1 9 (s, 1 H), 7. 1 1 (d, J = 7.6 H z, 1 H), 3.

9 5 (s, 3 H), 1.3 7 (s, 1 2 H)

Example 2 Synthesis of borate ester 8b

 Borate ester 5 a Triflate 7 b (2 5 2 mg, 0.5

6 mm o I), bispinacola todipolone (1700 mg, 0.67 mm o I

), Palladium chloride (11 mg, 0.06 mm o I), diphenylphosphinopherocene (33 mg, 0.06 mm o I), potassium acetate (165 mg

, 1.6 8 mm o I), 8 b (

5 1 mg, 0.12 mm o I, 2 1%).

[0106] (3—Black mouth 4—Fluorophenyl) One [7—Methoxy 1—— (4,4,

5, 5-tetramethyl 1 [1, 3, 2] dioxapololane 2 _ yl) quinazoline _ 4 _ yl] ammine (8 b).

¹ H _ NMR (4 00 MHz; CDCI ₃ ) (5: 8. 70 (s, 1 Η), 8. 25 (s, 1 Η), 7. 9 3 (dd, J = 2. 8 Η ζ, 6.4 Η ζ, 1 Η), 7.59 (bs, 1 Η), 7.5 3-7.57 (m, 1 Η), 7. 1 9 (s, 1 Η ), 7. 1 6 (t, J = 8.4 Η ζ, 1 Η), 3. 96 (s, 3 Η), 1, 3 8 (s, 1 2 Η)

 M S (ESI) m / z 4 3 0 ([M + H] +)

(Example 3) Synthesis of boric acid compound 9a

Boric acid compound 6 a In the same manner, boric acid ester 8 a (2 2 mg, 0. 0 5 mm o I), methanol zole (2 mL), KHF ₂ (29 mg, 0.37 mm o I), water (2 mL), phenylboric acid (26 mg, 0.21 mmol) (8 mg, 0.02 mm o I, 48%) was obtained.

[0108] 4- (3_Phenolamino) _ 7-Methoxyquinazoline_ 6-Illporonate (9 a).

H-NMR (400 MHz; CD ₃ OD) δ: 8. 41 (s, 1 H), 8. 20 (bs, 1 H), 7. 85 (t, J = 2.0 H z, 1 H) , 7. 56 (dq, J = 0.8 Hz, 8.0 Hz, 1 H), 7.24 (t, J = 8. OH z, 1 H), 7.04 (s, 1 H ), 7. 04 (dq, J = 0.8 Hz, 8.0 Hz, 1 H), 3.89 (s, 3 H)

MS (ES I) m / z 330 ([C ₁₅ H "CIN ₃ OB (OH) ₂ + H] +), 344 ([C ₁₅ H" CIN ₃ OB (OH) (OMe) + H] +)

 Example 4 Synthesis of boric acid compound 9b

Boric acid compound 6a In the same manner, boric acid ester 8b (4 Omg, 0.09mm o I), methanol zole (2mL), KHF ₂ (51mg, 0.65mm o I), water ( 9 b (13 mg, 0.04 mmo I, 41%) was obtained using phenylboric acid (33 mg, 0.27 mm o I).

 [0110] 4-(3_Black and 4-fluorophenylamino) _7-Methoxyquinazoline-6-ylpolonic acid (9 b).

¹ H_NMR (400 MHz; CD ₃ OD) δ: 8. 39 (s, 1 Η), 8. 18 (bs, 1 Η), 7. 90-7. 92 (m, 1 Η), 7. 54 -7. 5 8 (m, 1 Η), 7. 14 (t, J = 8.8 ζ ζ, 1 Η), 7. 04 (s, 1 Η), 3. 89 (s, 3 Η)

MS (ES I) m / z 348 ([C ₁₅ H ₁₀ CI FN ₃ OB (OH) ₂ + H] +), 362 ([C ₁₅ H ₁₀ CI FN ₃ OB (OH) (OMe) + H] + )

[0111] [Chemical 23]

 [Synthesis Example 9] Synthesis of boric acid compound 1a

 4_black mouth 6, 7-dimethoxyquinazoline (97 mg, 0.43 mm o IN ak am ura, H. et. A I. T etrahedron Letters. 2006, 47, 2539) After dissolving in isopropyl alcohol (3 mL), 3-aminophenylboric acid monohydrate (74 mg, 0.48 mmol) and concentrated hydrochloric acid (0.1 mL) were added, and the mixture was stirred at room temperature. After 6 hours, the precipitated solid was filtered and washed with isopropyl alcohol. The obtained solid was dried with a vacuum pump to obtain the hydrochloride of ananilinoquinazoline 1a (15 Omg, 0.41 mmoI, 96%). 1 a hydrochloride (55 mg, 0.15 mmo I) was stirred in aqueous sodium bicarbonate solution, the solid was filtered and washed with water. The obtained solid was dried with a vacuum pump to obtain 1 a (46 mg, 0.14 mmo I, 95%).

[0113] 3-(6,7-Dimethoxyquinazoline 4_Illamino) phenylpolonic acid

 (1 a).

¹ H_NMR (400 MHz; CD ₃ OD) δ: 8. 28 (s, 1 Η), 7. 83 (s, 1 Η), 7. 66 (m, 2 Η), 7. 39 (br, 1 Η ), 7. 3 1 (t, J = 3.6 Η ζ), 7. 05 (s, 1 Η), 3.93 (s, 3 Η), 3.90 (s, 3 Η)

MS (ES I) m / z 326 ([C ₁₆ H ₁₄ N ₃ 0 ₂ B (OH) ₂ + H] +), 340 ((C ₁₆ H ₁₄ N ₃ 0 ₂ B (OH) (OM e) + H] +)

[0114] [Chemical 24]

 [0115] (Synthesis Example 1 0) Synthesis of borate ester 2

 4_ (6,7-Dimethoxyquinazoline (1 78 mg, 0.79 mm o I) dissolved in isopropyl alcohol (12 mL), 4_ (4, 4, 5, 5—tetramethyl 1, 3, 3, 2-Dioxapoloran-2-yl) aniline (1 73 mg, 0.79 mmo I) was added and heated to reflux. After 24 hours, the mixture was allowed to stand at room temperature, and then the isopropyl alcohol was removed with a rotary evaporator, and the solid was washed with dichloromethane. The obtained solid was dried with a vacuum pump to obtain Compound 2 (256 mg, 0.5 Ommo I, 63%).

 [0116] (6,7-Dimethoxyquinazoline 1_yl) One [4— (4, 4, 5, 5-Tetramethyl 1 [1,3,2] Dioxapololaline 2_yl) Monophenyl] Ammin (2).

H-NMR (400 MHz; CDC I ₃ ) (5: 8.17 (s, 1 H), 8.10 (s, 1 H), 7.96 (d, J = 8.8 Hz, 2 H), 7.82 (d, J = 8.4, 2 H), 7. 18 (s, 1 H), 4.23 (s, 3 H), 3.79 (s, 3 H) , 1.35 (s, 1 2 H)

[0117] (Synthesis Example 1 1) Boric acid compound 1 b

Compound 2 (1 7 mg, 0.04 mmol) was dissolved in methanol (1.5 mL), and potassium hydrogen fluoride (16 mg, 0.4 Ommo I) aqueous solution (1.5 mL) was added. . After stirring for 30 minutes, the methanol was removed with a mouth-to-mouth evaporator, and acetonitrile and hexane were added and transferred to a separatory funnel to remove the hexane layer. The remaining acetonitrile layer was acidified by adding 6 N hydrochloric acid, and then the solvent was removed using a mouth-to-mouth evaporator. Saturated carbonic acid on the precipitated solid An aqueous sodium hydrogen solution was added and filtered, and the solid was washed with water. The obtained solid was dried with a vacuum pump to obtain 1 b (13 mg, 0.04 mm o I, quant).

 [0118] 4- (6,7-Dimethoxyquinazoline_4-ylamino) phenpololonic acid (1b).

H-NMR (400 MHz; CD ₃ OD) δ: 8. 34 (s, 1 H), 7. 62-7. 69 (m, 5 H), 7. 09 (s, 1 H), 3. 95 (s, 3 H), 3. 92 (s, 3 H)

MS (ES I) m / z 326 ((C ₁₆ H ₁₄ N ₃ 0 ₂ B (OH) ₂ + H] +), 340 ((C ₁₆ H ₁₄ N ₃ 0 ₂ B (OH) (OMe) + H ] +)

[0119] [Chemical 25]

[0120] (Example 5) Boric acid compound 1 0 a

 4_Black mouth 6, 7-Dimethoxyquinazoline (75 mg, 0.33 mm o I) dissolved in isopropyl alcohol (5 mL), 3-hydroxyphenyl boric acid (51 mg, 0.37 mmo I), carbonic acid Potassium (91 mg, 0.66 mmo I) was added and heated to reflux. After 6 hours, the mixture was allowed to stand at room temperature, and the precipitated solid was filtered and washed with water and isopropyl alcohol. The obtained solid was dried with a vacuum pump to obtain 10 a (88 mg, 0.27 mm o I, 82%).

 3- (6,7-Dimethoxyquinazoline_4_yloxy) phenylboric acid (1 0 a).

¹ H_NMR (400 MHz; CD ₃ OD) δ: 8. 39 (s, 1 Η), 7. 57 (s, 1 Η), 7. 41 -7. 63 (m, 3 Η), 7. 21- 7. 24 (m, 2 mm), 3.97 (s, 3 mm), 3.95 (s, 3 mm)

MS (ES I) m / z 327 ([C ₁₆ H ₁₃ N ₂ 0 ₃ B (OH) ₂ + H] +), 341 ([C ₁₆ H ₁₃ N ₂ 0 ₃ B (OH) (OMe) + H] +)

[0121] [Chemical 26]

 Example 6 Synthesis of boric acid compound 3a

 Anthropinoquinazoline 1a was synthesized in the same manner as the synthesis of 4a, 6,7-dimethoxy-toxyquinazoline (Nak amu ra, H. et. A and T etrahedron Lette r. 2006, 47, 2539 1 1 1 mg, 0.35 mmo I), 3-aminophenylboronic acid monohydrate (61 mg, 0.39 mmo I), isopropyl alcohol (3 mL), concentrated hydrochloric acid (0 1 mL) was used to obtain the hydrochloride of anilinoquinazoline 3a (1 41 mg, 90%). Ananilinoquinazoline 3a (49 mg, 0.11 mmo I) from which hydrochloric acid had been removed using 3 a hydrochloride (51 mg, 0.11 mmoI) was quantitatively obtained.

 [0123] 3- (6,7_Bis (2-methoxyxoxy) quinazoline_4-ylmonoamino) phenylpolonic acid (3a).

H-NMR (400 MHz; CD ₃ OD) δ 8. 27 (s, 1 H), 7. 83 (s, 1 H), 7. 66-7. 69 (m, 2 H), 7. 39 ( m, 1 H), 7.31 (t, J = 7.6 H z, 1 H), 7. 08 (s, 1 H), 4.21-4.25 (m, 4 H), 3. 75-3.79 (m, 4 H), 3.39 (s, 3 H), 3.38 (s, 3 H)

MS (ES I) m / z 428 ((C ₂₀ H ₂₃ N ₃ O ₄ B (OH) (OMe) + H] +), 450 ([C ₂ .H ₂₃ N ₃ 0 ₄ B (OH) (OM e) + N a] +)

(Example 7) Synthesis of boric acid compound 3b

 4 _ Black mouth 6, 7-Bis (2-methoxetoxy) Quinazoline (42 mg, 0.1 4 mm o I) dissolved in isopropyl alcohol (5 ml) 4-(4, 4, 5, 5- Tetramethyl-1,3,2-dioxapololane-2-yl) aniline (33 mg, 0.15 mm o I) and concentrated hydrochloric acid (0.05 mL) were added and stirred at room temperature. After 6 hours, the precipitated solid was filtered and washed with isopropyl alcohol. The obtained solid was treated in the same manner as in the synthesis of 1b to obtain anilinoquinazoline 3b (11 mg, 0.03 mm o I, 2 st p s 19%).

 [0125] 4-(6,7_Bis (2-methoxetoxy) quinazoline_4-ylmonoamino) Finulpolonic acid (3b).

¹ H_ NMR (400 MHz; CD ₃ OD) δ: 8. 29 (s, 1 Η), 7. 6 7 (s, 1 Η), 7. 6 3 (m, 4 Η), 7. 06 ( s, 1 Η), 4. 1 8-4. 24 (m, 4 Η), 3. 7 4-3. 7 7 (m, 4 Η), 3.3 8 (s, 3 Η), 3. 3 7 (s, 3 Η)

MS (ESI) m / z 4 1 4 ([C ₂₀ H ₂₃ N ₃ O ₄ B (OH) ₂ + H] +), 42 8 ((C ₂₀ H ₂₃ N ₃ O ₄ B (OH) (OM e ) + H] +), 450 ([C ₂ o H ₂₃ N ₃ 0 ₄ B (OH) (OM e) + N a] +).

[0126] (Test Example 1)

Lの p o l y (G l u : T y r , 4 : 1 ) ぺプチド （ S i g m a社製） P B S溶液を 1 00 l /w e I I となるように撒き、 4 °Cで一昼夜インキュべ —シヨンしてコートした。 1 00 Μの A T P、 1 0 n gの組換え E G F R 、 H E R 2、 F I t _ 1もしくは K D R ( I n v i t r o g e n社製， いず れも触媒ドメイン） および合成した各種含ホウ素キナゾリン誘導体を含むキ ナ一ゼ緩衝液 （50mM H EP ES、 1 25mM N a C I および 1 0m M M g C I ₂, p H 7. 4) 50 I をプレートに加え、 キナーゼ反応を行 つた。 20分後、 プレートを洗浄緩衝液 （T w e e n 20の 0. 1 % P B S溶液） で 3回洗浄し、 0. 2 g/rnLの HRP標識リン酸化チ口シン抗 体 （S a n t a C r u z社製） を 50 I / \N e I I となるようにプレー 卜に添加し、 20分間インキュベートした。 2回洗浄した後、 テトラメチル ベンジジン （S i gma社製） を 50 I / w e I I となるようにプレート に加えて反応させ、 50;U l /we l Iの 2 N H ₂ S O ₄を加えて反応を停 止させた。 96— we l I p l a t e r e a d e r ( e c a nネ工製) を用いて、 450 n mの吸光度を測定し、 被験化合物の 50 %阻害濃度 （ I C₅₀) を求めた。 The kinase activity of tyrosine kinase was measured by ELISA (Cancer Res., 6 3, 4450-4459, 2003). EIA / RIA stripwe II ™ plate (Corning), 50 g /

L poly (G lu: T yr, 4: 1) peptide (manufactured by Sigma) PBS solution was sprinkled to 100 l / we II and incubated at 4 ° C all day and night to coat . 100 Μ ATP, 10 ng recombinant EGFR, HER 2, FI t _ 1 or KDR (Invitrogen, both catalytic domains) and various boron-containing quinazoline derivatives synthesized Na one peptidase buffer (50mM H EP ES, 1 25mM N a CI and _{1 0m MM g CI 2, p} H 7. 4) was added to 50 I the plate, the kinase reaction rows ivy. After 20 minutes, the plate was washed three times with a washing buffer (0.1% PBS solution of Tween 20), and 0.2 g / rnL of HRP-labeled phosphorylated thycin antibody (manufactured by Santa Cruz) ) Was added to the plate so that it was 50 I / \ N e II and incubated for 20 minutes. After washing twice, tetramethylbenzidine (Sigma) was added to the plate to react to 50 I / we II, and 50; Ul / we I I 2 NH ₂ SO ₄ was added. The reaction was stopped. Using 96-well I platereader (manufactured by ecan Neko), absorbance at 450 nm was measured to determine the 50% inhibitory concentration (IC ₅₀ ) of the test compound.

 [0127] The results are shown in Table 1 below. The figures written in Katsuko indicate the inhibition rate of kinase activity when a test compound is added at a concentration of 1 M. “1” in the table indicates that no inhibitory effect was observed even when the test compound was added at a concentration of 1; UM.

 [0128] [Table 1]

As is clear from the above results, the compound of the present invention having a boron functional group on the benzene ring of the quinazoline skeleton has a specific inhibitory action on EG FR, and the benzene ring at the end of the 4-position of the quinazoline skeleton The compound having a boron functional group on the It had a specific inhibitory effect on VEG FR2 (KDR).

Claims

Claims A boron-containing quinazoline derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof. [Chemical 1]

[Wherein, R ¹ and R ² are each independently a hydrogen atom, an alkoxy group, 1 0_ (CH ₂ ) _n _OCH ₃ (n represents an integer of 1 to 10), 2]

 (m represents an integer from 1 to 10) [Chemical 3]

 (p represents an integer from 1 to 10) Or _X_B_ (OR ⁶ ) (OR ⁷ ) (where X is a single bond, _OCH ₂ OCH ₂ CH = CH_ or Four]

R ⁶ and R ⁷ represent a hydrogen atom, or OR ⁶ and OR ⁷ are connected to each other to form a boron-containing heterocyclic group which may have a substituent together with an adjacent boron atom) Indicates; R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group, a haloalkyl group, Represents an alkoxy group or a halogen atom; R ⁵ represents a hydrogen atom or —B (OR ⁸ ) (OR ⁹ ) (wherein R ⁸ and R ⁹ each independently represent a hydrogen atom or an alkyl group, or OR ⁸ and OR ⁹ And a boron-containing heterocyclic group which may have a substituent together with an adjacent boron atom is formed, and D represents —O— or —N H —. Provided that when R ⁵ represents a hydrogen atom, R ¹ or R ² is an alkoxy group, _0_ (CH ₂ ) _n _OCH ₃ (n is as defined above), [Chemical 5]

 (m is as defined above) [Chemical 6] -0- (CH ₂ ) ^ N ^ O (p is as defined above) Or B_ (OR ⁶ ) (OR ⁷ ) (wherein R ⁶ and R 7 are the same as defined above). When R ⁵ represents _B (OH) ₂ and D represents _N H—, both R ¹ and R ² do not represent a methoxy group. When R ⁵ represents a hydrogen atom, at least one of R ¹ and R ² represents -B (OR ⁶ ) (OR ⁷ ), and R ⁵ represents _B (OR ⁸ ) (OR ⁹ ) When it is shown, it shall be bonded to the linking group D at the meta position or the para position. ] R ¹ and R ² are a hydrogen atom, an alkoxy group, _0_ (CH ₂ ) _n -OCH ₃ (n is as defined above), [Chemical 7]

The compound according to claim 1, wherein The compound according to claim 2, wherein R ⁵ is bonded to the para position. R ¹ and R ² both represent an alkoxy group having 1 to 5 carbon atoms or _0_ (CH ₂ ) -OCH ₃ (η 'represents an integer of "! To 4"). 3. The compound according to 3. ^5. A compound according to claim 4, characterized in that R5 represents 1B (OH) ₂ . At least one of R ¹ and R ² represents — B_ (OR ⁶ ) (OR ⁷ ) (wherein R ⁶ and R 7 are the same as defined above), and at least one of R 3 and R 4 The compound according to claim 1, wherein represents a halogen atom. [7] R ¹ represents one B_ (OR ⁶ ) (OR ⁷ ) (wherein R ⁶ and R 7 are as defined above), R ² is an alkoxy group, _0_ (CH ₂ ) _n -OCH ₃ ( (n is as defined above) [Chemical 9]

 (m is as defined above)  Or [Chemical 10]

(p is as defined above) The compound according to claim 6, wherein [8] R ² is The compound of claim 7, wherein the an alkoxy group of from 1 to 5 carbon.  [9] The compound according to any one of claims 1 to 8, wherein D represents 1 NH_.  [10] 4- (6,7_bis (2-methoxetoxy) quinazoline_4-ylamino) Phenylboric acid or a pharmaceutically acceptable salt thereof.  [11] A pharmaceutical composition comprising a boron-containing quinazoline derivative represented by the following formula (1a) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  [Chemical 11]

[Wherein, R ¹ and R ² are each independently a hydrogen atom, an alkoxy group, _0_ (CH ₂ ) _n -OCH ₃ (n represents an integer of 1 to 10), [Chemical 12]

(m represents an integer from 1 to 10) [Chemical 13] -0- (CH ₂ ) p ~ N 0 (p represents an integer from 1 to 10) Or _X_B_ (OR ⁶ ) (OR ⁷ ) (where X is a single bond, _OCH ₂ 'OCH ₂ CH = CH_ or [Chemical 14]

R ⁶ and R ⁷ represent a hydrogen atom, or OR ⁶ and OR ⁷ are connected to each other to form a boron-containing heterocyclic group which may have a substituent together with an adjacent boron atom) Indicate R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group or a halogen atom, R ⁵ represents a hydrogen atom or —B (OR ⁸ ) (OR ⁹ ) (wherein R ⁸ and R ⁹ each independently represent a hydrogen atom or an alkyl group, or OR ⁸ and OR ⁹ And a boron-containing heterocyclic group which may have a substituent together with the adjacent boron atom, and D represents —O— or —N H —. However, when R ⁵ represents a hydrogen atom, ¹ or ² is _ 乂 '-B- (OR ⁶ ) (OR ⁷ ) (where X 'is _OCH ₂ _, _OCH ₂ CH = CH_ or [Chemical 15]

And R ⁶ and R ⁷ are the same as defined above. When R ⁵ represents a hydrogen atom, at least one of R ¹ and R ² represents -B (OR ⁶ ) (OR ⁷ ), and R ⁵ represents _B (OR ⁸ ) (OR ⁹ ) When it is shown, it shall be bonded to the linking group D at the meta position or the para position. ]  An antitumor agent comprising a boron-containing quinazoline derivative represented by the following formula (1a) or a pharmaceutically acceptable salt thereof as an active ingredient. [Chemical 16]

[Wherein, R ¹ and R ² are each independently a hydrogen atom, an alkoxy group, _0_ (CH ₂ ) _n -OCH ₃ (n represents an integer of 1 to 10), [Chemical 17]

 (m represents an integer from 1 to 10) [Chemical 18]

 (P represents an integer from 1 to 10) Or _X_B_ (OR ⁶ ) (OR ⁷ ) (where X is a single bond, _OCH ₂ _, -OCH ₂ CH = CH_ or [Chemical 19]

R ⁶ and R ⁷ represent a hydrogen atom, or OR ⁶ and OR ⁷ are connected to each other to form a boron-containing heterocyclic group which may have a substituent together with an adjacent boron atom) Indicate R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group or a halogen atom, R ⁵ represents a hydrogen atom or —B (OR ⁸ ) (OR ⁹ ) (wherein R ⁸ and R ⁹ each independently represent a hydrogen atom or an alkyl group, or OR ⁸ and OR ⁹ And a boron-containing heterocyclic group which may have a substituent together with the adjacent boron atom, and D represents —O— or —N H —. However, when R ⁵ represents a hydrogen atom, ¹ or ² is _ 乂 '-B- (OR ⁶ ) (OR ⁷ ) (where X' is _OCH ₂ _, _OCH ₂ CH = CH_ or [Chemical 20]

And R 6 and R 7 are the same as defined above. When R ⁵ represents a hydrogen atom, at least one of R ¹ and R ² represents -B (OR ⁶ ) (OR ⁷ ), and R ⁵ represents _B (OR ⁸ ) (OR ⁹ ) When it is shown, it shall be bonded to the linking group D at the meta position or the para position. ]  Use of a boron-containing quinazoline derivative represented by the following formula (1a) or a pharmaceutically acceptable salt thereof for producing an antitumor agent. [Chemical 21]

[Wherein, R ¹ and R ² are each independently a hydrogen atom, an alkoxy group, _0_ (CH ₂ ) _n -OCH ₃ (n represents an integer of 1 to 10), [Chemical 22]

(m represents an integer from 1 to 10) [Chemical 23]

(P represents an integer from 1 to 10) Or _X_B_ (OR ⁶ ) (OR ⁷ ) (where X is a single bond, _OCH ₂ _,- OCH ₂ CH = CH_ or [Chemical 24]

R ⁶ and R ⁷ represent a hydrogen atom, or OR ⁶ and OR ⁷ are connected to each other to form a boron-containing heterocyclic group which may have a substituent together with an adjacent boron atom) Indicate R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group or a halogen atom, R ⁵ represents a hydrogen atom or —B (OR ⁸ ) (OR ⁹ ) (wherein R ⁸ and R ⁹ each independently represent a hydrogen atom or an alkyl group, or OR ⁸ and OR ⁹ And a boron-containing heterocyclic group which may have a substituent together with the adjacent boron atom, and D represents —O— or —N H —. However, when R ⁵ represents a hydrogen atom, ¹ or ² is _ 乂 '-B- (OR ⁶ ) (OR ⁷ ) (where X 'is _OCH ₂ _, _OCH ₂ CH = CH_ or [Chemical 25]

And R ⁶ and R ⁷ are the same as defined above. When R ⁵ represents a hydrogen atom, at least one of R ¹ and R ² represents -B (OR ⁶ ) (OR ⁷ ), and R ⁵ represents _B (OR ⁸ ) (OR ⁹ ) When it is shown, it shall be bonded to the linking group D at the meta position or the para position. ] A method for treating a tumor, which comprises administering an effective amount of a boron-containing quinazoline derivative represented by the following formula (1a) or a pharmaceutically acceptable salt thereof. [Chemical 26]

[Wherein, R ¹ and R ² are each independently a hydrogen atom, an alkoxy group, _0_ (CH ₂ ) _n -OCH ₃ (n represents an integer of 1 to 10), [Chemical 27]

(m represents an integer from 1 to 10) [Chemical 28]

(P represents an integer from 1 to 10) Or _X_B_ (OR ⁶ ) (OR ⁷ ) (where X is a single bond, _OCH ₂ _, -OCH ₂ CH = CH_ or [Chemical 29]

R ⁶ and R ⁷ represent a hydrogen atom, or OR ⁶ and OR ⁷ are connected to each other to form a boron-containing heterocyclic group which may have a substituent together with an adjacent boron atom) Indicate R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group or a halogen atom, R ⁵ represents a hydrogen atom or —B (OR ⁸ ) (OR ⁹ ) (wherein R ⁸ and R ⁹ each independently represent a hydrogen atom or an alkyl group, or OR ⁸ and OR ⁹ And a boron-containing heterocyclic group which may have a substituent together with an adjacent boron atom. ) And D represents —O— or —N H_. However, when R ⁵ represents a hydrogen atom, ¹ or ² is _ 乂 '-B- (OR ⁶ ) (OR ⁷ ) (where X 'is _OCH ₂ _, _OCH ₂ CH = CH_ or [Chemical 30]

And R ⁶ and R ⁷ are the same as defined above. When R ⁵ represents a hydrogen atom, at least one of R ¹ and R ² represents -B (OR ⁶ ) (OR ⁷ ), and R ⁵ represents _B (OR ⁸ ) (OR ⁹ ) When it is shown, it shall be bonded to the linking group D at the meta position or the para position. ]