KR101704386B1 - Inhibitory activity of thieno[3,2-d]pyrimidine derivatives on T315I-Bcr-Abl point mutation - Google Patents

Abstract

The present invention relates to a Gleevec-resistant anticancer agent comprising a thieno [3,2- d ] pyrimidine derivative having an inhibitory activity against a point mutation species generated from a Bcr-Abl gene of a protein kinase as an active ingredient.

Description

[Inhibitory activity of thieno [3,2-d] pyrimidine derivatives on T315I-Bcr-Abl point mutation of thieno [3,2-d] pyrimidine derivatives

The present invention relates to a Gleevec-resistant anticancer agent comprising a thieno [3,2- d ] pyrimidine derivative having an inhibitory activity against a point mutation species generated from a Bcr-Abl gene of a protein kinase as an active ingredient.

Chronic myeloid leukemia (CML) is a type of hematologic malignancy that is expressed in chromosomal abnormalities of hematopoietic stem cells present in the bone marrow. In other words, while the Bcr (breakpoint cluster region) gene on chromosome 22 and Abl (V-abl Abelson murine leukemia viral oncogene homolog) gene on chromosome 9 crossed and reversed, a gene for tyrosine fusion gene Bcr- . Tyrosine kinase, which is produced by the Bcr-Abl gene, is active and activates signal transduction systems associated with intracellular mitosis, resulting in hyperproliferation of leukocytes and signaling associated with apoptosis It is known to inhibit transmission and cause leukemia. p210-Bcr-Abl is known to be a direct tumor factor that causes chronic myelogenous leukemia (CML).

Gleevec (Gleevec ™, imatinib mesylate) is the first targeted anticancer drug developed as an inhibitor that selectively acts on Bcr-Abl tyrosine kinase. Gleevec has excellent therapeutic efficacy and excellent safety and is widely used as the first standard therapy for the treatment of chronic myelogenous leukemia.

However, many of the patients treated with Gleevec are resistant, and recently, resistance mutations have been identified. Gleevec resistance is caused by a point mutation that occurs at the active site of the Bcr-Abl tyrosine kinase. For example, a mutation (T315I) in which the 315th threonine changes to isoleucine and a mutation that changes the 253rd tyrosine to histidine (T253H) is the most frequent. Of the Gleevec resistant point mutations, T315I-Bcr-Abl accounts for the highest percentage.

Cells with point mutations are no longer regulated by Gleevec, and it is known that increasing the dose of Gleevec does not improve the therapeutic effect at all.

Currently, a second-generation anticancer drug that can treat Gleevec's resistance has been developed. As second-generation anticancer drugs, nilotinib (Tasigna) and dasatinib (Sprycel) have been found to have very poor ability to inhibit the T315I-Bcr-Abl mutant species. However, ponatinib has activity to inhibit the T315I-Bcr-Abl mutant, and its drug development has been actively promoted, but there is still room for improvement.

Therefore, it is urgently required to develop a new next-generation anticancer drug capable of preventing or treating Gleevec resistance.

On the other hand, the thieno [3,2- d ] pyrimidine derivative used as an active ingredient of the present invention is known as an anticancer agent having an inhibitory activity against protein kinase. [Korean Patent No. 1147550]

In the present invention, by confirming that some compounds in the thieno [3,2- d ] pyrimidine derivatives simultaneously exhibit the inhibitory activity against protein kinase and the point mutation cells generated from Bcr-Abl gene of protein kinase, Thereby completing the present invention.

Therefore, a problem to be solved by the present invention is to provide a second generation anticancer agent capable of treating Gleevec resistance.

That is, the object of the present invention is to provide a medicinal use in which a thieno [3,2- d ] pyrimidine derivative is used as an activity inhibitor of T315I-Bcr-Abl point mutant cells.

In order to solve the above problems, the present invention provides a pharmaceutical composition comprising a thieno [3,2- d ] pyrimidine derivative represented by the following general formula (1), a pharmaceutically acceptable salt, hydrate and solvate thereof as an active ingredient Gleevec-resistant anticancer agent.

[Chemical Formula 1]

In Formula 1,

A and B are the same or different from each other and represent a phenyl group; Or a 5- to 6-membered heteroaryl group containing 1 to 4 hetero atoms selected from nitrogen and sulfur atoms,

R ^a is a hydrogen atom; A halogen atom; A C ₁ -C ₆ alkyl group; A C ₁ -C ₆ alkoxy group; NR ⁴ R ⁵ -C ₁ -C ₆ alkoxy group; A phenyl group substituted or unsubstituted with -C (O) OR < ^{1 &} gt ;; A heterocyclic group substituted or unsubstituted with C ₁ -C ₆ alkyl; Or a (C ₁ -C ₆ alkyl substituted or unsubstituted heterocycle) -C ₁ -C ₆ alkyl group,

R ^b is a hydrogen atom; A nitro group; An amino group; A hydroxyl group; A C ₁ -C ₆ haloalkyl group; A C ₁ -C ₆ alkoxy group; - (CH ₂ ) _n R ² ; -C (O) OR < ^{2 &} gt ;; ^{-C (O) NR 4 R 5} ; -NR ³ C (O) R ⁵ ; -NR ³ C (O) NR ⁴ R ⁵ ; ^{_{-S (O) 2 NR 4 R}} 5; Or -NR ³ S (O) ₂ R ⁵ ,

n represents 1, 2 or 3,

R ¹ is a hydrogen atom; Or a C ₁ -C ₆ alkyl group,

R ² is a hydrogen atom; Or a heterocyclic group,

R ³ is a hydrogen atom; Or a C ₁ -C ₆ alkyl group,

R ⁴ and R ⁵ are the same or different and each is a hydrogen atom; A hydroxyl group; A C ₁ -C ₆ alkyl group; A C ₁ -C ₆ haloalkyl group; A methanesulfonyl group; A phenyl group substituted or unsubstituted with 1 to 3 substituents selected from halo and C ₁ -C ₆ haloalkyl; Or a heterocyclic group,

Or R ³ , R ^4, and R ⁵ may be connected to each other to form a 5- to 7-membered ring.

Further, the present invention is characterized by novel thieno [3,2- d ] pyrimidine derivatives wherein the substituent A is a phenyl group among the compounds represented by the above-mentioned formula (1).

Most of the drugs for the treatment of tumors having protein kinase inhibitory activity have a problem of resistance to gene mutation, so they are limited to be applied as anticancer drugs.

From this point of view, the thieno [3,2- d ] pyrimidine derivative of the present invention as an active ingredient has an inhibitory activity against a point mutation species occurring in the Bcr-Abl kinase domain together with a protein kinase inhibitory activity It can be widely applied as an ideal anticancer agent.

In particular, the anticancer agent of the present invention is useful as a therapeutic agent for Gleevec-resistant chronic myeloid leukemia (CML).

 The substituents used to define the compounds according to the invention are described in more detail below.

In the present invention, the term "halogen atom" means fluorine, chlorine, bromine and iodine atoms.

La 'alkyl group' in the present invention means the methyl, ethyl, n - propyl, i - propyl, cyclo-propyl, n - butyl, i - butyl, t - butyl, cyclo-butyl, cyclo propyl methyl, n - pentyl, i - Means an aliphatic saturated hydrocarbon group having from one to six carbon atoms, including pentyl, neopentyl, t -pentyl, cyclopentyl, cyclobutylmethyl, n -hexyl, i -hexyl, cyclohexyl, cyclopentylmethyl, and the like .

The "haloalkyl group" in the present invention means an alkyl group substituted by a hydrogen atom by one or more halogen atoms such as a trifluoromethyl group.

The term "alkoxy group" used in the present invention includes C ₁ -C ₆ alkoxy groups such as methoxy, ethoxy, n -propoxy, i -propoxy, n -butoxy, i -butoxy and t- Quot; means a hydroxy group substituted with a hydrogen atom by a substituent selected from an alkyl group of < RTI ID = 0.0 >

The term "heteroaryl group" used in the present invention includes pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, Wherein the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, fluorine, chlorine, fluorine, chlorine, bromine, iodine, Benzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, dibenzothiophenyl, naphthyridyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalyl Means a monocyclic, bicyclic or tricyclic aromatic heterocyclic group containing at least one hetero atom, including, for example, benzyl, naphthyl, phthalazinyl, quinolinyl, quinazolinyl and the like.

In the present invention, the term "heterocyclic group" means a hetero hydrocarbon ring group containing at least one hetero atom, including morpholino, piperidinyl, piperazinyl, N -protected piperazinyl and the like.

In the thieno [3,2- d ] pyrimidine compound represented by the above formula (1) according to the present invention, the following are preferable.

A is a phenyl group; A pyridinyl group; A tetrazolyl group; Or a thiazolyl group,

B is a phenyl group; Or a quinolinyl group,

R ^a is a hydrogen atom; A C ₁ -C ₆ alkoxy group; Di (C ₁ -C ₆ alkyl) amino-C ₁ -C ₆ alkoxy group; A phenyl group; A morpholino group; A piperazinyl group substituted or unsubstituted with C ₁ -C ₆ alkyl; (C ₁ substituted or piperazinyl ring by -C ₆ alkyl) -C ₁ -C ₆ alkyl group; Or a piperidinyl group substituted or unsubstituted with hydroxy,

R ^b is a hydrogen atom; A hydroxyl group; A C ₁ -C ₆ haloalkyl group; A C ₁ -C ₆ alkoxy group; - (CH ₂ ) _n R ² ; ^{-C (O) NR 4 R 5} ; -NR ³ C (O) R ⁵ ; -NR ³ C (O) NR ⁴ R ⁵ ; ^{_{-S (O) 2 NR 4 R}} 5; Or -NR ³ S (O) ₂ R ⁵ ,

Wherein n represents 1, 2 or 3,

R ² is a hydrogen atom; Or a piperidinyl group,

R ³ represents a hydrogen atom; Or a C ₁ -C ₆ alkyl group,

R ⁴ and R ⁵ are the same or different from each other and each represents a hydrogen atom; A C ₁ -C ₆ alkyl group; Or a phenyl group substituted or unsubstituted with 1 to 3 substituents selected from halo, C ₁ -C ₆ haloalkyl,

Or R < ³ >, R < ⁴ > and R < ⁵ > may form a 5- to 7-membered ring by adjacent substituents.

Further, in the thieno [3,2- d ] pyrimidine compound represented by the above formula (1) according to the present invention, the following are more preferable.

A is a phenyl group; Pyridin-3-yl group; Tetrazol-5-yl group; Or a thiazol-2-yl group,

B is a phenyl group; Or a quinolin-3-yl group,

R ^a is a hydrogen atom; Methoxy group; Diethylaminoethoxy group; A phenyl group; A morpholino group; 4-hydroxy-piperidin-1-yl group; 4-ethyl-piperazin-1-yl group; 4-ethyl-piperazin-1-ylmethyl group; (4-methylpiperazin-1-yl) -piperidin-1-yl group,

R ^b is a hydrogen atom; A hydroxyl group; A trifluoroalkyl group; Methoxy group; Piperidin-1-ylmethyl group; -C (O) NHCH _3; -NHC (O) -cyclopropyl group; -NHC (O) NH- (4-chloro-3-trifluoromethylphenyl); -S (O) ₂ NHCH _3; -NHS (O) ₂ CH _3; Or a 1,1-dioxydiisothiazolidin-2-yl group.

The thieno [3,2- d ] pyrimidine derivatives represented by Formula 1 according to the present invention are shown in Table 1 below.

Active compound Chemical structure Compound name MS ( m / z ) Compound 1

N- (3- (2- (6- ( 4- ethyl-piperazin-1-yl) pyridin-3-ylamino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) methane sulfonamide 510.60 [M + 1] Compound 2

N- (3- (2 - (( 4- (4- ethyl-piperazin-1-yl) phenyl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) methanesulfonamide 509.17 [M + 1] <  Compound 3

N- (3-2 - ((2- methoxy-6-morpholinophenyl-3-yl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) methane sulfonamide  513.13 [M + 1] < Compound 4

N- (3- (2 - (( 6- (4- ethyl-piperazin-1-yl) -2-methoxy-3-yl) amino) thieno [3,2 -d] pyrimidin-7 Yl) phenyl) methanesulfonamide  540.18 [M + 1] < Compound 5

N- (3- (2 - (( 3,4,5- trimethoxyphenyl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) methanesulfonamide  487.1 [M + 1] < Compound 6

N- (3- (2 - (( 2- methoxy-4-morpholinophenyl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) methanesulfonamide  512.13 [M + 1] Compound 7

Amino] thieno [3,2- d ] pyrimidin-7-yl) phenyl) methanesulfonamide The title compound was prepared from N- (3- (2- amides  523.19 [M + l] Compound 8

N- (3- (2 - (( 4- (2- ( diethylamino) ethoxy) phenyl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) methanesulfonamide  512.17 [M + 1] Compound 9

N- (3- (2- ( 1H -tetrazol-5-yl) amino) thieno [3,2- d ] pyrimidin-7-yl) phenyl) methanesulfonamide;  389.48 [M + l] Compound 10

N- (3- (2 - ((4-phenylthiazol-2-yl) amino) thieno [3,2- d ] pyrimidin-7-yl) phenyl) methanesulfonamide;  480.46 [M + 1] < Compound 11

N- (2- (2 - (( 6- (4- ethyl-piperazin-1-yl) pyridin-3-yl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) methane Sulfonamide 510.60 [M + 1] Compound 12

N- (2- (2 - (( 6- (4- (4- methylpiperazin-1-yl) piperidin-1-yl) pyridin-3-yl) amino) thieno [3,2 -d ] Pyrimidin-7-yl) phenyl) methanesulfonamide MS m / z: 579.2 [M + 1] < Compound 13

Amino] thieno [3,2- d ] pyrimidin-7-yl) - N -methylbenzenesulfonamide MS m / z: 509.2 [M + 1] < Compound 14

Amino] thieno [3,2- d ] pyrimidin-7-yl) - N -methylbenzenesulfonamide 512.17 [M + 1] Compound 15

N- (3- (2 - (( 4- (4- ethyl-piperazin-1-yl) phenyl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) cyclopropane carboxamide 499.23 [M + 1] < Compound 16

N- (3- (2 - (( 4- (4- hydroxypiperidine-l-yl) phenyl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) cyclopropane O Copy Mid 486.19 [M + l] Compound 17

N- (3- (2 - (( 4 - ((4- ethyl-piperazin-1-yl) methyl) phenyl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) cyclopropane Carboxamide; 513.24 [M + 1] < Compound 18

N- (3-2 - ((3- (4-ethylpiperazin-1-yl) phenyl) amino) thieno [3,2- d ] pyrimidin-7-yl) phenyl) cyclopropanecarboxamide; 499.22 [M + l] Compound 19

N- (4-4 (ethyl-piperazin-1-yl) phenyl) -7- (4-methoxyphenyl) thieno [3,2 -d] pyrimidin-2-amine 446.1 [M + 1] < Compound 20

7- (4-methoxyphenyl) - N- (3,4,5- trimethoxyphenyl) thieno [3,2 -d] pyrimidin-2-amine 424.2 [M + 1] < Compound 21

Amino] thieno [3,2- d ] pyrimidin-7-yl) -N- methylbenzamide Compound 22

Amino] thieno [3,2- d ] pyrimidin-7-yl) phenyl) isothiazolidin-1- , 1-dioxide 535.19 [M + l] Compound 23

N- (6- (4- ethyl-piperazin-1-yl) pyridin-3-yl) -7- (2- (trifluoromethyl) phenyl) thieno [3,2 -d] pyrimidin-2 Amine 485.12 [M + l] Compound 24

N- (6- morpholinophenyl-3-yl) -7- (quinolin-3-yl) thieno [3,2 -d] pyrimidin-2-amine 441.2 [M + 1] < Compound 25

Amino] thieno [3,2- d ] pyrimidin-4-yl) -3- (3- (2- Pyrimidin-7-yl) phenyl) urea 626.09 [M + 1] < Compound 26

N- (6- morpholinophenyl-3-yl) -7- (4- (piperidin-1-yl) phenyl) thieno [3,2 -d] pyrimidin-2-amine 487.2 [M + l] Compound 27

3 - (2 - ((4 -morpholinophenyl) amino) thieno [3,2- d ] pyrimidin- 405.2 [M + 1] <

The thieno [3,2- d ] pyrimidine derivative wherein A is a heteroaryl group in the compound represented by formula (1) as an active ingredient in the anticancer agent of the present invention is a known compound disclosed in Korean Patent No. 1147550.

On the other hand, thieno [3,2- d ] pyrimidine derivatives wherein A is a phenyl group in the compound represented by the above formula (1) are novel compounds which are not disclosed in the literature. Accordingly, thieno [3,2- d ] pyrimidine derivatives in which A in the above formula (1) is a phenyl group are included in the scope of the present invention.

The thieno [3,2- d ] pyrimidine derivative represented by the above formula (1) can be easily synthesized by a conventional organic synthesis method. Accordingly, the thieno [3,2- d ] pyrimidine derivative represented by Formula 1 can be easily synthesized by referring to the preparation method disclosed in Korean Patent No. 1147550.

In addition, the thieno [3,2- d ] pyrimidine derivative represented by Formula 1 according to the present invention may exist as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts should be low in toxicity to humans and should not adversely affect the biological activity and physico-chemical properties of the parent compound, and such salts may be prepared by conventional methods in the art. The pharmaceutically acceptable salts of the present invention include acid addition salts of pharmaceutically acceptable free acids with basic compounds of the general formula (1), alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts) 1 < / RTI > carboxylic acid, and an amino acid addition salt. Free acids that can be used in the preparation of pharmaceutically acceptable salts can be divided into inorganic and organic acids. As the inorganic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid and the like can be used. The organic acids may be selected from the group consisting of acetic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, Benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used. Organic bases that can be used to prepare organic base addition salts include tris (hydroxymethyl) methylamine, dicyclohexylamine, and the like. Amino acids that can be used in the production of amino acid addition salts are natural amino acids such as alanine and glycine.

The thieno [3,2- d ] pyrimidine derivative represented by Formula 1 according to the present invention includes all the hydrates and solvates as well as the pharmaceutically acceptable salts described above. Hydrates and solvates thereof can be prepared by mixing the 2,4,7-substituted thieno [3,2- d ] pyrimidine derivative represented by the above formula (1) with water such as methanol, ethanol, acetone, 1,4- May be dissolved in the solvent and then crystallized or recrystallized after addition of the free acid or free base. In such cases, solvates (especially hydrates) may be formed. Thus, compounds of the present invention also include stoichiometric solvates, including hydrates, in addition to varying amounts of water-containing compounds that can be prepared by methods such as lyophilization.

In addition, the anticancer agent of the present invention comprises a thieno [3,2- d ] pyrimidine derivative represented by the general formula (1), a pharmaceutically acceptable salt thereof, a solvate thereof or a hydrate thereof as an active ingredient, For example, tablets, capsules, troches, liquids, suspensions, or the like, or parenteral administration preparations such as tablets, capsules, solutions, suspensions and the like in the form of tablets, capsules, . ≪ / RTI >

The dose of the compound according to the present invention to the human body may vary depending on the age, body weight, sex, dosage form, health condition, and disease severity of the patient. In general, 0.01 to 1,000 mg / day. Depending on the judgment of a physician or a pharmacist, it may be administered once or several times a day at a predetermined time interval.

Examples of excipients that can be used in the anticancer agent of the present invention include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, perfumes and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, Water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like.

Some formulations containing the compound represented by the formula (1) as an active ingredient are exemplified as follows, but the present invention is not limited by the following formulation examples.

[Formulation Example]

Formulation Example 1: Tablets (Direct Pressurization)

After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

Formulation Example 2: Tablet (wet assembly)

After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Formulation Example 3: Powders and capsules

5.0 mg of the active ingredient was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. 5 gelatin capsules.

Formulation Example 4: Injection

100 mg as an active ingredient, 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water were added to prepare an injection.

The following Experimental Examples are intended to illustrate specific experimental results of the pharmacological activity of thieno [3,2- d ] pyrimidine derivatives used as active ingredients in the present invention, but the present invention is not limited by the following experimental examples.

[Experimental Example]

Experimental Example 1. Measurement of inhibitory activity against T315I-Bcr-Abl-Ba / F3

T315I-Bcr-Abl-Ba / F3 cells were then loaded with 10% FBS (Welgene), 1 % penicillin / streptomycin (Welgene) in RPMI medium (Welgene, Daegu, Korea) incubated in 5% CO _2/37 ℃ . T315I-Bcr-Abl-Ba / F3 cells were placed in 96-well plates at 5 × 10 ³ per well. In 5% CO _2/37 ℃ prior to processing the test compound and incubated for 24 hours. The experimental compounds were treated at various concentrations. MTT assay (CellTiter 96 Assay, Promega) was used to measure cell viability. 15 μl of dye was added per well and incubated for 2 hours. Then, 100 μl of stop solution was added and the absorbance was measured after 24 hours. For compound treatment, a 10 mM raw material solution was prepared, sterilized and diluted one by one with dimethyl sulfoxide (DMSO) and diluted to 12 points sequentially, and 0.5 μl of a test compound plate was added (final concentration DMSO 0.5%). Use EnVision2103 was read at 590 nm wavelength, IC ₅₀ values were calculated using GraphPad Prism 4.0 software.

The results of evaluating the ability of T315I-Bcr-Abl-Ba / F3 inhibitory activity for each experimental compound are shown in Table 2 below.

Experimental compound IC ₅₀ (uM) Experimental compound IC ₅₀ (uM) Compound 1 <10 Compound 15 <10 Compound 2 0.11 Compound 16 <10 Compound 3 <10 Compound 17 <10 Compound 4 <10 Compound 18 <10 Compound 5 <10 Compound 19 <10 Compound 6 <10 Compound 20 <10 Compound 7 <10 Compound 21 <10 Compound 8 <10 Compound 22 <10 Compound 9 <10 Compound 23 <10 Compound 10 <10 Compound 24 <10  Compound 11 <10 Compound 25 <10 Compound 12 <10 Compound 26 <10 Compound 13 0.040 Compound 27 <10 Compound 14 <10

As described above, the thieno [3,2- d ] pyrimidine derivative represented by the formula (1) according to the present invention, its pharmaceutically acceptable salts, hydrates and solvates has an inhibitory activity against point mutants It is excellent as a Gleevec resistant anticancer drug because it is excellent.

Claims (8)

An anticancer drug for treating Gleevec-resistant chronic myelogenous leukemia comprising, as an active ingredient, a compound selected from a thieno [3,2- d ] pyrimidine derivative represented by the following formula (1), a pharmaceutically acceptable salt, a hydrate and a solvate thereof ;
[Chemical Formula 1]

In Formula 1,
A represents a phenyl group or a pyridinyl group,
B represents a phenyl group,
R ^a represents a 4-ethyl-piperazin-1-yl group,
R ^b represents an -NHC (O) -cyclopropyl group, -S (O) ₂ NHCH ₃ , or -NHS (O) ₂ CH ₃ .
The method according to claim 1,
remind

The

or

, And

The

Anticancer agent for the treatment of chronic myelogenous leukemia with Gleevec resistance.
delete The method according to claim 1,
The compound represented by the above formula (1)
N- (3- (2 - (( 6- (4- ethyl-piperazin-1-yl) pyridin-3-yl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) methane Sulfonamide (Compound 1);
N- (3- (2 - (( 4- (4- ethyl-piperazin-1-yl) phenyl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) methanesulfonamide (compound 2);
Amino] thieno [3,2- d ] pyrimidin-7-yl) -N -methylbenzenesulfonamide (Compound 13 );
N- (3- (2 - (( 4- (4- ethyl-piperazin-1-yl) phenyl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) cyclopropane carboxamide (Compound 15);
N- (3- (2 - (( 4 - ((4- ethyl-piperazin-1-yl) methyl) phenyl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) cyclopropane Carboxamide (Compound 17); And
Amino] thieno [3,2- d ] pyrimidin-7-yl) -N- methylbenzamide (Compound 21) ;
Wherein the anticancer agent is selected from the group consisting of: &lt; RTI ID = 0.0 &gt;
delete delete Compounds selected from thieno [3,2- d ] pyrimidine derivatives represented by the following formula (1), pharmaceutically acceptable salts, hydrates and solvates thereof;
[Chemical Formula 1]

In Formula 1,
A represents a phenyl group or a pyridinyl group,
B represents a phenyl group,
R ^a represents a 4-ethyl-piperazin-1-yl group or a 4-ethyl-piperazin-1-ylmethyl group,
R ^b represents an -NHC (O) -cyclopropyl group, -S (O) ₂ NHCH ₃ , or -NHS (O) ₂ CH ₃ .
The method of claim 7,
N- (3- (2 - (( 6- (4- ethyl-piperazin-1-yl) pyridin-3-yl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) methane Sulfonamide (Compound 1);
N- (3- (2 - (( 4- (4- ethyl-piperazin-1-yl) phenyl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) methanesulfonamide (compound 2);
Amino] thieno [3,2- d ] pyrimidin-7-yl) -N -methylbenzenesulfonamide (Compound 13 );
N- (3- (2 - (( 4- (4- ethyl-piperazin-1-yl) phenyl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) cyclopropane carboxamide (Compound 15);
N- (3- (2 - (( 4 - ((4- ethyl-piperazin-1-yl) methyl) phenyl) amino) thieno [3,2 -d] pyrimidin-7-yl) phenyl) cyclopropane Carboxamide (Compound 17); And
Amino] thieno [3,2- d ] pyrimidin-7-yl) -N- methylbenzamide (Compound 21) ;
&Lt; / RTI &gt;