JPH1025294A - Fused heterocyclic derivative, method for producing the same, and therapeutic agent for malignant tumor containing the same - Google Patents

Abstract

(57) [Summary] [Problem] To provide an anti-malignant tumor agent having a growth inhibitory effect and an angiogenesis inhibitory effect on Ras cancer gene-introduced cells. [Solution] General formula (1) [Wherein, R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted amino group, a phenoxy group, a mercapto group, a phenylmercapto group, a phenylsulfinyl group or a phenylsulfonyl group, R ² is a hydrogen atom or an amino group, R ³ is a hydrogen atom or a halogen atom, A is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxy group, a substituted or unsubstituted amino group, a lower acylamino group, a lower acyloxy group, An alkyl group, a nitro group, a formyl group, a substituted phenylcarbamoyl group or a substituted phenylsulfonylamide group, etc.] or a salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel condensed heterocyclic compound, a method for producing the same, and a pharmaceutical containing the condensed heterocyclic compound. The fused heterocyclic compound of the present invention and a salt thereof have a ras oncogene growth inhibitory action and an angiogenesis inhibitory action, and are useful as, for example, a medicament for preventing and treating malignant tumors such as colon cancer, bile duct cancer, and pancreatic cancer. .

[0002]

2. Description of the Related Art It is becoming clear that cancer is caused by abnormalities in control mechanisms for cell differentiation and proliferation. Therefore, the signal transduction system that controls the differentiation and proliferation of cells has attracted attention as a new target for cancer treatment. It has been reported that the oncogene ras is mutated in many pancreatic and colon cancers. P21, a product of the oncogene ras, is a guanosine 5'-diphosphate (GDP) / guanosine 5'-triphosphate (GTP) binding protein localized at the plasma membrane and is widely found in signaling systems It is a member of the G protein family. Mutated
p21 is known to not function properly,
This is thought to be the trigger of cell carcinogenesis. It is well known that the G protein plays an important role in the signal transduction system.
The product p21 of s may be a new target for cancer therapy. Nutrition, oxygen and growth factors are necessary for cancer cells to continue growing, but the amount of diffusion from existing blood vessels is insufficient.
Therefore, cancer cells form collateral arteries by angiogenic factors produced or secreted by themselves or from host cells and continue to proliferate. Thus, an angiogenesis inhibitor can be a new prophylactic and therapeutic agent for cancer growth and cancer development. L-651,
582 is a compound developed by Merck as a therapeutic agent for coccidiosis in livestock. After that, US NC
Group I reported that this compound has an activity of suppressing the growth and metastatic potential of human uterine cancer cells. Studies on the mechanism of action of this compound have indicated the possibility of binding to G proteins [Kohn et al., J. Natl. Cancer Inst., 82, 54.
Pp. 65, 1990; JP-A-64-68321]. However, there is no description on the growth inhibitory activity of L-651,582 on ras oncogene-transfected cells, and the selectivity of action on normal cells and cancer cells has not been clarified. On the other hand, as compounds having an angiogenesis inhibitory action, fumagillin derivatives are disclosed in JP-A-1-279828, and triazole compounds L-651,582 are disclosed in WO9508327.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to find a novel derivative which exhibits a potent inhibitory action on ras oncogene growth and an inhibitory action on angiogenesis and selectively acts on cancer cells.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object, and as a result, it has been found that condensed heterocyclic derivatives having a specific structure have excellent inhibitory action on ras oncogene growth and inhibition of angiogenesis. It has been found to have an effect. That is, the present invention relates to the general formula (1)

Embedded image [Wherein, R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted amino group, a phenoxy group, a mercapto group, a phenylmercapto group, a phenylsulfinyl group or a phenylsulfonyl group, R ² is a hydrogen atom or an amino group, R ³ is a hydrogen atom or a halogen atom, A is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxy group, a substituted or unsubstituted amino group, a lower acylamino group, a lower acyloxy group, Alkyl group, nitro group, formyl group or

Embedded image (Wherein, R ⁴ is a hydrogen atom, a halogen atom, a hydroxyalkyl group, a lower alkyl group, a cyano group, a trihalogenomethylsulfonylamino group or a tetrazole group, X is a group —OCO—, —COO—, —CONR ⁵ —, -NR ⁵ CO
—, —NR ⁵ SO ₂ — or a group having two or less carbon atom chains, and R ⁵ represents a hydrogen atom or a lower alkyl group). Or a salt thereof.

The present invention further relates to a method for producing the compound of the general formula (1) and a therapeutic agent for malignant tumors containing the compound of the general formula (1). Examples of the halogen atom of the substituents R ¹ , R ³ , R ⁴ and A in the fused heterocyclic derivative represented by the general formula (1) include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The amino group of R ¹ and A may be an unsubstituted, monosubstituted or disubstituted amino group. Examples of the substituent include a lower alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, and butyl.
The substituent is a mono- or di-substituted phenyl group.Examples of the substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a lower alkyl group such as methyl, ethyl, propyl and isopropyl, a hydroxyl group, methoxy, ethoxy and propoxy. , Lower alkoxy groups such as isopropoxy and butoxy, methoxycarbonyl, alkoxycarbonyl groups such as ethoxycarbonyl, amino, methylamino,
Examples include amino groups such as dimethylamino, acylamino groups such as acetylamino and propionylamino, and lower alkylthio groups such as methylthio and ethylthio.

The lower alkyl group represented by R ⁴ , R ⁵ and A may be linear or branched and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. And lower alkyl groups having 1 to 4 carbon atoms which may be substituted by a halogen atom such as trifluoromethyl and trichloromethyl. Examples of the lower alkoxy group for A include methoxy, ethoxy, propoxy, isopropoxy, n-
Examples thereof include linear or branched lower alkoxy groups having 1 to 4 carbon atoms such as butoxy, sec-butoxy and tert-butoxy. Examples of the lower alkoxycarbonyl group of A include lower alkoxycarbonyl groups having 1 to 4 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and tert-butoxycarbonyl. .

The lower acylamino group of A includes, for example, acetylamino, trifluoroacetylamino, propionylamino, butyrylamino, isobutyrylamino,
Pivaloylamino and the like. Examples of the lower acyloxy group of A include acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy and the like. Examples of the hydroxyalkyl group for R ⁴ and A include C 1 -C ⁴ , such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxybutyl, and 4-hydroxybutyl. Four hydroxyalkyl groups are included. Examples of the trihalogenomethylsulfonylamino group for R ⁴ include trifluoromethylsulfonylamino, trichloromethylsulfonylamino and the like. As a group indicating that X is bonded via a spacer having 2 or less carbon atom chains,
Specifically ^{-CO -, - CH (OR 6} ) -, - CH 2 -,
—C≡C—, —CH ＝ CH—, —CH ₂ CH ₂ — and the like. R ⁶ represents a protecting group for a hydroxyl group, and examples of the protecting group include methoxymethyl, methylthiomethyl, benzyloxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl, tetrahydropyranyl and the like. In addition, both the E-form and the Z-form which are isomers derived from the double bond are included. Examples of the salt of the compound represented by the general formula (1) include acid addition salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and acid addition salts of organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid. Salt, acetic acid, tartaric acid, maleic acid, fumaric acid, oxalic acid,
Lactic acid, acid addition salts of organic carboxylic acids such as citric acid, or salts with alkali metals such as sodium salts and potassium salts,
It can lead to salts of physiologically acceptable acids or bases, such as salts with alkaline earth metals such as calcium salts.

[Embodiment of the Invention] The production method of the compound of the invention represented by the general formula (1) will be described in detail below. The compound of the general formula (1) of the present invention can be produced by a production method described by the following reaction formula. [Production method 1]

Embedded image (Wherein, W represents a halogen atom, and R ¹ , R ² , R ³ and A are as defined above)

[Production method 2]

Embedded image (In the formula, Y represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and R ² , R ³ and A are as defined above.)

[Manufacturing method 3]

Embedded image (In the formula, R ¹ ′ represents a hydroxyl group, a substituted or unsubstituted amino group, a phenoxy group, a mercapto group, a phenylmercapto group, a phenylsulfinyl group or a phenylsulfonyl group, and R ² , R ³ , A and Y are as defined above. Synonymous)

[Production Method 1] Compound (1) can be produced by reacting compound (2) with compound (3) in the presence of a base. Examples of the base include organic bases such as triethylamine and pyridine, sodium hydride,
n-butyllithium, sec-butyllithium, ter
alkali metal salts such as t-butyllithium, potassium tert-butoxy, sodium amide, lithium amide,
Amide bases such as lithium diisopropylamide, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate can be used. The reaction is preferably performed in a solvent. Examples of the solvent include tetrahydrofuran (THF), N, N-dimethylformamide (DMF), N, N-dimethylacetamide, dimethyl sulfoxide (DMSO), methylene chloride, benzene, toluene, acetone, methyl ethyl ketone, and the like, or a mixture thereof. Used. The amount of the base to be used is 1 equivalent to 10 equivalents relative to compound (2).
The equivalent is preferably 1 to 4 equivalents. The reaction temperature is from −30 ° C. to around the boiling point of the solvent used, preferably from −20 ° C. to room temperature. The reaction time is generally 15 minutes to 24 hours, preferably 15 minutes to 4 hours.

[Production Method 2] Compound (1b) is prepared by reacting compound (1)
It can be produced by subjecting a) to catalytic reduction in a solvent. The reaction is performed under a hydrogen atmosphere. As the solvent,
For example, water, methanol, ethanol, ethyl acetate and the like, or a mixture thereof can be used. The reaction can be carried out at normal pressure or under pressure using a transition metal catalyst such as palladium carbon, palladium black, and rhodium carbon. The reaction temperature is from room temperature to around the boiling point of the solvent, preferably from room temperature to 60 ° C. The reaction time is generally 1 hour to 48 hours, preferably 3 hours to 24 hours. In addition, if necessary, an organic base such as triethylamine or pyridine may be added to perform the reduction reaction.

[Production Method 3] Compound (1c) is prepared by reacting compound (1c)
a) is subjected to a hydrolysis reaction or compound (1a)
And compound (B) [Compound (B) is a substituted or unsubstituted amine, and may be a mono- or di-substituted amine. As the substituent, for example, methyl, ethyl, propyl, butyl, etc. 4 lower alkyl groups,
The substituent is a mono- or di-substituted phenyl group. Examples of the substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and a lower alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl and butyl. Groups, methoxy, ethoxy, propoxy, isopropoxy, lower alkoxy groups such as butoxy, methoxycarbonyl, alkoxycarbonyl groups such as ethoxycarbonyl,
Amino, methylamino, amino groups such as dimethylamino,
Acylamino groups such as acetylamino and propionylamino, and lower alkylthio groups such as methylthio and ethylthio, etc., and represents thiourea, thiophenol or phenol], and if necessary, oxidation. it can.

In the case of hydrolysis of the compound (1a), examples of the base used in the reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate. And the like. As the solvent used in the reaction, for example, water,
Methanol, ethanol, THF, DMF, DMSO,
Acetone, methyl ethyl ketone, and the like, or a mixture thereof are mentioned. The reaction temperature is from 0 ° C. to near the boiling point of the solvent, preferably from 60 ° C. to 150 ° C. The reaction time is generally 12 hours to 120 hours, preferably 24 hours.
Hours to 72 hours.

When reacting the compound (1a) with the compound (B), as a base used as necessary, for example, an organic base such as triethylamine or pyridine, or a hydrogen such as lithium hydride, sodium hydride or potassium hydride may be used. And alkali metal amides such as sodium amide and lithium amide, and alkali metal carbonates such as sodium carbonate and potassium carbonate. Examples of the solvent used for the reaction include methanol, ethanol, THF, acetonitrile, DMF, DMSO, benzene, toluene, acetone, methyl ethyl ketone, and the like, or a mixture thereof. The reaction temperature is from 0 ° C to near the boiling point of the solvent, preferably from 60 ° C to 150 ° C. The reaction time is generally 1 hour to 60 hours, preferably 3 hours to 40 hours.

When an oxidation reaction is carried out after reacting the compound (1a) with the compound (B), examples of the oxidizing agent used for the reaction include hydrogen peroxide, peracetic acid, trifluoroperacetic acid, and the like.
m-chloroperbenzoic acid, sodium metaperiodate and the like. Examples of the solvent used for the reaction include methanol, ethanol, propanol, ether, THF,
Examples include dichloromethane, chloroform, DMF, DMSO, ethyl acetate, acetonitrile, acetic acid, formic acid, aqueous ammonia, water, and the like, and mixtures thereof. The reaction temperature is from -20 ° C to near the boiling point of the solvent, preferably from -10 ° C to 40 ° C. The reaction time is usually 10
Minutes to 8 hours, preferably 30 minutes to 5 hours. The compound used as a starting material can be a compound known per se in the literature, or a method known in the literature or a method described in the literature.

<Actions and Effects of the Invention> Among the compounds (1) of the present invention, the cell growth inhibitory activity of the following representative compounds will be described in detail below. The cultured cancer cell lines were NIH3T3 cells derived from mouse fibroblasts as normal cells, Ki-ras gene derived from Kirsten sarcoma virus and Har-
vey sarcoma virus-derived Ha-ras gene
Cells NIH3T3-Ki-ras and NIH3T3-
Ha-ras was used as a cancer cell. • 6-chloro-9- [4- (4-chlorobenzoyl) -3,5-dichlorobenzyl] -9H-purine. (Compound A: Example 10a) • 2-amino-9- [3,5-dichloro -4- (4-chlorobenzoyl)
[Benzyl] -6-mercapto-9H-purine. (Compound B: Example 23) • 2-amino-9- (4-methoxycarbonylbenzyl) -6-phenylamino-9H-purine. (Compound C: Example 40) -2-amino-6-benzenesulfonyl-9- (4-benzoylaminobenzyl) -9H-purine (Compound D: Example 49)-2-amino-9- (4-hydroxymethylbenzyl) -6-phenyl Amino-9H-purine. (Compound E: Example 81) 2-Amino-6-chloro-9- [4-[(Z) -phenylvinylene] benzyl] -9H-purine. (Compound F: Example 86) ) ・ 2-amino-6-chloro-9- [4- (phenylmethyl) benzyl]
-9H-purine. (Compound G: Example 88) L-651,582. (Comparative control compound)

<NIH3T3 cells, NIH3T3-Ki-ras cells and
Measurement of proliferation inhibitory activity using NIH3T3-Ha-ras cells> Each of the cultured cancer cells (2 × 10 ³ ) and the culture solution containing the test compound were placed in a 96-well plate (NUNC, 016700).
8) Add 200 μl to each well of 37).
The cells were cultured for 72 hours under 95% CO ₂ -95% air. After culture, M
TT [3- (4,5-dimethylthiazol-2-yl)
-2,5-diphenyl-2H-tetrazolium bromide] solution (2 mg / ml) was added to each well in an amount of 25 μl,
The cells were further cultured for 4 hours at 37 ° C. in a 5% CO ₂ -95% air atmosphere. After removing the culture solution, 200 μl of dimethyl sulfoxide was added to each well to dissolve the formed MTT-formazan, and the absorbance at 540 nm was measured using a microplate photometer to obtain an index of the number of cells. The inhibition rate was calculated from the following formula, and the concentration (I
_C50 ) was determined.

(Equation 1) Each cancer cell line was RPM containing 10% FCS.
The cells were cultured in an I1640 medium (Nissui Pharmaceutical). The obtained IC
_{The 50} (μg / ml) values are shown in Table 1.

[0019]

[Table 1] <Measurement of angiogenesis inhibitory effect using fertilized chicken eggs> A hole was made in a 7-day-old fertilized chicken egg, about 4 ml of egg white was extracted, and the shell on the air chamber side was removed together with the eggshell membrane. Capped with 35 mm Petri dishes and incubated at 37 ° C. for 2-3 days. An 8 mm Teflon ring was allowed to stand on the developed chorioallantoic membrane, and a test solution of 50 μM was added into the ring. After incubation at 37 ° C. for several days, the presence or absence of angiogenesis was observed. When the angiogenesis inhibitory effect was significantly recognized as compared with the control, it was evaluated as +, and when it was not observed,-. Table 2 shows the results.

[Table 2]

The novel condensed heterocyclic compound represented by the general formula (1) and a salt thereof are different from L-651,582 in that NIS3T3-Ki-ras cells, which are ras oncogene-introduced cancer cells,
It had a strong growth inhibitory effect on NIH3T3-Ha-ras cells, and a weaker growth inhibitory effect on normal NIH3T3 cells. Compound (1) and its salt had a weak growth inhibitory effect on normal cells, and a strong and selective growth inhibitory effect on cancer cells into which the ras oncogene was introduced was observed. In addition, it showed angiogenesis inhibitory action comparable to that of L-651,582. Accordingly, the compounds of the present invention include, for example, colon cancer,
It is useful as an agent for preventing and treating malignant tumors such as bile duct cancer and pancreatic cancer. Compound (1) and a salt thereof are themselves
Alternatively, it can be mixed with an appropriate pharmacologically acceptable carrier excipient or diluent and administered orally or parenterally in the form of powder, granules, tablets, capsules, injections and the like.
The dose varies depending on the target disease, symptom, administration subject, administration method and the like. For example, when administered to an adult, the daily dose is 600 to 1200 mg by oral administration, and 5 times by intravenous injection.
0 to 100 mg. In the case of oral administration, it is preferable to administer it in two or three divided doses.

[0021]

EXAMPLES The starting compounds used in the present invention and the method for producing the compound (1) of the present invention will be specifically and specifically described below with reference examples and examples. Reference Example 1 4- (4-chlorobenzoyl) -3,5-dichloroben
Ziryl chloride 4- (4-chlorobenzoyl) -3,5-dichlorobenzyl alcohol (4.73 g, 15 mmol) was dissolved in acetonitrile (50 ml) and 4-dimethylaminopyridine (7.33 g, 60 mmol,
4.0eq.), Methanesulfonyl chloride (3.48ml, 45mmol,
3.0 eq.) And stirred at room temperature for 4 hours. After diluting the reaction solution by adding excess dichloromethane, water (10 ml) was added and the mixture was stirred at room temperature for 30 minutes. Excess water was added to carry out a liquid separation operation, and the organic layer was dried over Na ₂ SO ₄ . After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (0%).
-2% AcOEt in hexane).
(3.66 g, 73%) was obtained as white crystals. EI-MS:. M / z 334 (M +) 1 H-NMR (CDCl 3) δ 7.76 (d, 2H, J = 8.5Hz), 7.47 (d, 2
H, J = 8.5 Hz), 7.44 (s, 2H), 4.57 (s, 2H). Reference Example 2 N- (4-chloromethylphenyl) benzamide N- (4-hydroxymethylphenyl) benzamide (227 mg,
1 mmol) was suspended in acetonitrile (15 ml), and triethylamine (0.18 ml, 1.3 mmol, 1.3 eq.) And methanesulfonyl chloride (0.1 ml, 1.3 mmol, 1.3 eq.) Were added under ice-cooling, and the mixture was stirred for 2.5 hours. An excess amount of chloroform was added to the reaction solution, washed with water, and the organic layer was dried over Na ₂ SO ₄ . After filtration, the residue was subjected to silica gel column chromatography (33% A
Purified with cOEtin hexane) to give the title compound (189 mg, 7
7%) as white crystals. EI-MS:. M / z 245 (M +) 1 H-NMR (CDCl 3) δ7.90-7.26 (m, 10H), 4.59 (s, 2H).

Reference Example 3 4-acetoxybenzyl chloride 4-acetoxybenzyl alcohol (499 mg, 3 mmol) was dissolved in dimethylformamide (5 ml), and carbon tetrachloride (0.87 m
l, 9mmol, 3.0eq.), triphenylphosphine (1.57g,
6 mmol, 2.0 eq.) And stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (1
-17% AcOEt in hexane).
77 mg, 68%) as a colorless oil. EI-MS:. M / z 184 (M +) 1 H-NMR (CDCl 3) δ7.40 (d, 2H, J = 8.6Hz), 7.08 (d, 2
H, J = 8.6 Hz), 4.58 (s, 2H), 2.30 (s, 3H). Reference Example 4 4- Phenoxycarbonylbenzyl chloride phenol (471 mg, 5 mmol) was dissolved in pyridine (8 ml), and cooled under ice-cooling. -Chloromethylbenzoyl chloride (1.13g,
6 mmol, 1.2 eq.) And stirred at room temperature for 2 hours. After adding methanol (1 ml) and stirring at room temperature for 5 minutes, the solvent was distilled off under reduced pressure. The residue was azeotroped with toluene (three times), dissolved in chloroform and washed with water. The organic layer was dried over Na ₂ SO _4,
After filtration, the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue (eluted with 2-17% AcOEt in hexane)
The title compound (555 mg, 45%) was obtained as a white powder. EI-MS:. M / z 246 (M +) 1 H-NMR (CDCl 3) δ8.24 (d, 2H, J = 8.3Hz), 7.80-7.20
(m, 7H), 4.69 (s, 2H).

Reference Example 5 4-hydroxybenzyl alcohol
Tert-butyldimethylsilyl ether 4-hydroxybenzyl alcohol (1.24 mg, 10 mmol) was dissolved in dichloromethane (10 ml), 4-dimethylaminopyridine (49 mg, 0.4 mmol, 0.04 eq.), Triethylamine
(1.53 ml, 11 mmol, 1.1 eq.) And t-butyldimethylsilyl chloride (1.66 g, 11 mmol, 1.1 eq.) Were added, and the mixture was stirred at room temperature for 10 minutes. After adding excess water and stirring for 10 minutes, dichloromethane was added to carry out a liquid separation operation. The organic layer Na ₂ SO ₄
, And the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (1-10% AcOEt in hexa
elution with ne) to give the title compound (1.26 g, 60%) as a colorless oil. EI-MS:. M / z 238 (M +) 1 H-NMR (DMSO-d 6) δ9.27 (s, 1H), 7.09 (d, 2H, J = 8.4
Hz), 6.71 (d, 2H, J = 8.4Hz), 4.57 (s, 2H), 0.88 (s,
9H), 0.04 (s, 6H). Reference Example 6 4-benzoyloxybenzyl alcohol 4-hydroxybenzyl alcohol t-butyldimethylsilyl ether (1.05 g, 5 mmol) was dissolved in pyridine (6 ml).
4-Dimethylaminopyridine (733 mg, 6 mmol, 1.2 eq.) Was added, and benzoyl chloride (0.7 ml, 6 mmol, 1.2 e.
q.) was added dropwise and stirred at room temperature for 10 minutes. Methanol (5ml)
Was added and stirred for 30 minutes, and the solvent was distilled off under reduced pressure. The residue was azeotroped with toluene (twice), dissolved in chloroform and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was distilled off under reduced pressure. After azeotropic distillation with toluene (three times), the residue was dissolved in tetrahydrofuran (3 ml), and a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (7.5 ml, 7.5
mmol, 1.5 eq.) and stirred for 30 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in chloroform and washed with water.
The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (1-33%
Purified with AcOEt in hexane) to give the title compound (301m
g, 26%) as white crystals. EI-MS:. M / z 228 (M +) 1 H-NMR (CDCl 3) δ 8.22 (d, 2H, J = 7.4Hz), 7.69-7.20
(m, 7H), 4.74 (s, 2H).

Reference Example 7 4-benzoyloxybenzylc
Dissolve chloride 4- benzoxybenzyl alcohol (194 mg, 1.2 mmol) in dimethylformamide (3 ml) and add carbon tetrachloride (0.3
5ml, 3.6mmol, 3.0eq.), Triphenylphosphine (629
mg, 2.4 mmol, 2.0 eq.) and stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 0-2% AcOEt in hexane) to give the title compound.
(232 mg, 78%) was obtained as white crystals. EI-MS:. M / z 246 (M +) 1 H-NMR (CDCl 3) δ8.22 (d, 2H, J = 7.4Hz), 7.69-7.19
(m, 7H), 4.63 (s, 2H). Reference Example 8 4-chloromethylbenzanilideaniline (0.46 ml, 5 mmol) was dissolved in pyridine (8 ml).
4-Chloromethylbenzoyl chloride (1.13g, 6mm
ol, 1.2 eq.) and stirred at room temperature for 2 hours. methanol
(1 ml) was added and the mixture was stirred at room temperature for 10 minutes, and the solvent was distilled off under reduced pressure. The residue was azeotroped with toluene (three times), dissolved in chloroform and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 10-50% AcOEt in hexane) to give the title compound (360 mg, 29%) as a white powder. EI-MS:. M / z 245 (M +) 1 H-NMR (CDCl 3) δ7.79-7.16 (m, 10H), 4.65 (s, 2H).

Reference Example 9 N- (4-chloromethylphenyl) -N
- methylbenzamide N-(4-hydroxymethylphenyl) -N- methylbenzamide (169 mg, 0.7 mmol) was dissolved in acetonitrile (2 ml), under ice-cooling triethylamine (0.20ml, 1.4mmol, 2.0e
q.), methanesulfonyl chloride (0.11 ml, 1.4 mmol, 2.
0 eq.) And stirred for 3 hours. Methanol (1m
l) was added and the mixture was stirred for 10 minutes, and the solvent was distilled off under reduced pressure. After dissolving the residue in chloroform and washing with water, the organic layer was washed with Na ₂ S
After drying over O ₄ and filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (33% AcOEt in hexa
elution with ne) to give the title compound (178 mg, 98%) as pale yellow crystals. EI-MS:. M / z 260 (M +) 1 H-NMR (CDCl 3) δ7.42-7.22 (m, 9H), 4.39 (s, 2H),
3.48 (s, 3H). Reference Example 10 4-iodobenzyl chloride 4-iodobenzyl alcohol (2.35 g, 10 mmol) was dissolved in acetonitrile (30 ml), and triethylamine (5.58 ml,
40mmol, 4.0eq.), 4-dimethylaminopyridine (214mg,
2 mmol, 0.2 eq.), And methanesulfonyl chloride (2.32 ml, 30 mmol, 3.0 eq.) Was added dropwise under ice cooling.
Stirred for hours. Add excess dichloromethane to the reaction,
Water (10 ml) was added and the mixture was stirred at room temperature for 10 minutes. Excess water was added to carry out a liquid separation operation, and the organic layer was dried over Na ₂ SO _4. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 0-17% AcOEt in hexane) to give the title compound (1.23 g, 49%) as white crystals. ¹ H-NMR (CDCl ₃ ) δ 7.70 (d, 2H, J = 8.2Hz), 7.13 (d, 2
H, J = 8.2Hz), 4.52 (s, 2H).

Reference Example 11 4-benzoylbenzyl chloride
De 4-benzoyl-benzyl alcohol (236 mg, 1.1 mmol) was dissolved in acetonitrile (5 ml), 4-dimethylaminopyridine (672mg, 5.5mml, 5.0eq.) Was added, under ice-cooling methanesulfonyl chloride (0.43 ml, 5.5 mmol, 5.0 eq.) and stirred at room temperature for 2 hours. After dilution with excess dichloromethane, water (5 ml) was added and the mixture was stirred at room temperature for 10 minutes. Excess water was added to carry out a liquid separation operation, and the organic layer was dried over Na ₂ SO _4. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 10-33% AcOEtin hexane) to give the title compound (143 mg, 56%) as a white powder. ¹ H-NMR (CDCl ₃ ) δ7.85-7.37 (m, 9H), 4.64 (s, 2H). Reference Example 12 4- [α- (2- oxapropoxy ) benzyl]
Emissions benzyl alcohol t-butyldiphenylsilyl ether Under argon atmosphere, 4-(t-butyldiphenylsiloxy methyl) benzhydrol (815 mg, 1.8 mmol) was dissolved in tetrahydrofuran (10 ml), sodium under ice-cooling hydride (7
9 mg, 2 mmol, 1.1 eq.) And stirred at room temperature for 30 minutes. Chloromethyl methyl ether (0.32ml, 4.4mmol, 2.4eq.)
Was added, and the mixture was stirred at room temperature for 17.5 hours and with heating under reflux for 30 hours.
Under ice-cooling, water was added until foaming stopped, excess dichloromethane was added, and the mixture was washed with water. The organic layer was dried over Na ₂ SO _4,
After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 0-4% AcOEt in hexane) to give the title compound (601 mg, 67%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ7.73-7.31 (m, 19H), 5.72 (s, 1H),
4.74 (s, 2H), 4.69 (s, 2H), 3.40 (s, 3H), 1.08 (s,
9H).

Reference Example 13 4- [α- (2-oxapropoxy)
Benzyl] benzyl alcohol 4- [α- (2-oxapropoxy) benzyl] benzyl alcohol t-butyldiphenylsilyl ether (583 mg, 1.2 mmo
l) in tetrahydrofuran (5 ml) and 1M tetrabutylammonium fluoride in tetrahydrofuran (2.
4 ml, 2.4 mmol, 2.0 eq.) And stirred at room temperature for 10 minutes.
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 10-33% AcOEt in hexane).
The title compound (198 mg, 64%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ7.38-7.41 (m, 9H), 5.72 (s, 1H),
4.73 (s, 2H), 4.68 (s, 2H), 3.40 (s, 3H). Reference Example 14 4- [α- (2-oxapropoxy) benzyl]
Benzyl chloride 4- [α- (2- oxapropoxy ) benzyl] benzyl alcohol (188 mg, 0.73 mmol) was dissolved in acetonitrile (5 ml), and 4-dimethylaminopyridine (446 mg, 3.7 mmol, 5.0e
q.) and add methanesulfonyl chloride (0.29 ml,
(3.7 mmol, 5.0 eq.) And stirred at room temperature for 2 hours. Excess dichloromethane was added, water (5 ml) was added, and the mixture was stirred at room temperature for 10 minutes. Add excess water and perform liquid separation to separate the organic layer.
After drying over Na ₂ SO ₄ and filtration, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (0-10% AcOEt i
The residue was purified with n-hexane to give the title compound (122 mg, 60%) as a white oil. ¹ H-NMR (CDCl ₃ ) δ7.35-7.32 (m, 9H), 5.72 (s, 1H),
4.67 (s, 2H), 4.56 (s, 2H), 3.39 (s, 3H).

Example 1 2-amino-6-chloro-9- (4-methyl
Benzyl) -9H-purine, and 2-amino-6-chloro-7
-(4-Methylbenzyl) -7H-purine 2-amino-6-chloropurine (339 mg, 2 mmol) was suspended in dimethylformamide (5 ml), and cesium carbonate (782 mg, 2.4
mmol, 1.2 eq.) and stirred at room temperature for 30 minutes, and then 4-methylbenzyl bromide (444 mg, 2.4 mmol, 1.2 eq.) was added and stirred for 10 minutes. After filtration, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with water, and the organic layer was washed with Na ₂ S
And dried over O _4. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (0-4% MeOH in CHCl3).
₍ Eluted with ₃ ) and purified with 2-amino-6-chloro-9- (4-methylbenzyl) -9H-purine (336 mg, 61%), and 2-amino-6-
Chloro-7- (4-methylbenzyl) -7H-purine (77mg, 14%)
Were each obtained as a white powder. 2-amino-6-chloro-9- (4-methylbenzyl) -9H-purine FAB-MS: m / z 274 (MH ⁺ ) .UV: λ _max (H ₂ O) 310, 222 nm; λ _max ( HCl) 315, 222 nm
_{;. λ max (NaOH) 310} , 223 nm 1 H-NMR (DMSO-d 6) δ8.21 (s, 1H), 7.16 (m, 4H), 6.9
3 (bs, 2H), 5.23 (s, 2H), 2.26 (s, 3H). 2-Amino-6-chloro-7- (4-methylbenzyl) -7H-purine FAB-MS: m / z 274 ( MH ⁺ ) .UV: λ _max (H ₂ O) 323, 236 nm; λ _max (HCl) 323, 235
_{nm;. λ max (NaOH)} 322, 235 nm 1 H-NMR (DMSO-d 6) δ8.55 (s, 1H), 7.17 (d, 2H, J = 8.0
Hz), 7.06 (d, 2H, J = 8.0Hz), 6.66 (bs, 2H), 5.52
(s, 2H), 2.28 ( s, 3H). The following table 2 the N ^{9-substituted} compound synthesized according to Example 1
9

[0029]

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[0030]

[Table 2]

[0031]

[Table 3]

[0032]

[Table 4]

[0033]

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[0034]

[Table 5]

[0035]

[Table 6]

[0036]

[Table 7]

[0037]

[Table 8]

[0038]

[Table 9]

The N ⁷ -substituted compounds synthesized according to Example 1 are shown in Tables 10 to 14.

Embedded image

[0040]

[Table 10]

[0041]

[Table 11]

[0042]

[Table 12]

[0043]

Embedded image

[Table 13]

[0044]

[Table 14]

Example 20 2,6-diamino-9- (4-methoxyca
(Rubonylbenzyl) -9H-purine 2,6-diaminopurine (150 mg, 1 mmol) was suspended in dimethylformamide (5 ml), and cesium carbonate (391 mg, 1.2 mmo
l, 1.2 eq.) and stirred for 30 minutes. Methyl 4-bromomethylbenzoate dissolved in dimethylformamide (2 ml)
(275 mg, 1.2 mmol, 1.2 eq.) And the mixture was further stirred for 5 hours. After filtration, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with water, and the organic layer was dried over Na ₂ SO ₄ .
After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 0-5% MeOH in CHCl ₃ ) to give the title compound (121 mg, 41%) as a white powder. FAB-MS: m / z 299 (MH ⁺ ). UV: λ _max (H ₂ O) 281, 222 nm; λ _max (HCl) 295, 23
_{4, 225 nm;. Λ max} (NaOH) 281, 235, 220 nm 1 H-NMR (DMSO-d 6) δ7.93 (d, 2H, J = 8.2Hz), 7.81
(s, 1H), 7.31 (d, 2H, J = 8.2Hz), 6.70 (bs, 2H), 5.79
(bs, 2H), 5.29 (s, 2H), 3.83 (s, 3H).

Example 21 2,6-Diamino-9- [4- (4-chloro
Benzoyl) -3,5-dichlorobenzyl] -9H-purine 2-amino-6-chloro-9- [4- (4-chlorobenzoyl) -3,5-dichlorobenzyl] -9H-purine (Example 9 Compound) (93 mg,
0.2 mmol) in methanolic ammonia (10 ml),
Stir at 100 ° C. for 12 hours in a steel sealed tube. After cooling at room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 0-5% MeOH in CHCl ₃ ) to give the title compound (88 mg, 98%) as a white powder. FAB-MS:. M / z 449 (MH +) 1 H-NMR (DMSO-d 6) δ7.88 (s, 1H), 7.76 (d, 2H, J = 8.
5Hz), 7.66 (d, 2H, J = 8.5Hz), 7.53 (s, 2H), 6.75 (b
s, 2H), 5.86 (bs, 2H), 5.29 (s, 2H). Elemental analysis Calculated C ₁₉ H ₁₃ Cl ₃ N ₆ O.MeOH: C, 50.07; H,
3.57; N, 17.44. Found: C, 50.29; H, 3.28; N, 17.44. The compounds synthesized according to Example 21 below are shown in Tables 15-24.

[0047]

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[0048]

[Table 15]

[0049]

[Table 16]

[0050]

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[0051]

[Table 17]

[0052]

[Table 18]

[0053]

[Table 19]

[0054]

[Table 20]

[0055]

[Table 21]

[0056]

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[0057]

[Table 22]

[0058]

[Table 23]

[0059]

[Table 24]

[0060]

[Table 25]

Example 47 2-amino-9- (4-methoxycarbo
Nylbenzyl) -6-phenylsulfinyl-9H-purine,
And 2-amino-9- (4-methoxycarbonylbenzyl) -6-
Phenylsulfonyl- 9H-purine 2-amino-9- (4-methoxycarbonylbenzyl) -6-phenylthio-9H-purine (compound of Example 43) (196 mg, 0.5 mmo
l) was dissolved in dichloromethane (3 ml), and m-chloroperbenzoic acid (70% pure 200 mg, 0.8 mmol, 1.6 eq.) was added under ice-cooling.
The mixture was stirred for 30 minutes. After dilution with dichloromethane, a saturated aqueous sodium hydrogen carbonate solution (1 ml) was added, and the mixture was stirred at room temperature for 5 minutes. An excess saturated aqueous sodium hydrogen carbonate solution was added to carry out a liquid separation operation, and the organic layer was dried over Na ₂ SO ₄ . After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 0-2% MeOH in CHCl ₃ ).
2-amino-9- (4-methoxycarbonylbenzyl) -6-phenylsulfinyl-9H-purine (60 mg, 30%), and 2-amino-9- (4-methoxycarbonylbenzyl) -6-phenylsulfonyl-9H -Purines (71 mg, 34%) were each obtained as a white powder. 2-amino-9- (4-methoxycarbonylbenzyl) -6-phenyl
Rusulfinyl-9H-purine FAB-MS: m / z 408 (MH ⁺ ). UV: λ _max (H ₂ O) 334, 231 nm; λ _max (HCl) 339, 230
_{nm;. λ max (NaOH)} 330, 283, 233 nm 1 H-NMR (CDCl 3) δ8.01-7.98 (m, 4H), 7.78 (s, 1H),
7.45-7.30 (m, 5H), 5.34 (bs, 2H), 5.28 (s, 2H), 3.9
1 (s, 3H). 2-amino-9- (4-methoxycarbonylbenzyl) -6-phenyl
Rusulfonyl - 9H-purine FAB-MS: m / z 424 (MH ⁺ ). UV: λ _max (H ₂ O) 346, 232 nm; λ _max (HCl) 349, 230 nm
_{;. λ max (NaOH) 352} , 282, 237, 221 nm 1 H-NMR (CDCl 3) δ8.25-8.02 (m, 4H), 7.97 (s, 1H),
7.64-7.54 (m, 5H), 5.43 (bs, 2H), 5.32 (s, 2H), 3.9
2 (s, 3H). Hereinafter, compounds synthesized according to Example 47 are shown in Tables 26 to 27.
Shown in

[0062]

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[0063]

[Table 26]

[0064]

[Table 27]

Example 53 2-amino-9- (4-aminobenzyl)
6-chloro-9H-purine 2-amino-6-chloro-9- (4-nitrobenzyl) -9H-purine
(Compound of Example 4) (4.57 g, 15 mmol) in methanol (400 m
l), platinum oxide (60 mg, 0.01% w / w) was added, and the mixture was stirred under a hydrogen atmosphere at normal pressure and room temperature for 4.5 hours. After filtration through celite, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 2-2.5% MeOH in CHCl ₃ ) to give the title compound (3.29 g, 80%) as a yellow powder. FAB-MS: m / z 275 (MH ⁺ ). UV: λ _max (H ₂ O) 309, 245, 223, 209 nm; λ _max (HCl) 31
_{7, 212 nm;. Λ max} (NaOH) 308, 240, 221, 212 nm 1 H-NMR (DMSO-d 6) δ8.13 (s, 1H), 6.97 (d, 2H, J = 8.3
Hz), 6.92 (bs, 2H), 6.50 (d, 2H, J = 8.3Hz), 5.11 (s,
. 2H), 5.05 (s, 2H) Analysis Calculated _{C 12 H 11 ClN 6 · 4} / 5H 2 O: C, 49.85; H,
4.39; N, 29.07. Found: C, 50.24; H, 4.26; N, 28.68.

Example 54 2-Amino-9- (4-aminobenzyl)
) -9H-purine 2-amino-6-chloro-9- (4-nitrobenzyl) -9H-purine
(Compound of Example 4) (609 mg, 2 mmol) in methanol (60 ml)
Suspended in triethylamine (0.33 ml, 2.4 mmol, 1.2e
q.) and 10% palladium on carbon (11 mg, 2% w / w), and the mixture was stirred at 40 ° C. and normal pressure for 22 hours under a hydrogen atmosphere. After allowing the reaction solution to cool at room temperature, it was filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (0-5%
MeOH in CHCl ₃ ) to give the title compound (277 mg, 58
%) As yellow crystals. FAB-MS: m / z 241 (MH ⁺ ). UV: λ _max (H ₂ O) 307, 244, 223, 207 nm; λ _max (HCl) 31
7, 226, 210 nm;. Λ max (NaOH) 319, 225, 210 nm 1 H-NMR (DMSO-d 6) δ8.64 (s, 1H), 8.13 (s, 1H), 7.0
8 (d, 2H, J = 7.1Hz), 6.58 (bs, 2H), 6.57 (d, 2H, J = 7.1
Hz), 5.16 (bs, 2H), 5.13 (s, 2H).

Example 55 2-amino-9- (4-aminobenzyl)
) -6-hydroxy-9H-purine 2-amino-9- (4-aminobenzyl) -6-chloro-9H-purine
(Compound of Example 53) (2.2 g, 8 mmol) in methanol (60 ml)
And add 10N aqueous sodium hydroxide solution (30 ml)
The mixture was heated under reflux for 4 hours. After cooling the reaction solution at room temperature, the solvent was distilled off under reduced pressure. The residue was suspended by adding water, filtered and washed with water to give the title compound (2.18 g, 91%) as a white powder. FAB-MS: m / z 257 (MH ⁺ ). UV: λ _max (H ₂ O) 250, 216 nm; λ _max (HCl) 259, 218 nm
_{;. λ max (NaOH) 271,246} , 219 nm 1 H-NMR (DMSO-d 6) δ7.33 (s, 1H), 6.95 (d, 2H, J = 8.
3Hz), 6.49 (d, 2H, J = 8.3Hz), 5.02 (bs, 4H), 4.89
(s, 2H).

Example 56 2-amino-9- (4-acetylamino
(Benzyl) -6-chloro-9H-purine 2-amino-9- (4-aminobenzyl) -6-chloro-9H-purine
(Compound of Example 53) (54 mg, 0.2 mmol) in pyridine (2 ml)
-20 ° C and acetic anhydride (23ml, 0.24mmol, 1.2eq.)
Was added and stirred for 1 hour. Methanol (1 ml) was added and the mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 0-10% MeOH in CHCl ₃ ) to give the title compound (58 mg, 91%) as a white powder. FAB-MS: m / z 317 (MH ⁺ ) .UV: λ _max (H ₂ O) 323, 246, 224 nm; λ _max (HCl) 325, 24
_{7, 221 nm;. Λ max} (NaOH) 323, 246, 221 nm 1 H-NMR (DMSO-d 6) δ9.95 (bs, 1H), 8.21 (s, 1H), 7.
55 (d, 2H, J = 8.5Hz), 7.22 (d, 2H, J = 8.5Hz), 6.94
(bs, 2H), 5.23 (s, 2H), 2.03 (s, 3H).

The compounds synthesized according to Example 56 are shown in Tables 28 to 36 below.

[0070]

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[0071]

[Table 28]

[0072]

[Table 29]

[0073]

[Table 30]

[0074]

[Table 31]

[0075]

[Table 32]

[0076]

[Table 33]

[0077]

[Table 34]

[0078]

[Table 35]

[0079]

[Table 36]

[0080]

[Table 37]

Example 80 2-amino-6-chloro-9- (4-hydrido
Roxymethylbenzyl) -9H-purine Lithium aluminum hydride (37m
g, 2.0 mmol, 4.0 eq.) were suspended in tetrahydrofuran (10 ml) and dissolved in ice-cooled tetrahydrofuran (5 ml) to give 2-amino-6-chloro-9- (4-methoxycarbonylbenzyl) -9H-.
Purine (the compound of Example 6) (318 mg, 1 mmol) was added dropwise, and the mixture was stirred at room temperature for 19 hours. Under ice-cooling, water (0.4 ml) and a 15% aqueous sodium hydroxide solution (0.4 ml) were added, and water (1.2 ml) was further added at room temperature, followed by stirring for 2 hours. After filtration through celite, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 0-4% MeOH in CHCl ₃ ) to give the title compound.
(133 mg, 46%) was obtained as a white powder. FAB-MS: m / z 290 (MH ⁺ ). UV: λ _max (H ₂ O) 309, 248, 222 nm; λ _max (HCl) 315, 21
_{8 nm;. Λ max (NaOH} ) 308, 220 nm 1 H-NMR (DMSO-d 6) δ8.59 (s, 1H), 7.31 (d, 2H, J = 8.
2Hz), 7.23 (d, 2H, J = 8.2Hz), 6.93 (bs, 2H), 5.28
(s, 2H), 5.16 (t, 1H, J = 5.6Hz), 4.47 (d, 2H, J = 5.6H
z). Elemental analysis Calculated value C ₁₃ H ₁₂ ClN ₅ O ・ 2 / 5MeOH ・ 1 / 2H ₂ O: C, 5
1.73; H, 4.60; N, 22.51.Measured: C, 52.02; H, 4.32; N, 22.42.

Example 81 2-amino-9- (4-hydroxymethyl
Benzyl) -6-phenylamino-9H-purine Under an argon atmosphere, 2-amino-9- (4-methoxycarbonylbenzyl) -6-phenylamino-9H-purine (the compound of Example 40) (187 mg, 0.5 mmol) Was dissolved in tetrahydrofuran (5 ml), a 1 M lithium aluminum hydride tetrahydrofuran solution (0.66 ml, 0.66 mmol, 3.0 eq.) Was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 22 hours. Under ice cooling, water (50 ml) and a 15% aqueous sodium hydroxide solution (50 ml) were added, and water (0.15 ml) was added at room temperature.
Was added and stirred overnight. After filtration through celite, the filtrate was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography.
(Eluted with 0-5% MeOH in CHCl ₃ ) to give the title compound (145
mg, 84%) as a white powder. FAB-MS: m / z 347 (MH ⁺ ). UV: λ _max (H ₂ O) 306, 254, 220 nm; λ _max (HCl) 309, 26
_{0, 220 nm;. Λ max} (NaOH) 306, 254, 220 nm 1 H-NMR (DMSO-d 6) δ9.57 (bs, 1H), 8.24 (d, 2H, J =
8.0Hz), 8.13 (s, 1H), 7.47-7.19 (m, 7H), 6.37 (bs,
2H), 5.45 (s, 2H), 5.37 (t, 1H, J = 5.8Hz), 4.68
(d, 2H, J = 5.8Hz). Elemental analysis Calculated C ₂₀ H ₁₉ N ₆ O ・ 3 / 10H ₂ O: C, 64.87; H,
5.33; N, 23.89.Measured: C, 65.03; H, 5.38; N, 23.55.

Example 82 2-Amino-6-chloro-9- (4-form
(Milbenzyl) -9H-purine 2-amino-6-chloro-9- (4-hydroxymethylbenzyl) -9
H-purine (the compound of Example 80) (29 mg, 0.1 mmol) was dissolved in dimethylformamide (2.5 ml), and molecular sieves 4Å (30 mg, 100% w / w), pyridinium dichromate (1
32 mg, 0.35 mmol, 3.5 eq.) And stirred at room temperature for 4 hours.
After ether (5 ml) was added for dilution, the mixture was filtered through Celite-silica gel, washed with ethyl acetate, and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (0-2%
MeOH in CHCl ₃ ) to give the title compound (17 mg, 59
%) As a white powder. FAB-MS: m / z 288 (MH ⁺ ). UV: λ _max (H ₂ O) 309, 249, 223 nm; λ _max (HCl) 315, 21
_{9 nm;. Λ max (NaOH} ) 309, 247, 220 nm 1 H-NMR (DMSO-d 6) δ9.98 (s, 1H), 8.59 (s, 1H), 7.8
9 (d, 2H, J = 7.9Hz), 7.42 (d, 2H, J = 7.9Hz), 6.94 (bs,
2H), 5.42 (s, 2H).

Example 83 2-Amino-9- (4-carboxyben
(Zyl) -6-chloro-9H-purine 2-amino-6-chloro-9- (4-hydroxymethylbenzyl) -9
H-purine (the compound of Example 80) (29 mg, 0.1 mmol) was suspended in acetone (3 ml), potassium permanganate (21 mg, 0.13 mmol, 1.3 eq.) Dissolved in water (1.5 ml) was added, and the mixture was added at room temperature. For 6 hours. After adding sodium thiosulfate (20 mg) and stirring for 5 minutes, the mixture was filtered through celite. After concentrating the filtrate and cooling with ice,
The precipitate was collected by filtration and washed with ether to give the title compound (22
mg, 73%) as a white powder. FAB-MS: m / z 305 (MH ⁺ ). UV: λ _max (H ₂ O) 322, 226 nm; λ _max (HCl) 316, 224 nm
_{;. λ max (NaOH) 309} , 229 nm 1 H-NMR (DMSO-d 6) δ12.96 (bs, 1H), 8.26 (s, 1H),
7.93 (d, 2H, J = 8.2Hz), 7.34 (d, 2H, J = 8.2Hz), 6.95
. (bs, 2H), 5.40 (s, 2H) Analysis Calculated _{C 13 H 10 ClN 5 O 2} · 1 / 2H 2 O: C, 49.93;
H, 3.55; N, 22.40.Measured: C, 49.60; H, 3.47; N, 22.07.

Example 84 2-amino-6-chloro-9- (4-fe
Nylethynylenebenzyl) -9H-purine 2-amino-6-chloro-9- (4-iodobenzyl) -9H-purine
(Compound of Example 8) (770 mg, 2 mmol) was dissolved in dimethylformamide (20 ml), and triethylamine (0.33 ml, 2.4 m
mol, 1.2eq.), copper (I) iodide (20mg, 0.1mmol, 0.005e
q.), phenylacetylene (0.26ml, 2.4mmol, 1.2e
q.) and bistriphenylphosphinepalladium (II) chloride (70 mg, 0.1 mmol, 5 mol%) were added, and the mixture was stirred at 80 ° C. for 18 hours in a glass sealed tube under an argon atmosphere. After confirming the completion of the reaction by a change in UV absorption, the reaction solution was allowed to cool at room temperature, and the solvent was distilled off under reduced pressure. After the residue was suspended in ethyl acetate and filtered through celite, the filtrate was washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 17-75% AcOEt in hexane) to give the title compound (408 mg, 57%) as a yellow powder. FAB-MS: m / z 361 (MH ⁺ ) .UV: λ _max (H ₂ O) 301, 291, 283, 268, 223 nm; λ _max (HC
l) 301, 291, 283,268, 223 nm; λ _max (NaOH) 301, 29
1, 283, 268, 223 nm . 1 H-NMR (CDCl 3) δ7.75 (s, 1H), 7.53-7.22 (m, 9H),
5.27 (s, 2H), 5.12 (bs, 2H).

Example 85 2-amino-6-chloro-9- [4-[(E,
Z) -Phenylvinylene] benzyl] -9H-purine 2-amino-6-chloro-9- (4-iodobenzyl) -9H-purine
(Compound of Example 8) (116 mg, 0.3 mmol) was dissolved in dimethylformamide (5 ml), and triethylamine (50 ml, 0.36
mmol, 1.2eq.), copper (I) iodide (3mg, 0.015mmol, 0.01e
q.), styrene (41 ml, 0.36 mmol, 1.2 eq.), bistriphenylphosphine palladium (II) chloride (11 mg, 30 m
l, 10mol%) and put in a glass sealed tube at 80 ° C under argon atmosphere
For 18 hours. After confirming the completion of the reaction by a change in UV absorption, the reaction solution was allowed to cool at room temperature, and the solvent was distilled off under reduced pressure. The residue was suspended in ethyl acetate / water and filtered through celite, and the filtrate was subjected to a liquid separation operation. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 17-67% AcOEt in hexane) to give the title compound (61 mg, 57%) as a yellow powder. FAB-MS:. M / z 363 (MH +) 1 H-NMR (CDCl 3) δ7.76-7.00 (m, 12H), 5.27, 5.20 (e
ach s, 2H, Z, E-CH ₂ ), 5.14 (bs, 2H).

Example 86 2-amino-6-chloro-9- [4-[(Z)-
Phenylvinylene] benzyl] -9H-purine 2-amino-6-chloro-9- (4-phenylethynylenebenzyl)
-9H-purine (compound of Example 84) (54 mg, 0.15 mmol) was suspended in methanol (3 ml), quinoline (4.5 ml, cat.), Palladium-barium carbonate (5% Pd) (5 mg, 10% w / w)
The mixture was stirred under a hydrogen atmosphere at normal pressure and room temperature for 17 hours. After adding chloroform to the reaction solution, the mixture was filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with 0-2% MeOH in CHCl ₃ ) to give the title compound.
(46 mg, 85%) was obtained as a yellow powder. FAB-MS:. M / z 363 (MH +) 1 H-NMR (CDCl 3) δ7.73 (s, 1H), 7.56-7.18 (m, 9H),
5.26 (s, 2H), 5.11 (bs, 2H).

Example 87 2-amino-6-chloro-9- [4- (2-f
Enylethyl) benzyl] -9H-purine 2-amino-6-chloro-9- (4-phenylethynylenebenzyl)
-9H-purine (the compound of Example 84) (44 mg, 0.12 mmol) was dissolved in ethanol (5 ml), and 10% palladium-carbon (10 mg,
25% w / w), and the mixture was stirred under a hydrogen atmosphere at normal pressure and room temperature for 13 hours. After filtration through celite, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (0-2% MeOH in
(Eluted with CHCl ₃ ) to give the title compound (33 mg, 75%) as a yellow powder. FAB-MS:. M / z 365 (MH +) 1 H-NMR (CDCl 3) δ7.69 (s, 1H), 7.29-7.16 (m, 9H),
. 5.20 (s, 2H), 5.08 (bs, 2H), 2.90 (s, 4H) Elemental analysis Calculated _{C 20 H 18 ClN 5 · 1} / 2H 2 O: C, 64.82;
H, 5.31; N, 18.44.Measured: C, 64.57; H, 4.99; N, 18.17.

Example 88 2-amino-6-chloro-9- [4- (fe
Nylmethyl) benzyl] -9H-purine 2-amino-6-chloro-9- [4- [α- (2- oxapropoxy) benzyl] benzyl] -9H -purine (compound of Example 19) (49m
g, 0.12 mmol) was dissolved in trifluoroacetic acid (2 ml), and triethylsilane (48 ml, 0.3 mmol, 2.5 eq.) was added under ice cooling, followed by stirring at room temperature for 2 hours. After adding excess dichloromethane, a saturated aqueous solution of sodium hydrogen carbonate (1 ml) was added, and the mixture was stirred for 10 minutes. An excess saturated aqueous sodium hydrogen carbonate solution was added to carry out a liquid separation operation, and the organic layer was dried over Na ₂ SO ₄ , filtered, and then dried.
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 17-67% AcOEt in hexane) to give the title compound (20 mg, 48%) as a white powder. FAB-MS:. M / z 351 (MH +) 1 H-NMR (CDCl 3) δ7.66 (s, 1H), 7.19-7.10 (m, 9H),
5.29 (s, 2H), 3.96 (bs, 2H), 3.06 (s, 1H), 3.00 (s,
1H).

Example 89 2-amino-9- (4-carboxyben
(Zyl) -6-hydroxy-9H-purine 2-amino-6-chloro-9- (4-methoxycarbonylbenzyl)
-9H-purine (compound of Example 6) (318 mg, 1 mmol) was dissolved in methanol (14 ml), and 10N aqueous sodium hydroxide solution (7
ml), and the mixture was heated under reflux for 12 hours. After allowing the reaction mixture to cool at room temperature, the pH was adjusted to 5 to 6 with 1N hydrochloric acid, and the mixture was cooled with ice. The precipitate was collected by filtration and washed with water to give the title compound (252 mg, 88%) as a white powder. FAB-MS: m / z 286 (MH ⁺ ) .UV: λ _max (H ₂ O) 252, 232 nm; λ _max (HCl) 259, 233 nm
_{;. λ max (NaOH) 275} , 220 nm 1 H-NMR (DMSO-d 6) δ11.38 (bs, 1H), 7.90 (d, 2H, J =
8.0Hz), 7.77 (s, 1H), 7.23 (s, 2H, J = 8.0Hz), 6.89
(bs, 2H), 5.24 (s, 2H).

Example 90 2-amino-9- (4-carboxyben
(Zyl) -6-phenylamino-9H-purine 2-amino-9- (4-methoxycarbonylbenzyl) -6-phenylamino-9H-purine (compound of Example 40) (37 mg, 0.1 mmo
l) was dissolved in methanol (1.5 ml), 1N aqueous sodium hydroxide solution (0.5 ml) was added, and the mixture was stirred at room temperature for 28 hours. With 1N hydrochloric acid
The pH was adjusted to 7 and cooled on ice. The precipitate was collected by filtration and washed with water to give the title compound (33 mg, 92%) as a white powder. FAB-MS: m / z 361 (MH ⁺ ). UV: λ _max (H ₂ O) 306, 235 nm; λ _max (HCl) 306, 230 nm
_{;. λ max (NaOH) 306} , 221 nm 1 H-NMR (DMSO-d 6) δ12.90 (bs, 1H), 9.39 (bs, 1H),
8.03-7.94 (m, 4H), 7.92 (s, 1H), 7.32-6.98 (m, 5H),
6.17 (bs, 2H), 5.36 (s, 2H). Elemental analysis Calculated C ₁₉ H ₁₆ N ₆ O ₂ 1 / 4H ₂ O: C, 62.76;
H, 4.65; N, 22.81. Found: C, 62.91; H, 4.67; N, 22.60.

Formulation Example 1 200 g of Compound B, 27.5 g of lactose and 20 g of potato starch are uniformly mixed, and 2.5 g of magnesium stearate is further added and mixed, followed by filling into hard gelatin capsules to prepare capsules. . This capsule contains 200 mg of compound B per capsule and 2 lactose.
It contains 7.5 mg, potato starch 20 mg and magnesium stearate 2.5 mg. Formulation Example 2 Compound B 200 g, lactose 22 g, potato starch 4
g and 30 g of crystalline cellulose, and then mixed.
After adding 10 g of hydroxypropylcellulose dissolved in 0% ethanol, granulating and drying, 15 g of carmellose sodium and 3 g of magnesium stearate were added and mixed, followed by compression molding to produce tablets. This tablet contains 200 mg of compound B and 22 lactose per tablet.
mg, potato starch 4 mg, crystalline cellulose 30
mg, hydroxypropylcellulose 10 mg, carmellose sodium 15 mg and magnesium stearate 3 mg.

[0093]

Industrial Applicability The compounds of the present invention have a potent and high selectivity on cancer cells and have a growth inhibitory action. It is also clear that it exhibits potent angiogenesis inhibition and can be an excellent antineoplastic agent with high utility in terms of efficacy and side effects. Accordingly, the compounds of the present invention include, for example, colorectal cancer,
It is useful as a therapeutic agent for malignant tumors such as bile duct cancer and pancreatic cancer.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication location C07D 473/38 C07D 473/38 (72) Inventor Akira Matsuda 12 Kita-ku, Kita-ku, Sapporo City, Hokkaido Chome 1-7-501 (72) Inventor Takuma Sasaki 4-12-5-401 Izuminocho, Kanazawa-shi, Ishikawa (72) Inventor Satoshi Shuto 3-10-10 Heiwa 3-10-10 Heiwa, Nishi-ku, Sapporo, Hokkaido (72) Invention Person Kazuhiro Uemoto 1 Tanaka, Yuno, Iizaka-cho, Fukushima City, Fukushima Prefecture Tor Ayo Corporation Fukushima Research Laboratories

Claims (6)

[Claims] 1. A compound of the general formula (1) [Wherein, R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted amino group, a phenoxy group, a mercapto group, a phenylmercapto group, a phenylsulfinyl group or a phenylsulfonyl group, R ² is a hydrogen atom or an amino group, R ³ is a hydrogen atom or a halogen atom, A is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxy group, a substituted or unsubstituted amino group, a lower acylamino group, a lower acyloxy group, Alkyl group, nitro group, formyl group or (Wherein, R ⁴ is a hydrogen atom, a halogen atom, a hydroxyalkyl group, a lower alkyl group, a cyano group, a trihalogenomethylsulfonylamino group or a tetrazole group, X is a group —OCO—, —COO—, —CONR ⁵ —, -NR ⁵ C
O—, —NR ⁵ SO ₂ — or a bond having a carbon atom chain of 2 or less, and R ⁵ represents a hydrogen atom or a lower alkyl group). A fused heterocyclic derivative represented by the following or a salt thereof. 2. A compound of the general formula (2) [Wherein, R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted amino group, a phenoxy group, a mercapto group, a phenylmercapto group, a phenylsulfinyl group or a phenylsulfonyl group, and R ² represents a hydrogen atom or an amino group. A compound represented by the general formula (3): Wherein R ³ is a hydrogen atom or a halogen atom, A is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxy group, a substituted or unsubstituted amino group, a lower acylamino group, a lower An acyloxy group, a hydroxyalkyl group, a nitro group, a formyl group or (Wherein, R ⁴ is a hydrogen atom, a halogen atom, a hydroxyalkyl group, a lower alkyl group, a cyano group, a trihalogenomethylsulfonylamino group or a tetrazole group, X is a group —OCO—, —COO—, —CONR ⁵ —, -NR ⁵ C
O—, —NR ⁵ SO ₂ — or a bond having a carbon atom chain of 2 or less, and R ⁵ represents a hydrogen atom or a lower alkyl group), and W represents a halogen atom. The method for producing a fused heterocyclic derivative represented by the general formula (1) or a salt thereof according to claim 1, characterized by reacting the compound with the compound represented by the formula (1). 3. A compound of the general formula (1a) [Wherein, R ² is a hydrogen atom or an amino group, R ³ is a hydrogen atom or a halogen atom, A is a hydrogen atom, a halogen atom,
Lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxy group, substituted or unsubstituted amino group, lower acylamino group, lower acyloxy group, hydroxyalkyl group, nitro group, formyl group or (Wherein, R ⁴ is a hydrogen atom, a halogen atom, a hydroxyalkyl group, a lower alkyl group, a cyano group, a trihalogenomethylsulfonylamino group or a tetrazole group, X is a group —OCO—, —COO—, —CONR ⁵ —, -NR ⁵ CO
—, —NR ⁵ SO ₂ — or linked via a spacer having 2 or less carbon atom chains, R ⁵ represents a hydrogen atom or a lower alkyl group), and Y represents a halogen atom. Wherein the compound or a salt thereof is subjected to a catalytic reduction reaction. (Wherein R ² , R ³ and A have the same meanings as described above) or a method for producing the fused heterocyclic derivative (1b) or a salt thereof. 4. A compound of the general formula (1a) [Wherein, R ² is a hydrogen atom or an amino group, R ³ is a hydrogen atom or a halogen atom, A is a hydrogen atom, a halogen atom,
A lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxy group, a substituted or unsubstituted amino group, a lower acylamino group, a lower acyloxy group, a hydroxyalkyl group, a nitro group, a formyl group or (Wherein, R ⁴ is a hydrogen atom, a halogen atom, a hydroxyalkyl group, a lower alkyl group, a cyano group, a trihalogenomethylsulfonylamino group or a tetrazole group, X is a group —OCO—, —COO—, —CONR ⁵ —, -NR ⁵ CO
—, —NR ⁵ SO ₂ — or linked via a spacer having 2 or less carbon atom chains, R ⁵ represents a hydrogen atom or a lower alkyl group), and Y represents a halogen atom. Or a salt thereof is subjected to a hydrolysis reaction, or after reaction with compound (B) (compound (B) represents a substituted or unsubstituted amine, thiourea, thiophenol or phenol), and then, if desired, to an oxidation reaction. General formula (1c): [Wherein R ¹ ′ is a hydroxyl group, a substituted or unsubstituted amino group, a phenoxy group, a mercapto group, a phenylmercapto group, a phenylsulfinyl group or a phenylsulfonyl group, and R ² , R ³ and A are as defined above] A method for producing the represented fused heterocyclic derivative (1c) or a salt thereof. 5. A therapeutic agent for malignant tumor, comprising the fused heterocyclic derivative according to claim 1 and a salt thereof. 6. An angiogenesis inhibitor comprising the fused heterocyclic derivative according to claim 1 and a salt thereof.