JPH05286963A - Pyrimidine derivative and platelet aggregation-inhibiting agent containing the same as active ingredient - Google Patents

Abstract

PURPOSE:To provide the novel compound having a remarkable action for inhibiting the collagen-inducing platelet aggregation. CONSTITUTION:A compound of formula I (R<1> is H, lower alkyl; R<2> is lower alkyl; Z is O, S, e.g. 1,2,4,5-tetrahydro-[1]benzoxepino[4,5e[imidazo[1,2- c]pyrimidine. The compound of formula I is obtained by reacting 4-chloro-5,6- dihydro-[1[benzoxepino[5,4-d]pyrimidine of formula II as an intermediate with an amino-alcohol compound, subjecting the reaction product to intramolecular dehydrative ring-closing reaction with phosphoryl chloride and subsequently treating the reaction product with an alkali. The compound of formula II is obtained by subjecting methyl O-(3-cyanopropyl)salicylate as a starting substance to ring-closing reaction, hydrolysis reaction, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel pyrimidine derivative and a platelet aggregation inhibitor (antiplatelet drug) containing the derivative as an active ingredient.

[0002]

2. Description of the Related Art Many of the diseases in the human body are caused by the increased coagulability of blood in blood vessels and the formation of thrombus. Since coagulation factors and platelets are involved in the formation of blood clots, their inhibitors are used for their prevention.

At present, various medicines are used as antithrombotic agents according to their purposes. For example, coagulation factor inhibitors include heparin, dicoumarol, warfarin potassium and the like, and antiplatelet agents include ticlopidine, dipyridamole, aspirin, indomethacin and the like. When thrombus formation is apparent, urokinase is used as a thrombolytic agent.

Recently, 5,6-dihydrobenzo [h]
Quinazoline derivative, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-d] pyrimidine derivative, 6,7-dihydro-5H-pyrimido [5,4-d]
[1] Various pyrimidine derivatives such as benzzine azepine derivatives have been found to have a platelet aggregation inhibitory activity, and are expected to be used as platelet aggregation inhibitors (JP-A-2-221262, JP-A-2-221262). 3-1671
No. 78).

[0005]

In recent years, the importance of platelets in thrombotic diseases has been recognized, and the role of platelets in arteriosclerosis has been clarified. Therefore, the importance of antiplatelet drugs has grown. There is.

[0006] However, the currently used antiplatelet drugs have some problems at present, and there are a lot of drugs having side effects and doubts on the onset of action.

[0007] For example, in aspirin, since its mechanism of action is cyclooxygenase inhibition, PGI
There is a problem of aspirin dilemma that suppresses the platelet aggregation inhibitory action by suppressing the production of ₂ (this is true not only for aspirin but also for cyclooxygenase inhibitors in general).

Since some of the antiplatelet drugs are used for the application of existing drugs, it is difficult to control the dose, and the original action of the drug often appears as a side effect.

The present inventor has paid attention to the platelet aggregation-inhibiting activity of pyrimidine derivatives, synthesized various new pyrimidine derivatives, and examined their platelet aggregation-inhibitory activity. The inventors have found that there is a compound having the above and arrived at the present invention.

An object of the present invention is to provide a pyrimidine derivative expected to be used as a platelet aggregation inhibitor.

[0011]

According to the present invention, a pyrimidine derivative represented by the following formula is provided.

(1). General formula

[0013]

[Chemical 10]

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a lower alkyl group or a lower alkyl group substituted with a hydroxyl group or a dialkylamino group, and Z represents an oxygen atom or a sulfur atom. ) (2). General formula

[0015]

[Chemical 11]

(Wherein R ³ represents a lower alkyl group or a lower alkyl group substituted with a hydroxyl group or a dialkylamino group, and Z represents an oxygen atom or a sulfur atom) (3).

[0017]

[Chemical 12]

(Wherein R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group, n represents 1 or 2, and Z represents an oxygen atom or a sulfur atom) (4). formula

[0019]

[Chemical 13]

(Wherein R ⁶ represents a hydrogen atom or a lower alkyl group, R ⁷ represents a residue obtained by removing an amino group from an amino acid, and Z represents an oxygen atom or a sulfur atom) (5).

[0021]

[Chemical 14]

(Wherein R ⁸ represents a chlorine atom or an amino group and Z represents an oxygen atom or a sulfur atom) (6).

[0023]

[Chemical 15]

(Wherein Z ¹ and Z ² are the same or different and each represents an oxygen atom or a sulfur atom) (7).

[0025]

[Chemical 16]

(Wherein Z represents an oxygen atom or a sulfur atom) (8).

[0027]

[Chemical 17]

(In the formula, R ⁹ represents a lower alkyl group, and Z
Represents an oxygen atom or a sulfur atom).

(9). General formula

[0030]

[Chemical 18]

A pyrimidine derivative represented by the formula (wherein Z represents an oxygen atom or a sulfur atom).

Next, representative ones of the pyrimidine derivatives provided by the present invention and their production methods will be explained.

First, methyl O (3- is obtained by reacting methyl salicylate with 4-chlorobutyronitrile in the presence of potassium carbonate in dry dimethylformamide.
Cyanopropyl) salicylate is obtained.

Next, the above methyl O (3-cyanopropyl) salicylate was added to potassium t-tetrahydrofuran in tetrahydrofuran.
-By ring closure in the presence of butoxide catalyst,
-Oxo-2,3,4,5-tetrahydro-1-benzoxepin-4-carbonitrile is obtained.

Next, the above-mentioned 5-oxo-2,3,4,5-
By reacting tetrahydro-1-benzoxepin-4-carbonitrile with formamide at 140 to 150 ° C. in a stream of ammonia to effect ring closure of pyrimidine, 4
-Amino-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine is obtained.

Next, the above-mentioned 4-amino-5,6-dihydro- [1] benzoxepino [5,4-d] pyrimidine is refluxed in a mixed solution of hydrochloric acid and acetic acid and hydrolyzed to give 5,6- Dihydro- [1] benzoxepino [5
4- d ] pyrimidin-4 (3 H ) -one is obtained.

Next, the above 5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine-4 ( 3H )-
By treating the on with phosphoryl chloride, the following formula

[0038]

[Chemical 19]

4-chloro-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine of the formula ## STR6 ## is obtained.

Then, 4-chloro-5,6-dihydro- [1] benzoxepino [5, obtained as described above, was used.
Various pyrimidine derivatives are synthesized using 4- d ] pyrimidine as an intermediate raw material.

First, the above-mentioned 4-chloro-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine is reacted with various amino alcohols to give the following general formula:

[0042]

[Chemical 20]

(Wherein R ¹⁰ and R ¹¹ are the same or different and each represents a hydrogen atom or a lower alkyl group), and 5,6-dihydro- [1 ] Benz oxepino [5,4-
d ]] pyrimidine derivatives are obtained.

Next, the above 5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine derivative is subjected to intramolecular dehydration ring closure using phosphoryl chloride and then treated with alkali to give the following compound. General formula

[0045]

[Chemical 21]

(Wherein R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group, and n represents 1 or 2), 1,2,4,5-tetrahydro- [1 ] Benzoxepino [4,5- e ] imidazo [1,2-c] pyrimidine derivatives are obtained.

When the aminoalcohol is N-alkylethanolamine, the following general formula

[0048]

[Chemical formula 22]

A 4-substituted-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine derivative represented by the formula: wherein R ⁹ represents a lower alkyl group is obtained, and this derivative is treated with phosphoryl chloride. By closing the ring, the following general formula

[0050]

[Chemical formula 23]

A tetracyclic compound represented by the formula: wherein R ⁹ represents a lower alkyl group is obtained.

Then, 4-chloro-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine is reacted with an alkylamine in a solvent such as dioxane to give an alkylamino group at the 4-position. Was introduced 5,
6-dihydro- [1] benzoxepino [5,4- d ]
A pyrimidine derivative is obtained.

Further, 4-chloro-5,6-dihydro-
[1] Benzoxepino [5,4- d ] pyrimidine is reacted with an alcoholate obtained from metallic sodium and an alcohol to give 5,6-dihydro- [1] benzoxepino [5] having an O-alkyl group introduced at the 4-position. A 5,4- d ] pyrimidine derivative is obtained.

Further, 4-chloro-5,6-dihydro-
[1] Benzoxepino [5,4- d ] pyrimidine is reacted with thiourea and then treated with alkali to give the following formula:

[0055]

[Chemical formula 24]

5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine-4 ( 3H )-represented by
After synthesizing thione, by reacting this with alkyl iodide in alkali, the following general formula

[0057]

[Chemical 25]

(In the formula, R ¹⁰ represents a lower alkyl group) 5,6-in which an O-alkyl group is introduced at the 4-position.
A dihydro- [1] benzoxepino [5,4- d ] pyrimidine derivative is obtained.

Next, 4-chloro-5,6-dihydro-
[1] Benzoxepino [5,4- d ] pyrimidine is reacted with ethylene glycol in the presence of triethylamine to give 5,6-dihydro- [1] benzoxepino [5] having a 2-hydroxyethoxy group introduced at the 4-position. A 4- d ] pyrimidine derivative is obtained.

Further, 4-chloro-5,6-dihydro-
[1] Benzoxepino [5,4- d ] pyrimidine was reacted with 2-mercaptoethanol using pyridine as a base to give 5,6-dihydro- [1] benzoxepino having a 2-hydroxyethylthio group introduced at the 4-position. A [5,4- d ] pyrimidine derivative is obtained.

Next, 4-chloro-5,6-dihydro-
[1] Benzoxepino [5,4- d ] pyrimidine is reacted with several moles of amino acid in the presence of potassium carbonate to give the following general formula:

[0062]

[Chemical formula 26]

(Wherein R ⁷ represents a residue obtained by removing an amino group from an amino acid), 5,6-dihydro- [1] benzoxepino [5,6, in which an amino acid is introduced at the 4-position.
A 4- d ] pyrimidine derivative is obtained.

On the other hand, ethyl S (3-cyanopropyl) thiosalicylate is obtained by reacting ethyl thiosalicylate with 4-chlorobutyronitrile in dioxane in the presence of potassium carbonate.

Then, the above-mentioned ethyl S (3-cyanopropyl) thiosalicylate is subjected to intramolecular ring closure using sodium hydride in toluene to give 5-oxo-2,3,4,5-tetrahydro- [ 1] Benzothiepine-4-carbonitrile is obtained.

Next, the above-mentioned 5-oxo-2,3,4,5-
Tetrahydro- [1] benzotiepine-4-carbonitrile 5-oxo-2,3,4,5-tetrahydro-1
-Benzoxepin-4-carbonitrile was reacted with formamide at 140-150 ° C under a stream of ammonia to form a pyrimidine ring-closure to give 4-amino-5,6
-Dihydro- [1] benzthioepino [5,4- d ] pyrimidine is obtained.

Then, 4-amino-5,6-dihydro- [1] benzthioepino [5,4-d] pyrimidine is hydrolyzed with 6N-hydrochloric acid under heating to give
5,6-Dihydro- [1] benzthioepino [5,4-
d ]] Pyrimidin-4 (3 H ) -one is obtained.

Next, the above 5,6-dihydro- [1] benzthioepino [5,4- d ] pyrimidine-4 ( 3H )-
By treating the on with phosphoryl chloride, the following formula

[0069]

[Chemical 27]

4-chloro-5,6-dihydro- [1] benzthioepino [5,4- d ] pyrimidine of the formula ## STR10 ## is obtained.

Next, 4-chloro-5,6-dihydro- [1] benzthioepino [5, obtained as described above, was used.
4- d ] pyrimidine as an intermediate raw material, and the 4-chloro-
5,6-Dihydro- [1] benzoxepino [5,4-
d ]] By performing the same operation as in the case of pyrimidine,
Various corresponding pyrimidine derivatives can be synthesized.

[0072]

In order to examine the platelet aggregation inhibitory activity of the compounds of the present invention, the change in light transmittance due to platelet aggregation was measured according to the Born turbidimetric method.

[Test Method] Preparation of Rabbit Platelet Rabbit blood collected from the auricular vein of a rabbit (Japanese white male, body weight about 3.5 Kg) was mixed with 1/10 volume of 3.8% sodium citrate solution. Then, centrifuge at 160 g for 10 minutes, and the upper layer is platelet rich plasma (Platelet Rich Plasma, PR
P). The lower layer was centrifuged at 2000 g for 10 minutes, and the upper layer was plated with platelet poor plasma (Platelet Poor Plasma, PP).
P).

Measurement of Platelet Aggregation Inhibitory Ability The platelet agglutination inhibitory ability was measured by using a platelet aggregometer (Aglycoda II PA-3220, Kyoto Daiichi Kagaku) and using Born.
According to the method described above, the change in light transmittance due to platelet aggregation at 650 nm was recorded by recording with time.

That is, 2 PRPs are attached to the attached cuvette.
50 μl aliquot, 25 μl of test sample (350 μmol / l)
[Sample and 10% DMSO] and 25 μl of 1M Tris-HCl buffer (pH 7.4) were added, and then the mixture was incubated at 37 ° C. for 2 minutes. Immediately thereafter, collagen (50 μl, final concentration 14.3 μg / ml) was added as the aggregating substance (final concentration of the sample was 25 μmol / l), and as a result, the change in light transmittance of PRP caused by platelet aggregation was observed with time. To 1
Recorded for 0-15 minutes.

As a method of expressing the inhibitory effect of the test substance on collagen-induced platelet aggregation, the light transmittance of PRP itself was set to 0%, and that of PPP was set to 100%. The point showing the transmittance was defined as the time of maximum aggregation. The control solvent (negative contro
l) The inhibition rate of the analyte was determined from the ratio of the maximum aggregation rate at the time of adding the sample to the maximum aggregation rate at the time of addition.

[0077]

[Equation 1]

This maximum aggregation inhibition rate is
Control's, Aspirin) compared to that of Student's
I only for compounds for which a significant difference was observed at a risk rate of 1% or less or 5% or less in t-test
The C ₅₀ was determined.

[Results] The maximum inhibition rate of each test compound and aspirin against the collagen-induced platelet aggregation and the IC ₅₀ are shown in Table 1 below.

Table 1 shows the average and standard error of the measurement results obtained at least 3 times at the final concentration of 25 μmol / l, and is expressed in%. The maximum aggregation inhibition rate is Student's t
-In test, the risk rate is 1% or less (**, p <0.01) or 5% or less (*, p <0.
The IC ₅₀ was determined only for those having a significant difference in 05).

In the table, the numerical value in the right column indicates IC ₅₀ , and the numerical value in parentheses indicates 95% reliability. These values were determined by the probit method from the results of measurements carried out three times or more at 5, 25 (or 10) and 50 μmol / l (25, 50 and 100 μmol / l only for aspirin).

[0082]

[Table 1]

[0083]

[Table 2]

[0084]

Example 1 Synthesis of methyl O- (3-cyanopropyl) salicylate A mixture of 50 g (329 mmol) of methyl salicylate, 51 g (493 mmol) of 4-chlorobutyronitrile and 125 g (904 mmol) of anhydrous potassium carbonate in 250 ml of dry dimethylformamide. The mixture was heated and stirred at 70 ° C. for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 50.5 g (yield 70%) of an oily target product.

[0085]

[Chemical 28]

[0086]

Example 2 Synthesis of 5-oxo-2,3,4,5-tetrahydro- [1] benzoxepin-4-carbonitrile Under ice cooling, 2.1 g (200 mmol) of t- BuOK was suspended in 300 ml of tetrahydrofuran, And methyl O-
(3-Cyanopropyl) salicylate 26.5 g (121
What was dissolved in 130 ml of tetrahydrofuran was added all at once, and the mixture was stirred at 0 to 5 ° C for 4 hours. Then, the reaction solution was poured into 900 ml of ice water, the pH was adjusted to 5 with acetic acid, and the white precipitate was collected by filtration. The obtained precipitate was recrystallized from methanol to give 16.6 g of the desired product as colorless columnar crystals (yield 74
%) Was obtained.

[0087]

[Chemical 29]

[0088]

Example 3 Synthesis of 4-amino-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 5-oxo-2,3,4,5-tetrahydro- [1] benzoxepin-4- Carbonitrile 26.7g (143
200 ml of formamide was added to
The mixture was stirred under an ammonia stream in an oil bath at ℃. (By TLC,
The end point of the reaction was followed. After that, the temperature was returned to room temperature and the mixture was left overnight in the refrigerator. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 23.8 g of the desired product as colorless columnar crystals (yield 78.3).
%) Was obtained.

[0089]

[Chemical 30]

[0090]

Example 4 5,6-Dihydro- [1] benzoxepino [5,4-
Synthesis of d ] pyrimidin-4 ( 3H ) -one To 4-amino-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 11.2 g (52.5 mmol)
180 ml of conc.HCl and 80 ml of acetic acid were added, and the mixture was heated to reflux. After 46 hours (on the way, conc.HCl was added 40 ml each 4 times), the excess solvent was distilled off under reduced pressure, a small amount of water was added, and the mixture was neutralized with 1N-NaOH while cooling. The mixture was stirred in an ice bath and the resulting precipitate was collected by filtration. The obtained precipitate was recrystallized from ethanol to give 9.9 g of the desired product as colorless columnar crystals (yield 8
3%) was obtained.

[0091]

[Chemical 31]

[0092]

Example 5 Synthesis of 4-chloro-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 5,6-dihydro- [1] benzoxepino [5,4-
d ] pyrimidin-4 ( 3H ) -one 21.1 g (98.5 mm
92 ml (985 mmol) of phosphoryl chloride was added to 53 ml of chloroform (ethanol-free), and the mixture was heated under reflux for 3 hours. After the reaction, excess phosphoryl chloride was distilled off under reduced pressure, the mixture was cooled on an ice bath, and ice water (about 70 ml) was added to the residue.
A white precipitate formed when the pH was adjusted to 8-9 with saturated aqueous NaHCO ₃ with stirring. This was collected by filtration and recrystallized from ethanol to obtain 19.6 g (yield: 85%) of the desired product as colorless needle crystals.

[0093]

[Chemical 32]

[0094]

Example 6 Synthesis of 4- (2-hydroxyethylamino) -5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 4-chloro-5,6-dihydro- [1] benzoxepino [ 1.8 g (30.1 mmol) of ethanolamine was added to 1 g (4.3 mmol) of 5,4- d ] pyrimidine, and the mixture was added at 70 ° C. for 1.5
Stir for hours. After the reaction, excess ethanolamine was distilled off under reduced pressure, ice water (about 20 ml) was added to the residue, and the mixture was stirred to give a white precipitate. This was collected by filtration and recrystallized from benzene to obtain 1.1 g (yield 94%) of the desired product as colorless columnar crystals.

[0095]

[Chemical 33]

[0096]

Example 7 Synthesis of 4- (2-hydroxypropylamino) -5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 4-chloro-5,6-dihydro- [1] benzoxepino [ DL-1 was added to 2 g (8.6 mmol) of 5,4- d ] pyrimidine.
2.6 g (34.6 mmol) of -amino-2-propanol was added, and the mixture was stirred at 70 ° C for 1 hour. After the reaction was completed, water (40 ml) was added to the reaction solution, the precipitate formed was collected by filtration, and ethanol-
Recrystallization from benzene gave 2.2 g (yield 94%) of the desired product as white granular crystals.

[0097]

[Chemical 34]

[0098]

Example 8 4- (2-hydroxy-1-methylethylamino)-
5,6-Dihydro- [1] benzoxepino [5,4-
Synthesis of d ] pyrimidine 4-chloro-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 2 g (8.6 mmol) in DL-2
1.9 g (25.8 mmol) of -amino-1-propanol was added, and the mixture was heated with stirring at 70 ° C for 4 hours. After the reaction was completed, water (40 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 ml × 4). The organic layer was washed with saturated brine and dried over anhydrous MgSO _4.
After drying with, the solvent was distilled off under reduced pressure. The obtained residue is recrystallized from benzene-ethanol to give 2.1 g of the target compound as colorless needles.
(Yield 90%) was obtained.

[0099]

[Chemical 35]

[0100]

Example 9 4- (2-hydroxy-1-ethylethylamino)-
5,6-Dihydro- [1] benzoxepino [5,4-
Synthesis of d ] pyrimidine 4-chloro-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 2 g (8.6 mmol) in DL-2
3.1 g (34.4 mmol) of -amino-1-butanol was added, and the mixture was heated with stirring at 70 ° C for 3 hours. After the reaction was completed, water was added to the reaction solution to cause precipitation. This precipitate was collected by filtration and recrystallized from benzene-ethanol to give colorless needle crystals of the target compound 2.3.
g (yield 93%) was obtained.

[0101]

[Chemical 36]

[0102]

Example 10 Synthesis of 1,2,4,5-tetrahydro- [1] benzoxepino [5,4- e ] imidazo [1,2- c ] pyrimidine 4- (2-hydroxyethylamino) -5,6 -Dihydro- [1] benzoxepino [5,4- d ] pyrimidine 1 g (3.9 mmol) to phosphoryl chloride 5.6 ml (60 mmol)
Was added and the mixture was heated under reflux for 2 hours. After the reaction, excess phosphoryl chloride was distilled off under reduced pressure, and after cooling on an ice bath, ice water (25 ml)
Was added. After adjusting the pH to 11 with 2N-NaOH, the mixture was extracted with ethyl acetate (10 ml × 4), the organic layer was washed with saturated brine and dried over anhydrous MgSO ₄ , and the solvent was evaporated. The obtained residue was recrystallized from ethyl acetate to obtain 0.81 g (yield 87%) of the desired product as yellow needle crystals.

[0103]

[Chemical 37]

[0104]

Example 11 1-Methyl-1,2,4,5-tetrahydro- [1] benzoxepino [4,5- e ] imidazo [1,2- c ]
-Synthesis of pyrimidine 4- (2-hydroxypropylamino) -5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 1.0 g (3.7 mmol) in 5.6 ml (60 mm of phosphoryl chloride)
ol) was added and the mixture was heated under reflux for 3 hours. After completion of the reaction, excess phosphoryl chloride was distilled off under reduced pressure, and after cooling on an ice bath, ice water (25 ml) was added, the pH was adjusted to 11 with 2N-NaOH, and the mixture was extracted with ethyl acetate (10 ml × 4). The organic layer was washed with saturated brine and dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. The obtained residue was subjected to column chromatography (silica gel 30 g; benzene / ethyl acetate = 4/1).
And was recrystallized from ethyl acetate-ethanol to obtain 0.86 g (yield 92%) of the desired product as yellow needle crystals.

[0105]

[Chemical 38]

[0106]

Example 12 2-Methyl-1,2,4,5-tetrahydro- [1] benzoxepino [4,5- e ] imidazo [1,2- c ]
Synthesis of pyrimidine 4- (2-hydroxy-1-methylethylamino)-
5,6-Dihydro- [1] benzoxepino [5,4-
d ] pyrimidine 1 g (3.7 mmol) and phosphoryl chloride 5.6
ml (60 mmol) was added and the mixture was heated under reflux for 2 hours. After completion of the reaction, excess phosphoryl chloride was distilled off under reduced pressure, cooled on an ice bath, iced water (25 ml) was added, and the pH was adjusted to 1 with 2N-NaOH.
It was adjusted to 1 and extracted with ethyl acetate (10 ml x 4). The organic layer was washed with saturated saline and dried over anhydrous MgSO ₄ ,
The solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (silica gel 30 g; benzene / ethyl acetate =
4/1) and recrystallized from ethyl acetate-ethanol to obtain 0.85 g (yield 91%) of the desired product as colorless needles.

[0107]

[Chemical Formula 39]

[0108]

Example 13 2-Ethyl-1,2,4,5-tetrahydro- [1] benzoxepino [4,5- e ] imidazo [1,2- c ]
Synthesis of pyrimidine 4- (2-hydroxy-1-ethylethylamino)-
5,6-Dihydro- [1] benzoxepino [5,4-
d ] pyrimidine 1 g (3.5 mmol) and phosphoryl chloride 5.6
ml (60 mmol) was added and the mixture was heated under reflux for 2 hours. After completion of the reaction, excess phosphoryl chloride was distilled off under reduced pressure. After cooling on an ice bath, ice water (25 ml) was added, and the pH was adjusted with 2N-NaOH.
It was adjusted to 11 and extracted with ethyl acetate (10 ml x 4).
The organic layer was washed with saturated brine and dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silica gel 30 g; benzene / ethyl acetate = 4/1) and recrystallized from ethanol-ether to obtain 0.84 g (yield 90%) of the desired product as a colorless powder. ..

[0109]

[Chemical 40]

[0110]

Example 14 Synthesis of 4- (3-hydroxypropylamino) -5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 4-chloro-5,6-dihydro- [1] benzoxepino [ 2.6 g (34.4 mmol) of 3-amino-1-propanol was added to 2 g (8.6 mmol) of 5,4- d ] pyrimidine,
The mixture was heated and stirred at 70 ° C. for 1 hour. After completion of the reaction, water (30 ml) was added to the reaction solution and extracted with chloroform (10 ml × 4). The organic layer was washed with saturated brine and dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give 2.04 g of the desired product as colorless needles (yield 87
%) Was obtained.

[0111]

[Chemical 41]

[0112]

Example 15 Synthesis of 4- (4-hydroxybutylamino) -5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 4-chloro-5,6-dihydro- [1] benzoxepino [ 3.1 g (34.4 mmol) of 4-amino-1-butanol was added to 2 g (8.6 mmol) of 5,4- d ] pyrimidine to give 7
The mixture was heated and stirred at 0 ° C for 1.5 hours. After completion of the reaction, water (30 ml) was added to the reaction solution and stirred to give a white precipitate. This was collected by filtration and recrystallized from ethanol-ether to obtain 1.98 g (yield 81%) of the desired product as colorless columnar crystals.

[0113]

[Chemical 42]

[0114]

Example 16 Synthesis of 2,3,5,6-tetrahydro-1 H- [1] benzoxepino [5,4- e ] pyrimido [1,2- c ] pyrimidine 4- (3-hydroxypropylamino)- 1 g (3.7 mmol) of 5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine was added to 5.4 ml (59.2 mm) of phosphoryl chloride.
ol) was added and the mixture was heated under reflux for 2 hours. After completion of the reaction, excess phosphoryl chloride was distilled off under reduced pressure. After cooling on an ice bath,
Ice water (25 ml) was added, the pH was adjusted to 11 with 2N-NaOH, and the mixture was extracted with ethyl acetate (10 ml × 4). The organic layer was washed with saturated brine and dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethanol to obtain 0.6 g (yield 62%) of the desired product as yellow needle crystals.

[0115]

[Chemical 43]

[0116]

Example 17 4- (4-chlorobutylamino) -5,6-dihydro-
[1] Synthesis of benzoxepino [5,4- d ] pyrimidine 4- (4-hydroxybutylamino) -5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 1 g (3.3 mmol) with chloride Phosphoryl 5.4 ml (59.2 mmo
l) was added and the mixture was heated under reflux for 2 hours. After completion of the reaction, excess phosphoryl chloride was distilled off under reduced pressure. After cooling on an ice bath,
Ice water (25 ml) was added, the pH was adjusted to 11 with 2N-NaOH, and the mixture was extracted with ethyl acetate (10 ml × 4). The organic layer was washed with saturated brine and dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethanol to obtain 0.92 g (yield 91%) of the desired product as colorless needle crystals.

[0117]

[Chemical 44]

[0118]

Example 18 Synthesis of 4- [ N- (2-hydroxyethyl) -N -methylamino] -5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 4-chloro-5,6 -Dihydro- [1] benzoxepino [5,4- d ] pyrimidine 1 g (4.3 mmol) was added with N-methylethanolamine 1.4 g (17 mmol), and
The reaction was carried out at 0 ° C for 2 hours. Add water (25 ml) to the reaction mixture,
It was extracted with ethyl acetate (10 ml x 4). The organic layer was washed with saturated brine, dried over anhydrous MgSO ₄ , and the solvent was evaporated. The obtained residue was recrystallized from ethyl acetate to obtain 0.76 g (yield 65%) of the desired product as colorless columnar crystals.

[0119]

[Chemical 45]

[0120]

Example 19 3-Methyl-1,2,4,5-tetrahydro- [1] benzoxepino [4,5- e ] imidazo [1,2- c ]
-Synthesis of pyrimidinium chloride 4- [ N- (2-hydroxyethyl) -N -methylamino] -5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 1 g (3.8 mmol) Phosphoryl chloride 5.4 ml (60 mmol) was added, and the mixture was heated under reflux for 2 hours. After completion of the reaction, excess phosphoryl chloride was distilled off, and after cooling, water (25 ml) was added. Water was distilled off and ethanol
Ether was added and cooled to obtain a white precipitate. It was collected by filtration and recrystallized from ethanol-benzene to obtain 1.1 g (yield 98%) of the desired product as colorless columnar crystals.

[0121]

[Chemical 46]

[0122]

Example 20 Synthesis of 4-ethylamino-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 4-chloro-5,6-dihydro- [1] benzoxepino [5,4- d ] ] Pyrimidine 1 g (4.3 mmol) in dioxane 20 ml ethylamine (70% aqueous solution) 1.94
g (43 mmol) and stirred for 72 hours at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was recrystallized from benzene to obtain 0.38 g (yield 37%) of the target product as colorless columnar crystals.

[0123]

[Chemical 47]

[0124]

Example 21 Synthesis of 4-ethoxy-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 0.2 g of metallic sodium is dissolved in 10 ml of ethanol, and 4-chloro-5,6-dihydro is added thereto. -[1] Benzoxepino [5,4- d ] pyrimidine 1 g (4.3 mmol) dissolved in ethanol (45 ml) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was neutralized with 1N-HCl and ethanol was distilled off. Then, it was extracted with ethyl acetate (15 ml × 3), the organic layer was washed with saturated saline, and anhydrous MgSO ₄
After drying with, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from n-hexane to obtain 1.02 g (yield 98%) of the desired product as colorless columnar crystals.

[0125]

[Chemical 48]

[0126]

Example 22 5,6-Dihydro- [1] benzoxepino [5,4-
Synthesis of d ] pyrimidine-4 ( 3H ) -thione 4-chloro-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 1 g (4.3 mmol) and thiourea 1.67 g (22 mmol). And were heated to reflux in 2-methoxyethanol (35.5 ml) for 16 hours. The solvent was evaporated, the residue was adjusted to pH 9 with 2N-NaOH, and then adjusted to pH 4 with acetic acid. The precipitated crystals were collected by filtration and recrystallized from ethanol to give yellow needle crystals (0.95 g, yield 93%).
Got

[0127]

[Chemical 49]

[0128]

Example 23 Synthesis of 4-methylthio-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 5,6-dihydro- [1] benzoxepino [5,4-
d ] pyrimidine-4 (3 H ) -thione 1 g (4 mmol),
6.6 ml (6.6 mmol) of 1N-KOH, 1.9 g of methyl iodide
(13.2 mmol) was mixed and shaken at 4 ° C. for 2 hours. The precipitated crystals were collected by filtration and recrystallized from benzene to obtain 0.49 g (yield 90%) of the target product as colorless columnar crystals.

[0129]

[Chemical 50]

[0130]

Example 24 4- (2-hydroxyethoxy) -5,6-dihydro-
[1] Synthesis of benzoxepino [5,4- d ] pyrimidine 4-chloro-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 1 g (4.3 mmol) and ethylene glycol 24 g (390 mmol) Was heated and stirred at 100 ° C. for 24 hours in the presence of 3.1 g (31 mmol) of triethylamine. After the reaction was completed, water (25 ml) was added, and the mixture was extracted with ethyl acetate (15 ml × 3). The organic layer was washed with saturated brine and dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 0.59 g (yield 53%) of the desired product as colorless columnar crystals.

[0131]

[Chemical 51]

[0132]

Example 25 Synthesis of 4- (2-hydroxyethylthio) -5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 4-chloro-5,6-dihydro- [1] benzoxepino [ 1 g (4.3 mmol) of 5,4- d ] pyrimidine and 0.67 g (8.6 mmol) of 2-mercaptoethanol were heated and stirred in pyridine (4.3 ml) at 110 ° C. for 6 hours. After the reaction was completed, a small amount of water (about 20 ml) was added, and ethyl acetate (15 ml) was added.
It was extracted with ml × 3). The organic layer was washed with saturated brine and dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. The residue was recrystallized from benzene-n-hexane to give the desired product as colorless needles.
0.32 g (yield 27%) was obtained.

[0133]

[Chemical 52]

[0134]

Example 26 Synthesis of 4- (2-dimethylaminoethylamino) -5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 4-chloro-5,6-dihydro- [1] benzoxepino 1 g (4.3 mmol) of [5,4- d ] pyrimidine has N 2 , N
-Dimethylethylenediamine (2.7 g, 30.6 mmol) was added, and the mixture was heated under reflux for 1.5 hours. After the reaction was completed, a small amount of water (about 20 ml) was added, and the mixture was extracted with chloroform (15 ml × 3). The organic layer was washed with saturated brine and dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 40 g; ethyl acetate) to obtain 1.06 g (yield 87%) of the target product as a yellow oil.

[0135]

[Chemical 53]

[0136]

Example 27 Synthesis of 4- (2-dimethylaminoethoxy) -5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 2-dimethylaminoethanol 0.58 g (6.5 mmol) in dioxane. 0.26 g (6.5%) of 60% NaH in (20 ml)
mmol) was added and the mixture was heated under reflux for 0.5 hr. Then, the temperature was returned to room temperature, 4-chloro-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 1 g (4.3 mmol) dissolved in dioxane (40 ml) was added, and the mixture was added at 70 ° C at 2 ° C. The mixture was heated and stirred for an hour. After the reaction is completed, a small amount of water (about 20 m
l) was added and extracted with chloroform (15 ml × 3).
The organic layer was washed with saturated brine and dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 40 g; ethyl acetate) to obtain 0.86 g (yield 70%) of the target product as a yellow oil.

[0137]

[Chemical 54]

[0138]

Example 28 Synthesis of 4- (2-dimethylaminoethylthio) -5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 2-Dimethylaminoethanethiol hydrochloride.
92% (6.5 mmol) in dioxane (20 ml) 60%
0.52 g (13 mmol) of NaH was added, and the mixture was heated under reflux for 0.5 hour. Thereafter, the temperature was returned to room temperature, 4-chloro-5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine 1 g (4.3 mmol) dissolved in dioxane (40 ml) was added, and the mixture was added at 70 ° C at 2 ° C. The mixture was heated and stirred for an hour. After the reaction was completed, a small amount of water (about 20 ml) was added and chloroform (15
It was extracted with ml × 3). The organic layer was washed with saturated brine and dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 40 g; ethyl acetate) to give 1.04 g of the desired product as a yellow oil (yield 8
0%).

[0139]

[Chemical 55]

[0140]

Example 29 Synthesis of N- (5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidin-4-yl) -L-alanine In the presence of 1.19 g (8.6 mmol) of potassium carbonate, 4-chloro-5,6-dihydro- [1] benzoxepino [5
4- d ] pyrimidine 1 g (4.3 mmol) and L-alanine 0.7
65 g (8.6 mmol) and 50% aq. Dioxane (15 m
Heated to reflux in l). After the reaction was completed, the solvent was distilled off under reduced pressure. Add a small amount of water (about 15 ml) and add ethyl acetate (10 ml).
5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine-4 ( 3H ) by-produced by extraction with x3)
-Excludes ON. Then, the aqueous layer was adjusted to pH 4 with acetic acid, and the deposited precipitate was collected by filtration. This precipitate is ethanol-
Recrystallization from water gave 0.75 g of the desired product as colorless columnar crystals (yield 61
%) Was obtained.

[0141]

[Chemical 56]

[0142]

Example 30 Synthesis of N- (5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidin-4-yl) -DL-valine In the presence of 1.19 g (8.6 mmol) of potassium carbonate, 4-chloro-5,6-dihydro- [1] benzoxepino [5
4- d ] pyrimidine 1 g (4.3 mmol) and DL-valine 1 g
(8.6 mmol) was heated to reflux in 50% aq. Dioxane (15 ml). After the reaction was completed, the solvent was distilled off under reduced pressure. A small amount of water (about 15 ml) was added, and the mixture was extracted with ethyl acetate (10 ml × 3), and by-produced 5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidin-4 (3 H ) -one. Excluded. Then, the aqueous layer was adjusted to pH 4 with acetic acid, and the deposited precipitate was collected by filtration. The precipitate was recrystallized from benzene-ethanol to give 0.28 g (yield 21%) of the desired product as colorless columnar crystals.
Got

[0143]

[Chemical 57]

[0144]

Example 31 Synthesis of N- (5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidin-4-yl) -DL-leucine In the presence of 1.19 g (8.6 mmol) of potassium carbonate, 4-chloro-5,6-dihydro- [1] benzoxepino [5
4- d ] pyrimidine 1 g (4.3 mmol) and DL-leucine 1.
13 g (8.6 mmol) and 50% aq. Dioxane (15 m
Heated to reflux in l). After the reaction was completed, the solvent was distilled off under reduced pressure. Add a small amount of water (about 15 ml) and add ethyl acetate (10 ml).
5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidine-4 ( 3H ) by-produced by extraction with x3)
-Excludes ON. Then, the aqueous layer was adjusted to pH 4 with acetic acid, and the deposited precipitate was collected by filtration. This precipitate is ethanol-
Recrystallization from benzene gave 0.21 g (yield 15%) of the target product as colorless needles.

[0145]

[Chemical 58]

[0146]

Example 32 Synthesis of N- (5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidin-4-yl) -DL-isoleucine 4-chloro in the presence of potassium carbonate (8.6 mmol). -5
6-dihydro- [1] benzoxepino [5,4- d ]
Pyrimidine 1 g (4.3 mmol) and DL-isoleucine 1.13
g (8.6 mmol) were heated to reflux in 50% aq. dioxane (15 ml). After the reaction was completed, the solvent was distilled off under reduced pressure. Add a small amount of water (about 15 ml) and add ethyl acetate (10 ml x 3).
And the by-produced 5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidin-4 ( 3H ) -one was removed. Then, the aqueous layer was adjusted to pH 4 with acetic acid, and the deposited precipitate was collected by filtration. This precipitate was recrystallized from ethanol-benzene to give 0.62 g of the desired product as colorless needles (yield 44
%) Was obtained.

[0147]

[Chemical 59]

[0148]

Example 33 Synthesis of N- (5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidin-4-yl) -DL-phenylglycine In the presence of 1.19 g (8.6 mmol) potassium carbonate. , 4-chloro-5,6-dihydro- [1] benzoxepino [5,
1 g (4.3 mmol) of 4- d ] pyrimidine and 1.3 g (8.6 mmol) of DL-phenylglycine were heated to reflux in 50% aq. Dioxane (15 ml). After the reaction was completed, the solvent was distilled off under reduced pressure. A small amount of water (about 15 ml) was added, and the mixture was extracted with ethyl acetate (10 ml × 3) to produce 5,6-dihydro-byproduct.
[1] Benzoxepino [5,4- d ] pyrimidine-4
The (3 H ) -one was removed. Then, the aqueous layer was adjusted to pH 4 with acetic acid.
The obtained precipitate was collected by filtration. The precipitate was recrystallized from ethanol-water to obtain 0.45 g (yield 30%) of the desired product as colorless columnar crystals.

[0149]

[Chemical 60]

[0150]

Example 34 Synthesis of N- (5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidin-4-yl) -N -methylglycine In the presence of 1.19 g (8.6 mmol) of potassium carbonate. , 4-chloro-5,6-dihydro- [1] benzoxepino [5,
1 g (4.3 mmol) of 4- d ] pyrimidine and 0.77 g (8.7 mmol) of N -methylglycine were heated to reflux in 50% aq. Dioxane (15 ml). After the reaction was completed, the solvent was distilled off under reduced pressure. A small amount of water (about 15 ml) was added, and the mixture was extracted with ethyl acetate (10 ml × 3) to produce 5,6-dihydro-byproduct.
[1] Benzoxepino [5,4- d ] pyrimidine-4
The (3 H ) -one was removed. Then, the aqueous layer was adjusted to pH 4 with acetic acid.
The obtained precipitate was collected by filtration. The precipitate was recrystallized from ethanol-water to obtain 0.99 g (yield 81%) of the desired product as colorless columnar crystals.

[0151]

[Chemical formula 61]

[0152]

Example 35 Synthesis of N- (5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidin-4-yl) -DL-proline In the presence of 1.19 g (8.6 mmol) of potassium carbonate, 4-chloro-5,6-dihydro- [1] benzoxepino [5
4- d ] pyrimidine 1 g (4.3 mmol) and DL-proline 1
g (8.7 mmol) were heated to reflux in 50% aq. dioxane (15 ml). After the reaction was completed, the solvent was distilled off under reduced pressure. Add a small amount of water (about 15 ml) and add ethyl acetate (10 ml x 3).
And the by-produced 5,6-dihydro- [1] benzoxepino [5,4- d ] pyrimidin-4 ( 3H ) -one was removed. Then, the aqueous layer was adjusted to pH 4 with acetic acid, and the deposited precipitate was collected by filtration. The precipitate was recrystallized from ethanol-water to obtain 1.04 g (yield 78%) of the desired product as colorless columnar crystals.

[0153]

[Chemical formula 62]

[0154]

Example 36 Synthesis of ethyl S- (3-cyanopropyl) thiosalicylate 5 g (27.4 mmol) of ethyl thiosalicylate, 4.26 g (41.1 mmol) of 4-chlorobutyronitrile, 5.69 g (46) of anhydrous potassium carbonate. 0.0 mmol) of dioxane (8
It was heated to reflux in 0 ml) for 20 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, 100 ml of water was added, and dichloromethane (40 ml) was added.
It was extracted in × 3). The organic layer was washed with saturated brine and dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. The oily residue was distilled under reduced pressure to obtain 6.15 g (yield 90%) of the oily target product.

[0155]

[Chemical 63]

[0156]

Example 37 Synthesis of 5-oxo-2,3,4,5-tetrahydro- [1] benzothiepine-4-carbonitrile Under ice cooling, 4.0 g (100 mmol) of 60% NaOH was suspended in toluene (300 ml). And ethyl S- (3-
Cyanopropyl) thiosalicylate 14.8 g (59.4 mm)
ol) dissolved in toluene (300 ml) was added, and the mixture was heated under reflux at room temperature for 0.5 hr. After completion of the reaction, the solvent was distilled off, the residue was poured into 300 ml of ice water, and the pH was adjusted to 5 with 2N-HCl. The deposited precipitate was collected by filtration and recrystallized from benzene-ethyl acetate to obtain 11.1 g of the desired product (yield 92%).

[0157]

[Chemical 64]

[0158]

Example 38 Synthesis of 4-amino-5,6-dihydro- [1] benzothiepino [5,4- d ] pyrimidine 5-oxo-2,3,4,5-tetrahydro- [1] benzothiepine-4- Carbonitrile 3.65 g (18.0
formamide (50 ml) was added to the solution, and the mixture was stirred at 150 ° C. for 24 hours under an ammonia stream. After that, the temperature was returned to room temperature and left overnight in the refrigerator. The precipitated crystals are collected by filtration,
To the filtrate, add 70 ml of water and add ethyl acetate (50 ml x
Extracted in 3). The organic layer was washed with saturated saline and dried with anhydrous M
After drying with gSO ₄ , the solvent was distilled off under reduced pressure. The residue and the crystals collected by filtration were combined and recrystallized from benzene-ethyl acetate to obtain 3.0 g of the desired product (yield 73%).

[0159]

[Chemical 65]

[0160]

Example 39 5,6-Dihydro- [1] benzthioepino [5,4-
Synthesis of d ] pyrimidin-4 (3 H ) -one 4-amino-5,6-dihydro- [1] benzthioepino [5,4- d ] pyrimidine 4.11 g (17.9 mmol)
6N-HCl (150 ml) was added, and the mixture was heated under reflux for 20 hours (10 ml on the way, 6N-HCl (75 ml) was added). After completion of the reaction, excess solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-ethanol to obtain 3.9 g (yield 95%) of the desired product as colorless needle crystals.

[0161]

[Chemical 66]

[0162]

Example 40 Synthesis of 4-chloro-5,6-dihydro- [1] benzthioepino [5,4- d ] pyrimidine 5,6-dihydro- [1] benzothiepino [5,4-]
d ] pyrimidin-4 ( 3H ) -one 3.97 g (17.2 mm)
30 ml of phosphoryl chloride was added to ol) and the mixture was heated under reflux for 2 hours. After completion of the reaction, excess phosphoryl chloride was distilled off under reduced pressure,
Ice water (about 50 ml) was added to the residue and saturated Na was added while stirring.
Neutralized with HCO ₃ water. This is ethyl acetate (20 ml x
3) Extraction, the organic layer was washed with saturated brine, anhydrous Mg
After drying with SO ₄ , the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 3.8 g of the desired product as colorless columnar crystals (yield 89
%) Was obtained.

[0163]

[Chemical 67]

[0164]

Example 41 Synthesis of 4- (2-hydroxyethylamino) -5,6-dihydro- [1] benzothiepino [5,4- d ] pyrimidine 4-chloro-5,6-dihydro- [1] benzothiepino [ 5,4- d ] pyrimidine (1 g, 4 mmol) and ethanolamine (1.24 g, 20.1 mmol) were combined with dioxane (20).
The mixture was heated to reflux in (ml) for 3 hours. After the reaction, the solvent was concentrated under reduced pressure and water (20 ml) was added to cause precipitation. This was collected by filtration and recrystallized from benzene to give the desired product as colorless columnar crystals.
95 g (yield 86%) was obtained.

[0165]

[Chemical 68]

[0166]

Example 42 Synthesis of 4- (2-hydroxypropylamino) -5,6-dihydro- [1] benzthioepino [5,4- d ] pyrimidine 4-chloro-5,6-dihydro- [1] benzothiepino [ 5,4- d ] pyrimidine 2 g (8 mmol) and DL-1-
Amino-2-propanol 1.8 g (24 mmol) and dioxane (30 ml) 2.21 g potassium carbonate (16 mmo)
In the presence of l), the mixture was heated under reflux for 17 hours. After completion of the reaction, potassium carbonate was filtered off and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to obtain 1.88 g (yield: 82%) of the desired product as colorless columnar crystals.

[0167]

[Chemical 69]

[0168]

Example 43 4- (2-hydroxy-1-methylethylamino)-
5,6-Dihydro- [1] benzthioepino [5,4-
Synthesis of d ] pyrimidine 4-chloro-5,6-dihydro- [1] benzthioepino [5,4- d ] pyrimidine 1 g (4 mmol) in DL-2-
1.5 g (20 mmol) of amino-1-propanol was added,
The mixture was heated under reflux at 70 ° C. for 6 hours. After completion of the reaction, water (40 ml) was added to the reaction solution to cause precipitation. This precipitate was collected by filtration and recrystallized from ethanol to give the target compound as colorless needles 1.0
6 g (yield 92%) was obtained.

[0169]

[Chemical 70]

[0170]

Example 44 Synthesis of 1,2,4,5-tetrahydro- [1] benzthioepino [4,5- e ] imidazo [1,2- c ] pyrimidine 4- (2-hydroxyethylamino) -5,6 10 ml of phosphoryl chloride was added to 1 g (3.66 mmol) of dihydro- [1] benzthioepino [5,4- d ] pyrimidine and 3
Heated to reflux for hours. After completion of the reaction, excess phosphoryl chloride was distilled off under reduced pressure, and after cooling on an ice bath, ice water (25 ml) was added. After neutralizing with saturated NaHCO ₃ water, ethyl acetate (1
It was extracted with 0 ml × 4). The organic layer was washed with saturated saline,
After drying over anhydrous MgSO ₄ , the solvent was distilled off. The obtained residue was recrystallized from ethyl acetate-ethanol to obtain 0.72 g (yield 77%) of the target product as colorless needle crystals.

[0171]

[Chemical 71]

[0172]

Example 45 1-Methyl-1,2,4,5-tetrahydro- [1] benzthioepino [4,5- e ] imidazo [1,2- c ]
Synthesis of pyrimidine 4- (2-hydroxypropylamino) -5,6-dihydro- [1] benzthioepino [5,4- d ] pyrimidine 1.0 g (3.5 mmol) was added with phosphoryl chloride 10 ml,
The mixture was heated under reflux for 2 hours. After completion of the reaction, excess phosphoryl chloride was distilled off under reduced pressure, and after cooling on an ice bath, ice water (25 ml)
Was added and neutralized with saturated aqueous NaHCO ₃ . It was extracted with ethyl acetate (10 ml x 4). The organic layer was washed with saturated brine and dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethanol-ether to obtain 0.86 g (yield 91%) of the desired product as colorless columnar crystals.

[0173]

[Chemical 72]

[0174]

Example 46 2-Methyl-1,2,4,5-tetrahydro- [1] benzthioepino [4,5- e ] imidazo [1,2- c ]
Synthesis of pyrimidine 4- (2-hydroxy-1-methylethylamino)-
5,6-Dihydro- [1] benzthioepino [5,4-
d ] pyrimidine 1 g (3.5 mmol) and phosphoryl chloride 10
ml was added and the mixture was heated under reflux for 2.5 hours. After completion of the reaction, excess phosphoryl chloride was distilled off under reduced pressure, cooled on an ice bath, ice water (25 ml) was added, neutralized with saturated NaHCO ₃ water, and extracted with ethyl acetate (10 ml × 3). did. The organic layer was washed with saturated brine and dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from benzene-ethyl acetate to obtain 0.84 g (yield 89%) of the desired product as yellow columnar crystals.

[0175]

[Chemical formula 73]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location C07D 495/04 116 9164-4C 495/14 Z 9164-4C

Claims (10)

[Claims] 1. A general formula: (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group,
R ² represents a lower alkyl group or a lower alkyl group substituted with a hydroxyl group or a dialkylamino group, and Z represents an oxygen atom or a sulfur atom). 2. A general formula: (In the formula, R ³ represents a lower alkyl group or a lower alkyl group substituted with a hydroxyl group or a dialkylamino group,
Z represents an oxygen atom or a sulfur atom), and is a pyrimidine derivative. 3. A general formula: (In the formula, R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group; n represents 1 or 2;
Represents an oxygen atom or a sulfur atom). 4. A general formula: (In the formula, R ⁶ represents a hydrogen atom or a lower alkyl group,
R ⁷ represents a residue obtained by removing an amino group from an amino acid, and Z represents an oxygen atom or a sulfur atom). 5. A general formula: (In the formula, R ⁸ represents a chlorine atom or an amino group, and Z represents an oxygen atom or a sulfur atom). 6. A general formula: (In the formula, Z ¹ and Z ² are the same or different and each represents an oxygen atom or a sulfur atom). 7. A general formula: (In the formula, Z represents an oxygen atom or a sulfur atom). 8. A general formula: (In the formula, R ⁹ represents a lower alkyl group, and Z represents an oxygen atom or a sulfur atom). 9. A general formula: (In the formula, Z represents an oxygen atom or a sulfur atom). 10. A platelet aggregation inhibitor comprising the pyrimidine derivative according to any one of claims 1 to 9 as an active ingredient.