JP2852538B2 - [1,2,4] triazolo [1,5-a] pyrimidine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel [1,2] having excellent vascular smooth muscle cell (hereinafter, referred to as “SMC”) growth inhibitory action and vascular intimal hyperplasia inhibitory action. , 4] Triazolo [1,5-a] pyrimidine derivatives and salts thereof and arteriosclerotic vascular hypertrophy inhibitors containing them.

[Conventional technology and its problems]

Conventionally, the following formula (IV) having a [1,2,4] triazolo [1,5-a] pyrimidine skeleton: Is known to have a mouse fibroblast proliferation inhibitory activity [Life Science (Li
fe sciences), 28, 1641-1646, 1981].

However, the SMC proliferation inhibitory activity of the compound (IV) is not sufficiently satisfactory, and a compound having a stronger activity has been desired.

[Means for solving the problem]

In view of the above situation, the present inventors have synthesized various [1,2,4] triazolo [1,5-a] pyrimidine derivatives and studied their pharmacological actions. As a result, they were represented by the following general formula (I). Novel [1,2,4] triazolo [1,5-a] pyrimidine derivatives or their pharmaceutically acceptable acid addition salts have strong SMC growth inhibitory activity and intimal thickening inhibitory activity, The present inventors have found that the present invention is useful as an agent for suppressing vascular hypertrophy and completed the present invention.

That is, the present invention provides a compound represented by the general formula (I): (Wherein, R ₁ represents a hydrogen atom or a lower alkyl group, and R ₂ represents a hydrogen atom, an acyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroaralkyl group, or a group having 1 to 1 carbon atoms.
6 represents an alkyl group or a cycloalkyl group, wherein the aryl part of the aryl group, aralkyl group, heteroaryl group and heteroaralkyl group is substituted with one or more halogen atoms, lower alkyl groups or lower alkoxy groups. At best, R ₃ represents an alkyl group or a cycloalkyl group or an aryl group, having 1 to 6 carbon atoms, R ₄ is formula by, or R ₃ and R ₄ represents a hydrogen atom - (CH ₂₎ n _- [wherein Medium, n
Represents an integer of 3 to 5], and R ₅ represents a primary amino group, a secondary or tertiary amino group substituted by a lower alkyl group, or an alicyclic amino group. Represents a group. ) [1,2,4] triazolo [1,5
-A] a pyrimidine derivative or a pharmaceutically acceptable acid addition salt thereof; The present invention also provides an arteriosclerotic vascular hypertrophy inhibitor containing these compounds as an active ingredient.

In the compound represented by formula (I) of the present invention, examples of the lower alkyl group include those having 1 to 6 carbon atoms, and specific examples include methyl, ethyl, propyl, isopropyl, butyl and Secondary and tertiary butyl groups and the like can be mentioned. The acyl group is preferably an alkanoyl group having 2 to 8 carbon atoms and an arylcarbonyl group, and specific examples include acetyl, propanoyl, butanoyl, benzoyl, and naphthoyl groups. Examples of the aryl group include those having 6 to 14 carbon atoms, such as phenyl, naphthyl and anthracenyl groups. Examples of the aralkyl group include those having 7 to 15 carbon atoms, such as benzyl, phenylethyl, and naphthylmethyl groups. Examples of the heteroaryl group include mono-hetero 5-membered rings such as furan, thiophene and pyrrole, di-hetero 5-membered rings such as pyrazole, imidazole and thiazole, mono-hetero 6-membered rings such as pyridine, and pyridazine.
Examples include dihetero 6-membered rings such as pyrimidine and pyrazine, and groups formed from two or more hetero rings including these monocyclic hetero rings. Examples of the heteroaralkyl group include a methyl and ethyl group substituted by the heteroaryl group. Examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms. Examples of the lower alkoxy group include those having 1 to 6 carbon atoms, and specific examples include methoxy, ethoxy, propoxy, and butoxy groups. Examples of the cycloalkyl group include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examples of the alicyclic amino group include a nitrogen-containing 5- to 7-membered ring, and specific examples thereof include a pyrrolidino group, a piperidino group, a morpholino group, and a piperazino group that may be substituted with a lower alkyl group. Can be

The compound (I) of the present invention has the above substituent, but R ¹ is a hydrogen atom, and R ₂ is a cyclohexyl group or an unsubstituted or phenyl group substituted with a chloro atom or a methyl group, Preferably, R ₃ is a cyclohexyl group or a phenyl group, R ₄ is a hydrogen atom, and R ₅ is an ethylamino group, a dipropylamino group or a 3-methylpiperazino group.

The acid addition salt of the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable acid addition salt.
Mineral salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate and sulfate, or methanesulfonate, 2-hydroxyethanesulfonate, p-toluenesulfonate and the like Organic sulfonates, as well as acetates,
Propanoate, oxalate, malonate, succinate,
Organic carboxylate salts such as glutarate, adipate, tartrate, maleate, malate, and mandelate are exemplified.

The compound (I) of the present invention can be produced, for example, according to the following reaction.

(Wherein, R ₁ , R ₂ , R ₃ and R ₄ represent the same as above, Represents a same group as the R _5, X ₁ and X ₂ represent, respectively, a halogen atom. That is, first, the 5,6-disubstituted-7 represented by the general formula (II)
-Halo-2-halomethyl- [1,2,4] triazolo [1,5-
methanol a] pyrimidine derivatives, lower aliphatic alcohols or methylene chloride and ethanol, halogenated hydrocarbons or diethyl ether such as chloroform, aliphatic ethers or mixtures thereof, such as tetrahydrofuran as a solvent, the R ₅ The corresponding amines are added, and if necessary, preferably one equivalent of an organic base such as triethylamine, dimethylamine, pyridine or the like or an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate is deacidified. The reaction temperature is below room temperature, preferably 0 ° C to 10 ° C.
And the amount of the amine to be added was limited to 1 equivalent, and the progress of the reaction was examined by thin-layer chromatography to adjust the reaction time appropriately, so that only the 7-position was selectively reacted. The compound represented by III) can be obtained.

Next, 1 to 2 equivalents of the 1- or 2-substituted or 1,2-disubstituted piperazines are added thereto, and if necessary, the above-mentioned deoxidizing agent is added and the mixture is heated under reflux in the above-mentioned solvent to give the compound of the present invention. (I) can be obtained.

The compound (I) of the present invention can also be obtained by treating the compound of the formula (III) continuously without isolation under the above reaction conditions.

The starting material represented by the general formula (II) in the above reaction formula is obtained, for example, by reacting β-ketocarboxylic acid esters with 3-amino-5-hydroxymethyl-1,2,4-triazole. 5,6-disubstituted-7-hydroxy-2
-Hydroxymethyl- [1,2,4] triazolo [1,5-a]
Pyrimidines are halogenated with a suitable conventional halogenating agent to give 5,6-disubstituted-7-halo-2-halomethyl- [1,2,
4] It can be produced by preparing triazolo [1,5-a] pyrimidines.

The compound (I) of the present invention and a salt thereof thus obtained have an excellent SMC growth inhibitory action and an inhibitory action on intimal hyperplasia, and have a low toxicity as a result of an acute toxicity test. It is useful as a sclerosing vascular hypertrophy inhibitor.

The compound of the present invention and a salt thereof can be made into a preparation for oral administration or parenteral administration by a known preparation technique.
Dosage forms for oral administration include, for example, tablets, powders, granules,
Examples include solid preparations such as capsules, solutions, syrups, elixirs, oily and aqueous suspensions, and the like. Dosage forms for parenteral administration include injections such as liquid preparations for injection and lyophilized preparations.

In preparing these preparations, excipients, lubricants, various solvents, surfactants and the like which are used in usual preparations can be added.

The dosage of the compound of the present invention or a salt thereof varies depending on the administration method, symptoms, administration timing, administration period and the like. In general, in the case of oral administration, 50 to 1000 mg per adult per day is suitable.

〔The invention's effect〕

The compounds of the present invention and salts thereof have excellent SCM growth inhibitory activity and intimal hyperplasia inhibitory activity. Accordingly, the compounds of the present invention and salts thereof are useful for treating arteriosclerotic diseases such as cerebral atherosclerosis, coronary atherosclerosis, peripheral arteriosclerosis, arteritis, and percutaneous coronary angioplasty (Percutaneous Translumina).
l Coronary Angioplaty) is effective against restenosis of blood vessels after surgery, and can treat or prevent the above-mentioned various diseases caused by abnormal blood vessels.

〔Example〕

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto.

First, among the starting compounds used in the method of the present invention,
A method for producing the compound represented by the general formula (II) will be specifically described in Reference Example I below.

Reference Example I-1 7-chloro-2-chloromethyl-5-cyclohexyl-
Synthesis of [1,2,4] triazolo [1,5-a] pyrimidine 5-cyclohexyl-7- in 500 ml of phosphorus oxychloride
After adding 294 g of hydroxy-2-hydroxymethyl- [1,2,4] triazolo [1,5-a] pyrimidine and heating under reflux for 2 hours, the reaction solution was concentrated to dryness. After neutralizing the residue by adding saturated aqueous sodium hydrogen carbonate to a chloroform solution,
The chloroform layer was separated. The chloroform layer was dried over anhydrous sodium sulfate and concentrated to dryness. The resulting oil was purified by silica gel column chromatography (eluent, chloroform) to give 7-chloro-2-chloromethyl-5-
327 g of cyclohexyl- [1,2,4] triazolo [1,5-a] pyrimidine crystals (mp 78-80 ° C.) were obtained.

^{IR (KBr) cm -1: 1640,1620,1160} NMR (CDCl 3, δppm): 1.10~2.10 (10H, m), 2.80 (1H,
m), 4.77 (2H, s ), 7.06 (1H, s) Elemental analysis (C ₁₂ H ₁₄ Cl as ₂ N ₄₎ Calculated: C 50.54, H 4.95, N 19,65% Analytical values: C 50.01, H 5.41, N 19,22% Reference Example I- shown in Table 1 according to the method of Reference Example I-1.
Compounds 2-I-7 were prepared.

Next, the starting material 7-hydroxy- used in Reference Example I was used.
2-hydroxymethyl- [1,2,4] triazolo [1,5-
a) A method for producing pyrimidines is specifically described in Reference Example II below.

Reference Example II-1 Synthesis of 5-cyclohexyl-7-hydroxy-2-hydroxymethyl- [1,2,4] triazolo [1,5-a] pyrimidine 3-amino-5-hydroxymethyl-1,2,4 -703 g of triazole glycolate and 3-cyclohexyl-
3-oxopropanoic acid ethyl ester 1103 g to acetic acid 1000m
and heated to reflux for 8 hours. After the reaction solution was concentrated to dryness, 1000 ml of methanol was added, and then concentrated aqueous ammonia was added to make the solution alkaline, followed by stirring overnight at room temperature. The precipitate is collected by filtration, dissolved in water, acidified with concentrated hydrochloric acid, and the precipitated crystals are collected by filtration to give 5-cyclohexyl-7-hydroxy-2-hydroxymethyl-.
Crystals of [1,2,4] triazolo [1,5-a] pyrimidine (m.
294 g).

^{IR (KBr) cm -1: 3430,1695,1620,1170,1050,850,750} NMR (DMSO-d 6, δppm): 1.00~2.20 (10H, m), 2.50 (1
H, m), 4.48 (2H , s), 5.70 (1H, s) Elemental analysis (C ₁₂ H ₁₆ N ₄ as O ₂₎ Calculated: C 58.05, H 6.50, N 22,57% Analytical values: C 57.72 , H 6.48, N 22,35% Reference Example II-2 shown in Table 2 in the same manner as Reference Example II-1.
~ II-7 were prepared.

Example 1 Synthesis of 2- [4- (4-chlorophenyl) piperazin-1-yl] methyl-5-cyclohexyl-7-diethylamino- [1,2,4] triazolo [1,5-a] pyrimidine a Method 7 To a solution of -chloro-2-chloromethyl-5-cyclohexyl- [1,2,4] triazolo [1,5-a] pyrimidine (20.0 g) in ethanol (130 ml) was added diethylamine (7.3 ml) and triethylamine (10 ml) under ice-cooling. Stirred at room temperature for 4 hours. After the reaction solution was concentrated to dryness, it was extracted with chloroform. After the extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated saline solution, and dried over anhydrous sodium sulfate,
Concentrate to dryness to give 2-chloromethyl-5-cyclohexyl-
7-diethylamino- [1,2,4] triazolo [1,5-a]
22.48 g of pyrimidine crystals (mp 95-96 ° C.) were obtained.

IR (KBr) cm ^-1 : 1260, 1065, 810, 750 NMR (CDCl ₃ , δ ppm): 1.33 (6H, t), 1.30 to 2.20 (10H,
m), 2.60 (1H, m), 3.83 (4H, q), 4.66 (2H, s), 5.92 (1
H, s) Elemental analysis (C ₁₆ H ₂₄ ClN as ₅₎ Calculated: C 59.71, H 7.52, N 21.76% Analytical values: C 59.30, H 7.46, N 21.75% The 2-chloromethyl-5-cyclohexyl - 7-
14.5 g of 1- (4-chlorophenyl) piperazine and 14 m of triethylamine were added to a solution of 19.95 g of diethylamino- [1,2,4] triazolo [1,5-a] pyrimidine in 200 ml of ethanol.
l and heated to reflux overnight. The residue obtained by concentrating the reaction solution to dryness was extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated to dryness. The resulting oil was purified by silica gel column chromatography (eluent, 2%
Purified with methanol-containing chloroform) to give 2- [4-
(4-Chlorophenyl) piperazin-1-yl] methyl-5-cyclohexyl-7-diethylamino- [1,2,
4] Triazolo [1,5-a] pyrimidine crystals (mp132
134134 ° C.).

b method To a solution of 7-chloro-2-chloromethyl-5-cyclohexyl- [1,2,4] triazolo [1,5-a] pyrimidine in 230 ml of ethanol was added 83.3 ml of diethylamine and 124.5 ml of triethylamine under ice-cooling. After stirring overnight at room temperature, then 1- (4-chlorophenyl) piperazine
152.9 g and 124.5 ml of triethylamine were added, and the mixture was heated under reflux for 6 hours. The residue obtained by concentrating the reaction solution to dryness was extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated saline solution, and then concentrated to dryness. The resulting oil was purified by silica gel column chromatography (eluent, 2
% Methanol-containing chloroform) to give 2- [4
-(4-Chlorophenyl) piperazin-1-yl] methyl-5-cyclohexyl-7-diethylamino- [1,2,
4] Triazolo [1,5-a] pyrimidine crystals (mp132
134134 ° C.).

^{IR (KBr) cm -1: 1250,1240,1150,1140,1010,820} NMR (CDCl 3, δppm): 1.30 (6H, t), 1.20~2.10 (10H,
m), 2.60 (1H, m), 2.85 (4H, m), 3.16 (4H, m), 3.80 (4
H, q), 3.83 (2H, s), 5.85 (1H, s), 6.73 (2H, d), 7.08
(2H, d) Elemental analysis (as C ₂₆ H ₃₆ ClN ₇ ) Calculated value: C 64.78, H 7.53, N 20.34% Analytical value: C 64.56, H 7.45, N 20.41% Example 2 2- [4- (4 -Chlorophenyl) piperazin-1-yl] methyl-5-cyclohexyl-7-diethylamino- [1,2,4] triazolo [1,5-a] pyrimidine trihydrochloride Synthesis of hemihydrate 2- [4- (4-chlorophenyl ) Piperazine-1-
Yl] methyl-5-cyclohexyl-7-diethylamino- [1,2,4] triazolo [1,5-a] pyrimidine 210.9 g
Was dissolved in hot ethanol, 150 ml of concentrated hydrochloric acid was added, and the mixture was concentrated to dryness. The residue was crystallized from ethanol to give 2- [4-
(4-Chlorophenyl) piperazin-1-yl] methyl-5-cyclohexyl-7-diethylamino- [1,2,
4) Triazolo [1,5-a] pyrimidine trihydrochloride hemihydrate crystals (mp 197-200 ° C.)
2 g were obtained.

IR (KBr) cm ^-1 : 3490,3420,3100〜2000,1665,1210,1100,
_{1020,840,790,720 NMR (DMSO-d 6,} δppm): 1.35 (6H, broad t), 1.20~2.1
0 (1H, m), 3.00 (1H, m), 3.55 (8H, m), 4.06 (4H, broad
q), 4.66 (2H, broad s), 6.52 (1H, s), 6.96 (2H, d),
7.23 (2H, d) Elemental analysis _{(C 26 H 36 ClN 7 ·} 3HCl · 1 / 2H 2 O ) Calculated value: C 52.01, H 6.71, N 16.33% Analytical values: C 52.14, H 6.87, N 16.06% implementation Example 3 Synthesis of 2- [4- (4-chlorophenyl) piperazin-1-yl] methyl-5-cyclohexyl-7-diethylamino- [1,2,4] triazolo [1,5-a] pyrimidine monomaleate 2- [ 4- (4-chlorophenyl) piperazine-1-
Yl] methyl-5-cyclohexyl-7-diethylamino- [1,2,4] triazolo [1,5-a] pyrimidine (30 g) and maleic acid (7.22 g) were dissolved by heating in 1000 ml of ethanol and then cooled to room temperature. And the precipitated 2- [4- (4-
Chlorophenyl) piperazin-1-yl] methyl-5
28.5 g of crystals of cyclohexyl-7-diethylamino- [1,2,4] triazolo [1,5-a] pyrimidine monomaleate (mp 173-174 ° C.) were obtained.

IR (KBr) cm ^-1 : 3450,1705,1615,1255,1220,1195,1120,1
_{080,1005,875,815,760 NMR (DMSO-d 6,} δppm): 1.25 (6H, t), 1.20~2.00 (10
H, m), 2.60 (1H, m), 3.30 (8H, m), 3.85 (4H, q), 4.32
(2H, s), 6.14 (2H, s), 6.25 (1H, s), 6.90 (2H, d), 7.
20 (2H, d) Elemental analysis (as C ₂₆ H ₃₆ ClN ₇ · C ₄ H ₄ O ₄ ) Calculated value: C 60.24, H 6.74, N 16.39% Analytical value: C 60.27, H 6.72, N 16.32% According to the method 1, 2, or 3, the compounds of Examples 4 to 56 shown in Table 3 were produced.

Test Example 1 Activity of the Compound (I) of the Present Invention for Inhibiting Proliferation of Aortic Smooth Muscle Cells: The activity of the compound of the present invention for inhibiting SMC proliferation was measured by the following method.

That is, Dulbecco's Modified Eagle containing 10% fetal bovine serum (FBS) and antibiotics.
gle, DME) medium, the intima-media section of New Zealand white rabbit thoracic aorta was cultured at 37 ° C. in an atmosphere containing 95% air and 5% carbon dioxide, and SMC was extended and grown from the tissue section. . After culturing for 10 days, trypsinization was performed, and the grown SMCs were collected and cultivated again in DME medium containing 10% FBS and antibiotics at a confluence of 1/3, whereby those cells were constantly transferred. Subculture was performed. After culturing for 4 days, trypsinization was performed, and SMC was seeded and cultured at a cell density of 120,000 cells per 35 × 10 mm Falcon dish in 2 ml of DME medium containing 10% FBS and antibiotics. After culturing for 24 hours, the medium was replaced with 2 ml of control medium or test medium. The control medium was DME medium containing 6% FBS and antibiotics and 0.25% (v / v) dimethyl sulfoxide (DMS
O). The test medium consisted of DME medium containing 6% FBS and antibiotics and the compound (I) of the present invention. Compound (I) of the present invention was dissolved in DMSO in advance so that the final concentration of DMSO in the medium was 0.25% (v / v). After replacing with control or test media, cells were incubated for an additional 2 days. At the end of the incubation period, cells are trypsinized and Coulter (Co
The cell number was counted by counting the cell suspension with an ulter) counter.

The results obtained were all expressed as the average value for cells in four dishes. The growth inhibition rate (%) was calculated using the following equation.

Growth inhibition rate (%) = 100 − [(TS) / (CS) × 100] (where S is the amount per plate at the start of the test (at the time of adding the control medium or the test medium)) Is the average cell number of
T is the average number of cells per dish of test medium at the completion of the test and C is the average number of cells per dish in control medium at the completion of the test. The results are shown in Table 4 as 50% inhibitory activity (IC ₅₀ ).

As is evident from Table 4, the compound of the present invention showed much stronger SMC growth inhibitory activity than the control compound (IV).

Test Example 2 Inhibitory Activity of Compound (I) of the Present Invention on Incorporation of Injured Aortic Thymidine in Rats: The inhibitory activity of compound (I) of the present invention on the uptake of injured aortic thymidine in rats was measured by the following method. The results are shown in Table-5.

Endothelial injury is described by Crows et al. [Laboratory Investigation, Volume 49,
208-215, 1983] and the method of Jaktion et al. (Atherosclerosis, 69, 115-122).
1988].

That is, a male SD rat weighing 210-230 g was laparotomized under pentobarbital anesthesia, a balloon catheter (Fogati, 3F) was inserted from the abdominal aorta to the thoracic aortic arch, and the balloon was inflated. To remove endothelial cells (de-endothelializatio
n).

A suspension of the compound (I) of the present invention in a 0.5% carboxymethylcellulose (CMC) aqueous solution at a concentration of 12.5 mg / ml (W / V) was added at 50 mg / ml 1 hour before endothelial removal, and 4 hours and 22 hours after removal. The rats were orally administered at a rate of kg (4 ml / kg) using an oral probe. As a control, the same amount of 0.5% CMC aqueous solution was orally administered at the same time. 48 hours after endothelial removal, ³ H-thymidine was intravenously administered to rats anesthetized with pentobarbital at a rate of 500 μCi / kg (18.5 MBq / kg).
Thirty minutes after administration of ³ H-thymidine, the animals were sacrificed by exsanguination, and the thoracic aorta, spleen, and bone marrow were removed. The excised blood vessel was opened in the direction of the blood vessel, and the adventitia and the intima were further separated using flat forceps to collect the intima-media portion as a material for measuring ³ H-thymidine uptake.

The collected inner media was dissolved by homogenization and heat treatment in the presence of a 0.5N aqueous sodium hydroxide solution, and then ice-cooled trichloroacetic acid was added to precipitate an acid-insoluble fraction.
Further, the precipitate fraction collected by centrifugation was dissolved again with a 0.5N aqueous sodium hydroxide solution, a predetermined amount of the precipitate was placed in a scintillation vial, a scintillator was added, and the radioactivity was measured.

The radioactivity of the spleen and bone marrow removed in the same manner was measured.

The ³ H-thymidine incorporation value was determined by the method of Fujimoto et al. For blood vessels [In Vitro, 13, 237-244.
Page, in terms of per DNA content in the samples was measured in accordance with 1977] The ³ spleen and control group and the compound of the present invention in terms of weight per wet each unit tissues Bone Marrow (I) administration group The inhibition rates were determined by comparing the H-thymidine incorporation values.

As described above, the compound of the present invention only inhibits thymidine uptake in the aorta, does not inhibit thymidine uptake in other spleen and bone marrow where cell proliferation is active, and shows that it selectively acts on the aorta. Was.

Test Example 3 Activity of Compound (I) of the Present Invention for Inhibiting Intimal Hyperplasia of Injured Aorta in Rats: The activity of compound (I) of the present invention for inhibiting intimal hypertrophy of injured aorta in rats was measured by the following method. The results are shown in Table-6.

Endothelial injury was performed in the same animals, conditions and methods as in Test Example 2. Then, 100, 25 and 10 of the compound (I) of the present invention
mg of each suspension in 4 ml of 0.5% CMC aqueous solution were orally administered to injured rats at a rate of 4 ml / kg.
The control group was orally administered a 0.5% CMC aqueous solution at a rate of 4 ml / kg. The administration was performed twice a day, one hour before and four hours after the injury, only on the day of endothelial injury surgery, but once a day from the second day to the 14th day. On the 15th day after the operation, the rats were sacrificed by exsanguination, and the thoracic aorta was removed. A tissue section of the excised blood vessel was prepared, and then a tissue specimen stained with Masson's trichrome was prepared.

Thickness of intimal thickening layer at maximum thickness of each specimen (I
Value) and the thickness (M value) of the media layer (I / M value)
Using the following formula, the control group and the drug-administered group were compared to calculate the inhibition rate (%) of intimal hyperplasia inhibition. In addition, 10 per group
Using ~ 13 rats, the average of the I / M values was
Used as / M value.

Inhibition rate of intimal hyperplasia (%) = (1−T / C) × 100 (where T represents the compound of the present invention (I),
Indicates the I / M value obtained from the control group of rats. ) Test Example 4 Activity of Compound (I) of the Invention for Inhibiting Intimal Hyperplasia of Injured Aorta in Rabbits: The activity of Compound (I) of the present invention for inhibiting intimal hyperplasia of injured aorta in rabbits was measured by the following method. The results are shown in Table-7.

Endothelial injury was performed according to Test Example 2, and subsequent tests were performed according to Test Example 3.

That is, a male New Zealand white rabbit weighing 2.0 to 2.5 kg was laparotomized under pentobarbital anesthesia, a balloon catheter (Fogati, 4F) was inserted from the femoral artery to the thoracic aortic arch, and the balloon was inflated. Endothelial cells were removed over the aorta (de-en
dothelialization).

Next, 50, 25, 10 and 5 mg of the compound (I) of the present invention, each suspended in 1 ml of a 0.5% CMC aqueous solution, were orally administered to the injured rabbit at a rate of 1 ml / kg. The control group was orally administered a 0.5% CMC aqueous solution at a rate of 1 ml / kg. The administration was performed twice a day, one hour before the injury and four hours after the injury, only on the day of endothelial injury surgery, but once a day from the second day to the 20th day. On the 21st day after the operation, the rabbit was sacrificed by exsanguination, and the thoracic aorta was removed. A tissue section of the excised blood vessel was prepared, and then a tissue specimen stained with Masson's trichrome was prepared.

Thickness of intimal thickening layer at maximum thickness of each specimen (I
Value) and the thickness (M value) of the media layer (I / M value)
In the same manner as in Test Example 3, the intimal thickening suppression rate (%) was calculated. However, a group of 7 to 11 rabbits was used.

Test Example 5 Oral acute toxicity of compound (I) of the present invention in mice: 1000 mg of compound (I) of the present invention dissolved or suspended in 10 ml of a 1% aqueous methylcellulose solution was applied to male ddy mice at a dose of 1 mg.
Oral administration was performed at a rate of 0 ml / kg. With the number of mice administered per group being four, the number of deaths was observed for 7 days after administration. The control group was orally administered a 1% aqueous solution of methylcellulose at a rate of 10 ml / kg.

As a result of the above test, none of the compounds of the present invention (I) shown in Table 4 showed any deaths and showed low toxicity.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Kenichi Nishida 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Inside the Daiichi Pharmaceutical Central Research Laboratories (56) References JP 1-156978 (JP, A) JP 57-35592 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 487/04 A61K 31/505 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula (I): (In the formula, R ₁ represents a hydrogen atom or a lower alkyl group, R ₂ represents a hydrogen atom, an acyl group, an aryl group, an aralkyl group or an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group, the aryl group and The aryl portion of the aralkyl group may be substituted with one or more halogen atoms, lower alkyl groups or lower alkoxy groups, and R ₃ has 1 to 1 carbon atoms.
6 represents an alkyl group, a cycloalkyl group, or an aryl group, R ₄ represents a hydrogen atom, or R ₃ and R ₄ represent a group represented by the formula — (CH ₂ ) _n — wherein n is an integer of 3 to 5; means〕
_May form a group represented by R ₅ is a primary amino group,
A secondary or tertiary amino group substituted by a lower alkyl group,
Alternatively, it represents an alicyclic amino group. ) [1,2,
4] Triazolo [1,5-a] pyrimidine derivatives or pharmaceutically acceptable acid addition salts thereof. 2. An arteriosclerotic vascular hypertrophy inhibitor comprising the compound according to claim 1 or a salt thereof.