JPS6232750B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to s-triazolo[1.5-a]pyrimidine derivatives having vasodilating, hypotensive, platelet aggregation-inhibiting and cholesterol-lowering effects.

Circulatory system diseases such as ischemic heart disease, cerebrovascular disorders, arteriosclerosis, and hypertension account for a large proportion of the causes of death in Japan, along with malignant tumors, and are extremely important diseases. Among these circulatory system diseases, ischemic heart disease and cerebral and peripheral circulation failure are caused by insufficient blood flow due to arterial thrombosis and arteriosclerosis, which causes malnutrition and oxygen deficiency in the ischemic area. It is believed that. Therefore, drugs that improve blood flow based on vasodilation in ischemic regions such as coronary arteries are effective for these diseases. Furthermore, drugs that suppress platelet aggregation, which is one of the causes of arterial thrombosis, and drugs that lower cholesterol, which causes arteriosclerosis, are considered useful in preventing the onset of these diseases.

On the other hand, among drugs that have a vasodilatory effect, there are some that have a hypotensive effect, such as hydralazine, and are frequently used in the treatment of hypertension. Recently, attempts have been made to use vasodilators in the treatment of heart failure, and Takashi Ito et al. [Japan Clinical (1978)
36, No. 11, p. 51] and Shinobu Matsui et al. [Japanese Circulation Society (1979) 43rd Annual General Meeting Lecture 165].

Based on the above findings, the present inventors believe that the above-mentioned circulatory system diseases are mutually related, and that the optimal treatment is one that comprehensively improves the circulatory system disorders. As a result of many years of research to find a compound that matches the general formula () (In the formula, R ₁ and R ₂ are the same or different straight-chain or branched alkyl groups having 1 to 6 carbon atoms, phenyl groups, or hydrogen atoms, and R ₃ is straight-chain or branched straight-chain or branched alkyl groups having 1 to 6 carbon atoms, or hydrogen atoms. A novel s-triazolo[1,5-a]pyrimidine represented by an alkyl group, a hydrogen atom, and R ₄ represents a linear or branched alkyl group having 1 to 6 carbon atoms, a phenyl group, or a substituted phenyl group. The present invention was completed based on the discovery that the derivative has a vasodilatory effect, a hypotensive effect, a platelet aggregation-inhibiting effect, and a cholesterol-lowering effect.

The compounds of the present invention can generally be produced as follows.

That is, 3-amino-5-hydroxymethyl-s
- By heating and condensing α-acylcarboxylic acid ester etc. with triazole,
A hydroxy-s-triazolo[1.5-a]pyrimidine derivative is obtained.

Next, this is halogenated using a suitable halogenating agent to obtain 2-halomethyl-7-halo-s-triazolo[1.5-a]pyrimidine. Further, this is reacted with a suitable amine to obtain an s-triazolo[1.5-a]pyrimidine derivative.

An example is as follows.

3-Amino-5-hydroxymethyl-s-triazole and ethyl acetoacetate are heated under neutral conditions without a solvent, or heated to reflux using a lower saturated fatty acid such as acetic acid as a solvent to obtain 7-hydroxy-2 -Hydroxymethyl-5-methyl-s-triazolo[1.5-a]pyrimidine is obtained. This is treated with a suitable halogenating agent, such as phosphorus oxychloride,
7-chloro-2-chloromethyl- is prepared using phosphorus pentachloride, etc., without a solvent or using a suitable solvent such as benzene, chloroform, carbon tetrachloride, at room temperature or, if necessary, by heating or heating to reflux.
5-Methyl-s-triazolo[1.5-a]pyrimidine is obtained. The s-triazolo[1,5-a]pyrimidine halogen derivative obtained in this way was
Dissolve in a solvent such as ethanol or methanol, and if necessary add triethylamine, dimethylaniline,
Pyridine or the like is added as a deoxidizing agent to react with diethylamine. In this case, in order to selectively react only the 7-position, the amount of amine, reaction temperature, reaction time, etc. may be adjusted. 2- obtained in this way
Chloromethyl-7-diethylamino-5-methyl-s-triazolo[1,5-a]pyrimidine,
Dissolve in a solvent such as methanol or ethanol, and if necessary add triethylamine, dimethylaniline,
By adding pyridine etc. as a deoxidizing agent, adding N-propylaniline to this, and heating under reflux, 7-diethylamino-5-methyl-2-(N
-phenyl-N-propyl)aminomethyl-s-
A triazolo[1,5-a]pyrimidine is obtained.

The compound represented by the general formula () thus obtained can be made into a pharmacologically acceptable salt form. Pharmaceutically acceptable salt forms include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or acetic acid, maleic acid, citric acid, tartaric acid, oxalic acid, succinic acid, etc. Mention may be made of acid addition salts with organic acids such as acids.

All of the s-triazolo[1,5-a]pyrimidine derivatives of the present invention have strong vasodilatory, antihypertensive, platelet aggregation-inhibiting, and cholesterol-lowering effects, and are water-soluble, making them excellent as pharmaceuticals. It is a compound that has properties. The compounds of the invention as well as their acid addition salts can therefore be used alone or together with other pharmaceutically active compounds and, if desired, with binders, fillers, flavorants, etc. used in the pharmaceutical industry. It can be converted into a pharmaceutically usable product by modification in any of the following ways.

The following examples show the method for producing the compounds of the present invention, but the present invention is not limited only to these examples.

Example 1 7-dimethylamino-5-methyl-2-(N-
phenyl-N-propyl)aminomethyl-s-
Triazolo[1,5-a]pyrimidine 220 ml of 70% glycolic acid and 2 ml of concentrated nitric acid were added to 136 g of aminoguanidine bicarbonate and heated to about 85°C. After dissolution, the mixture was heated under reflux for 24 hours. After the reaction was completed, the reaction mixture was cooled and precipitated crystals were collected. This was recrystallized from ethanol to obtain 3-amino-5-hydroxymethyl-s-triazole.

Yield 50g, yield 51%, melting point 114-115°C 3-amino-5-hydroxymethyl-s-triazole 40g, acetoacetic acid ethyl ester 43.5g
was dissolved in 130 ml of acetic acid and heated under reflux for 6 hours. After the reaction was completed, the reaction mixture was cooled and precipitated crystals were collected. This was recrystallized from ethanol and 7-hydroxy-2-hydroxymethyl-5-methyl-s-
Triazolo[1.5-a]pyrimidine was obtained.

Yield 76g, yield 50%, melting point 276-278°C 7-hydroxy-2-hydroxymethyl-5-
25 g of methyl-s-triazolo[1.5-a]pyrimidine was dissolved in 100 ml of phosphorus oxychloride and heated under reflux for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 200 ml of chloroform and washed with 70 ml of water and then with 70 ml of saturated sodium bicarbonate solution. After drying the chloroform solution over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to give 7-chloro-
2-chloromethyl-5-methyl-s-triazolo[1.5-a]pyrimidine was obtained.

Yield 25g, yield 83%, melting point 264-266°C 7-chloro-2-chloromethyl-5-methyl-
s-triazolo[1,5-a]pyrimidine 10g,
Dissolve 8 g of diethylamine in 90 ml of ethanol and add 3
The mixture was heated to reflux for an hour. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in 50 ml of chloroform and washed with 10 ml of water.

After drying the chloroform solution over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was diluted with methylene chloride.
Recrystallization from a mixed solvent of n-hexane gave 2-chloromethyl-7-diethylamino-5-methyl-s-triazolo[1.5-a]pyrimidine.

Yield 6g, yield 45%, melting point 101-102℃ NMR (δ: _CDCl3 ) 5.97 1Hs , 4.71 2Hs ,
3.84 4H ( q , 7Hz), 2.48 3H s , 1.33 6H
( t , 7Hz) 2-chloromethyl-7-diethylamino-5-
2.4 g of methyl-s-triazolo[1.5-a]pyrimidine, 1.4 g of N-propylaniline, and 1.5 g of triethylamino were dissolved in 50 ml of ethanol and heated under reflux for 3 hours.

After concentrating the reaction mixture under reduced pressure, the residue was dissolved in chloroform.
It was dissolved in 100 ml and washed with 10 ml of water.

After drying the chloroform solution over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7-dimethylamino-5-methyl-2-(N-phenyl-N-propyl)-s-triazolo[1.5-a]pyrimidine.

Yield 1.8g, yield 50% NMR (δ: _CDCl3 ) 7.41-6.74 5H m , 5.91 1H
s , 4.74 2H s , 3.78 4H ( q , 7Hz), 3.55
2H ( t , 7Hz), 2.52 3H s , 1.77 2H ( sx , 7
Hz), 1.28 6H ( t , 7Hz), 1.02 3H ( t , 7
Hz) Example 2 7-dimethylamino-5-methyl-2-(N-
p-hydroxyphenyl-N-propyl)aminomethyl-s-triazolo[1,5-a]pyrimidine 2-chloromethyl-7-diethylamino-5-
20 g of methyl-s-triazolo[1,5-a]pyrimidine, 1.45 g of p-propylaminophenol,
1.9 g of triethylamine was dissolved in 200 ml of ethanol and heated under reflux for 15 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in 100 ml of chloroform and washed with 50 ml of water.

After drying the chloroform solution over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7-diethylamino-5-methyl-2-(N-p-hydroxyphenyl-N-propyl)aminomethyl-s-triazolo[1,5-a]pyrimidine. .

Yield 1.5g, yield 48%, melting point 153-155℃ NMR (δ: CDCl ₃ ) 6.72 5H br s , 5.85 1H
s , 4.68 2H s , 3.74 4H ( q , 7Hz), 3.45
2H m , 2.46 3H s , 1.60 2H m , 1.24 6H
( t , 7 Hz), 0.84 3H ( t 7 Hz) Example 3 5-Methyl-2-(N-phenyl-N-propyl)aminomethyl-7-(N-phenyl-N-
propyl)amino-s-triazolo[1,5-
a] Pyrimidine 3 g of 2,7-dichloro-5-methyl-s-triazolo[1,5-a]pyrimidine, 4.0 ml of N-propylaniline, and 2.1 ml of triethylamine were dissolved in 100 ml of ethanol and heated under reflux for 3 hours.

After concentrating the reaction mixture under reduced pressure, the residue was dissolved in chloroform.
It was dissolved in 100 ml and washed with 50 ml of water.

After drying the chloroform solution over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5-methyl-2-
(N-phenyl-N-propyl)aminomethyl-
7-(N-phenyl-N-propyl)amino-s
-triazolo[1.5-a]pyrimidine was obtained.

Yield 2.1g, yield 39%, melting point 86-88℃ NMR (δ: _CDCl3 ) 7.46-6.76 10H m , 5.61
1H s , 4.66 2H s , 4.28 2H ( t 7Hz), 3.48
2H ( t , 7Hz), 2.35 3H s , 1.71 4H ( q , 7
Hz), 0.96 3H ( t , 7Hz), 0.80 3H ( t , 7
Hz) Example 4 7-diethylamino-2-N.N-di-n-propylaminomethyl-5-methyl-s-triazolo[1.5-a]pyrimidine 2-chloromethyl-7-diethylamino-5-
1.0 g of methyl-s-triazolo[1.5-a]pyrimidine and 1.2 g of di-n-propylamine were dissolved in 100 ml of ethanol and heated under reflux for 4 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in 100 ml of chloroform and washed with 50 ml of water.

After drying the chloroform solution over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 7-diethylamino-2-N.N-di-n-propylaminomethyl-5-methyl-s-triazolo[1.5-a].
Pyrimidine was obtained.

Yield 0.9g, yield 72% NMR (δ: CDCl ₃ ) 5.91 1H s , 3.95 2H s ,
3.86 4H ( q , 7Hz) 2.57 4H ( t , 7Hz),
2.49 3H s , 1.60 4H ( sx , 7Hz), 1.33 6H
( t , 7Hz), 0.89 6H ( t , 7Hz) Example 5 7-diethylamino-2-(N-isoamyl-
N-phenyl)aminomethyl-5-methyl-s
-triazolo[1,5-a]pyrimidine 2-chloromethyl-7-diethylamino-5-
Dissolve 1.85 g of methyl-s-triazolo[1,5-a]pyrimidine, 1.45 g of N-isoamylaniline, and 1.0 g of triethylamine in 100 ml of ethanol.
The mixture was heated to reflux for an hour.

After concentrating the reaction mixture under reduced pressure, the residue was dissolved in chloroform.
It was dissolved in 100 ml and washed with 50 ml of water.

After drying the chloroform solution over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 7-diethylamino-2-(N-isoamyl-N-phenyl)aminomethyl-5-methyl-s-triazolo[1.5
-a] Pyrimidine was obtained.

Yield 1.3g, yield 38%, melting point 89-91℃ NMR (δ: _CDCl3 ) 6.84 5Hbr s , 5.90 1Hs ,
4.54 2H s , 3.73 4H ( q , 7Hz), 3.45 2H
( t , 7Hz), 2.463Hs , 1.60~ 1.405Hm ,
1.27 6H ( t , 7Hz), 0.84 6H ( d , 7Hz) Example 6 2-(N-p-acetylphenyl-N-propyl)aminomethyl-7-diethylamino-5-
Methyl-s-triazolo[1,5-a]pyrimidine 7-diethylamino-5-methyl-2-(N-
1.5 g of phenyl-N-propyl)-s-triazolo[1.5-a]pyrimidine was dissolved in 50 ml of anhydrous chloroform. Add this to 0.4 acetyl chloride
The mixture was gradually added dropwise while cooling into 30 ml of anhydrous chloroform solution containing 0.65 g of aluminum chloride. After the dropwise addition was completed, the reaction mixture was heated under reflux for 50 minutes, cooled to room temperature, and then hydrolyzed with saturated aqueous sodium bicarbonate solution.
This aqueous solution was extracted with 100 ml of chloroform, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating chloroform under reduced pressure, the residue was purified by silica gel column chromatography to obtain 2-(N-p-acetylphenyl-N-propyl)aminomethyl-7-diethylamino-5-methyl-s-triazolo[1.5
-a] Pyrimidine was obtained.

Yield 0.5g, yield 30% NMR (δ: _CDCl3 ) 8.05 2H ( d , 6Hz), 6.84
2H ( d , 6Hz), 6.04 1H s , 4.63 2H s , 3.68
4H ( q , 7Hz), 3.45 2H ( t , 7Hz), 2.55
6Hbr s , 1.60 2H ( sx , 7Hz), 1.33 6H ( t ,
7Hz), 0.89 3H ( t , 7Hz)

Claims (1)

[Claims] 1 General formula () (In the formula, R ₁ and R ₂ are the same or different straight-chain or branched alkyl groups having 1 to 6 carbon atoms, phenyl groups, or hydrogen atoms, and R ₃ is straight-chain or branched straight-chain or branched alkyl groups having 1 to 6 carbon atoms, or hydrogen atoms. an alkyl group or a hydrogen atom; R ₄ represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a phenyl group, or a substituted phenyl group, provided that R ₁ ,
Except when R ₂ , R ₃ and R ₄ are all ethyl groups. ) is a new s-triazolo [1.5
-a] Pyrimidine derivative.