JPS6232751B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel pyrrolo[3,2-e]-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 to comprehensively improve the circulatory system disorders. As a result of many years of research to find a compound that matches the
The present invention was completed based on the discovery that -triazolo[1,5-a]pyrimidine derivatives have vasodilatory effects, antihypertensive effects, platelet aggregation inhibitory effects, and cholesterol-lowering effects.

The compound of the present invention has the general formula (I): (In the formula, R ₁ is a straight chain or branched alkyl group having 1 to 6 carbon atoms, R ₂ and R ₃ are the same or different straight chain or branched alkyl groups having 1 to 6 carbon atoms, phenyl group, substituted A new pyrrolo[3.2-e]-s-triazolo[1.
5-a] A pyrimidine derivative, which can generally be produced as follows. That is, α-acetyl-γ is added to 3-amino-5-hydroxymethyl-s-triazole as a 1,3-diketone compound.
-Butyrolactone is condensed and ring-closed in the presence of a base catalyst to obtain 7-hydroxy-6-(2-hydroxyethyl)-2-hydroxymethyl-5-methyl-s-triazolo[1.5-a]pyrimidine. This was then halogenated using a suitable halogenating agent to give 7-halo-6-(2-haloethyl)-
2-halomethyl-5-methyl-s-triazolo[1.5-a]pyrimidine is obtained. This was reacted with a suitable alkylamine to produce 8-alkyl-2-halomethyl-5-methyl-6,7-dihydro-8H.
-pyrrolo[3・2-e]-s-triazolo[1・
5-a] Obtain pyrimidine. Further, a suitable alkyl or arylamine is reacted to obtain the pyrrolo[3.2-e]-s-triazolo[1.5-a]pyrimidine derivative of the present invention. An example is as follows.

3-Amino-5-hydroxymethyl-s-triazole () in the presence of a mineral acid such as hydrochloric acid
-Acetyl-γ-butyrolactone is condensed at room temperature, and the ring is further closed with a metal hydroxide such as potassium hydroxide, and 7-hydroxy-6-(2-hydroxyethyl)-2-hydroxymethyl-5-methyl-
s-triazolo[1,5-a]pyrimidine ()
get. This is heated to reflux using a suitable halogenating agent such as phosphorus oxychloride, phosphorus pentachloride, etc. without a solvent or in the presence of a suitable solvent such as benzene, chloroform, carbon tetrachloride, etc., and 7-chloro-6-(2
-chloroethyl)-2-chloromethyl-5-methyl-s-triazolo[1.5-a]pyrimidine () is obtained.

The compound () obtained in this way is dissolved in a solvent such as ethanol or methanol, and if necessary,
Triethylamine, dimethylaniline, pyridine, etc. are added as a deoxidizing agent, and isoamylamine is reacted under heating under reflux. In order to selectively form a pyrrolo ring, the amount of amine, reaction temperature, and reaction time may be adjusted.

2-chloromethyl-8- thus obtained
Isoamyl-5-methyl-6,7-dihydro-
8H-pyrrolo[3,2-e]-s-triazolo[1,5-a]pyrimidine () in methanol,
8-isoamyl-
5-Methyl-2-(N-phenyl-N-propyl)aminomethyl-6,7-dihydro-8H-pyrrolo[3,2-e]-s-triazolo[1,5-
a] Obtain pyrimidine ().

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.

The novel pyrrolo[3,2-e]-s-triazolo[1,5-a]pyrimidine derivatives of the present invention all have strong vasodilatory, antihypertensive, platelet aggregation-inhibiting, and cholesterol-lowering effects. It is a compound that has excellent properties as a pharmaceutical because it is soluble in Therefore, the compounds of the present invention as well as their acid addition salts may be used alone as
or with other pharmaceutically active compounds and, if desired, with binders, fillers, flavorants, etc. used in the pharmaceutical industry, to products which can be used medically by conditioning in any of the usual ways. It can be changed.

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

Example 1 8-isoamyl-5-methyl-2-(N-phenyl-N-propyl)aminomethyl-6.7-
Dihydro-8H-pyrrolo[3.2-e]-s-triazolo[1.5-a]pyrimidine 680 g of aminoguanidine bicarbonate was dissolved in 1.1 ml of 70% glycolic acid and 2 ml of concentrated nitric acid and heated under reflux for 24 hours. After heating, the reaction mixture was cooled and precipitated crystals were collected and recrystallized from ethanol to obtain 3-amino-5-hydroxymethyl-s-triazole.

Yield 305g, yield 53%, melting point 114-115℃ 270g of 3-amino-5-hydroxymethyl-s-triazole and 456g of α-acetyl-γ-butyrolactone were dissolved in 60ml of concentrated hydrochloric acid and 1.5ml of water and reacted at room temperature for 2 days. I let it happen. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and then ethanol 2 was added to remove the precipitated crystals.
triazolo-2-yl)aminoethylidene]-γ
-Butyrolactone was obtained.

Yield: 480 g, yield: 87%, melting point: 211-214℃
ml and allowed to react at room temperature for 2 days. After the reaction was completed, the reaction mixture was adjusted to pH 5-6 with acetic acid, and then 1/3-1/5
It was concentrated to volume under reduced pressure and crystallized under ice-cooling. Take the crystals and 7-hydroxy-2-hydroxymethyl-
6-(2-hydroxyethyl)-5-methyl-s-
Triazolo[1.5-a]pyrimidine was obtained.

Yield 240g, yield 54%, melting point 275-277°C 7-hydroxy-2-hydroxymethyl-6-
220 g of (2-hydroxyethyl)-5-methyl-s-triazolo[1.5-a]pyrimidine was dissolved in 1 liter of phosphorus oxychloride and heated under reflux for 3 hours. After refluxing, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in 3 chloroform. This chloroform solution was washed with 100 ml of water and then with 250 ml of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After evaporating the solvent, the residue was recrystallized from ethyl acetate to give 7-chloro-6-
(2-chloroethyl)-2-chloromethyl-5-methyl-s-triazolo[1.5-a]pyrimidine was obtained.

Yield 190 g, yield 80%, melting point 118-123°C 7-chloro-6-(2-chloroethyl)-2-chloromethyl-5-methyl-s-triazolo[1.
5-a] Pyrimidine 124.0g isoamylamine
39.0g, triethylamine 43.7g to ethanol 1.5g
The mixture was dissolved in water and heated under reflux for 3 hours. After refluxing, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in 1.5 ml of chloroform. This chloroform solution was washed with 200 ml of water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of methylene chloride-n-hexane to give 2-chloromethyl-8-isoamyl-5-
Methyl-6,7-dihydro-8H-pyrrolo[3.
2-e]-s-triazolo[1.5-a]pyrimidine was obtained.

Yield 81 g, yield 80%, melting point 113-115 °C NMR (δ, _CDCl3 ) 4.52 2H s , 3.91 2H ( t , 7Hz), 3.70 2H
( t , 7Hz), 2.81 2H ( t , 9Hz), 2.11 3H
s , 1.70-1.40 3H m , 0.96 6H ( d , 7Hz) 2-chloromethyl-8-isoamyl-5-methyl-6,7-dihydro-8H-pyrrolo[3,2-
e]-s-triazolo[1,5-a]pyrimidine
25 g of N-propylaniline, and 11 g of triethylamine were dissolved in 200 ml of ethanol and heated under reflux for 10 hours. After refluxing, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 500 ml of chloroform. This chloroform solution was washed with 80 ml of water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 8-isoamyl-5-methyl-2-(N-phenyl-N -propyl)aminomethyl-6,7-dihydro-8H-
Pyrrolo[3,2-e]-s-triazolo[1,5]
-a] Pyrimidine was obtained.

Yield 12 g, yield 40%, melting point 117-121 °C NMR (δ, _CDCl3 ) 7.1-6.6 5H m , 4.64 2H s , 4.00 2H ( t , 7
Hz), 3.77 2H ( t , 9Hz), 3.51 2H ( t , 7
Hz), 3.00 2H ( t , 9Hz), 2.31 3H s , 1.8~
1.3 5H m , 0.90 6H ( d , 7Hz) Example 2 8-isopropyl-5-methyl-2-(N-phenyl-N-propyl)aminomethyl-6.7
-dihydro-8H-pyrrolo[3.2-e]-s-
Triazolo[1,5-a]pyrimidine 7-chloro-6-(2-chloroethyl)-5-methyl-s-triazolo[1,5-a]pyrimidine
41 g of isopropylamine, 9 g of isopropylamine, and 15 g of triethylamine were dissolved in 500 ml of ethanol and reacted at 80° C. for 10 hours using a closed container. After the reaction, ethanol was distilled off under reduced pressure, and the residue was dissolved in 300 ml of chloroform. After washing this chloroform solution with 80ml of water,
It was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from 500 ml of n-hexane to give 2-
Chloromethyl-8-isopropyl-5-methyl-
6,7-dihydro-8H-pyrrolo[3,2-e]-
s-triazolo[1.5-a]pyrimidine was obtained.

Yield 31g, yield 80%, melting point 172-173℃ NMR (δ, _CDCl3 ) 5.58 1H ( sp , 7Hz), 4.69 2H s , 3.84 2H
( t , 9Hz), 3.08 2H ( t , 9Hz), 2.35 3H
s , 1.30 6H ( d , 7Hz) 2-chloromethyl-8-isopropyl-5-methyl-6,7-dihydro-8H-pyrrolo[3,2
-e]-s-Triazolo[1,5-a]pyrimidine (20 g), N-propylaniline (7 g), and triethylamine (5 g) were dissolved in 300 ml of ethanol and heated under reflux for 12 hours. After refluxing, the solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of chloroform. This chloroform solution was washed with 30 ml of water and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to give 8-isopropyl-5-methyl-2-(N-phenyl-N-propyl)aminomethyl-6,7-dihydro-8H-
Pyrrolo[3,2-e]-s-triazolo[1,5]
-a] Pyrimidine was obtained.

Yield 8.2 g, yield 38%, melting point 90-92°C NMR (δ, _CDCl3 ) 7.31-6.81 5H m , 5.49 1H ( sp , 7Hz), 4.64
2H s , 3.78 2H ( t , 9Hz), 3.50 2H ( t , 7
Hz), 3.00 2H ( t , 9Hz), 2.32 3H s , 1.22
6H ( d , 7Hz), 0.95 3H ( t , 7Hz) Example 3 8-n-butyl-5-methyl-2-(N-phenyl-N-propyl)aminomethyl-6,7-
Dihydro-8H-pyrrolo[3,2-e]-s-triazolo[1,5-a]pyrimidine 7-chloro-6-(2-chloroethyl)-2-chloromethyl-5-methyl-6,7-dihydro −
21 g of 8H-pyrrolo[3,2-e]-s-triazolo[1,5-a]pyrimidine, 5.46 g of n-butylamine, and 8.2 g of triethylamine were dissolved in ethanol.
The solution was dissolved in 400 ml and heated under reflux for 3 hours. After refluxing, the solvent was distilled off under reduced pressure, and the residue was dissolved in 300 ml of chloroform. This chloroform solution was washed with 70 ml of water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from 500 ml of n-hexane to give 2-
Chloromethyl-8-n-butyl-5-methyl-
6,7-dihydro-8H-pyrrolo[3,2-e]-
s-triazolo[1.5-a]pyrimidine was obtained.

Yield 18 g, yield 85%, melting point 104-105 °C NMR (δ, _CDCl3 ) 4.71 2H s , 4.06 2H ( t , 7Hz), 3.89 2H
( t , 9Hz), 3.09 2H ( t , 9Hz), 2.33 3H
s , 1.75-1.25 4H m , 0.97 3H ( t , 7Hz) 2-chloromethyl-8-n-butyl-5-methyl-6,7-dihydro-8H-pyrrolo[3,2-
8 g of e]-s-triazolo[1.5-a]pyrimidine, 4 g of N-propylaniline, and 3.2 g of triethylamine were dissolved in 300 ml of ethanol and heated under reflux for 10 hours. After refluxing, the solvent was distilled off under reduced pressure, and the residue was dissolved in 200 ml of chloroform. This chloroform solution was washed with 60 ml of water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 8-n-butyl-5
-Methyl-2-(N-phenyl-N-propyl)
Aminomethyl-6,7-dihydro-8H-pyrrolo[3,2-e]-s-triazolo[1,5-a]pyrimidine was obtained.

Yield 4.8 g, yield 40%, melting point 88-92 °C NMR (δ, _CDCl3 ) 7.10-6.63 5H m , 4.63 2H s , 3.85 2H ( t ,
7Hz), 3.52 2H ( t , 9Hz), 3.10 2H ( t ,
9Hz), 2.35 3H s , 1.70-1.22 6H m , 0.95
3H ( t , 7Hz) Example 4 8-isopropyl-5-methyl-2-[1-piperidino]methyl-6,7-dihydro-8H-
Pyrrolo[3・2-e]-s-triazolo[1・
5-a] Pyrimidine 2-chloromethyl-8-isopropyl-5-methyl-6,7-dihydro-8H-pyrrolo[3,2
-e]-s-Triazolo[1,5-a]pyrimidine (11 g) and piperidine (8.5 g) were dissolved in 300 ml of ethanol and heated under reflux for 3 hours. After refluxing, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 200 ml of chloroform. This chloroform solution was washed with 50 ml of water and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 8-
Isopropyl-5-methyl-2-(1-piperidino)methyl-6,7-dihydro-8H-pyrrolo[3,2-e]-s-triazolo[1,5-a]pyrimidine was obtained.

Yield 6.5 g, yield 50% NMR (δ, _CDCl3 ) 5.63 1H ( sp , 7 Hz), 3.81 2H ( t , 9 Hz),
3.07 2H ( t , 9Hz), 3.50 4H m , 2.35 3H
s , 1.60-1.20 6H m , 1.28 6H ( d , 7Hz) Example 5 8-isoamyl-5-methyl-2-(1-piperidino)methyl-6,7-dihydro-8H-pyrrolo[3,2-e ]-s-triazolo[1・5
-a]Pyrimidine 2-chloromethyl-8-isoamyl-5-methyl-6,7-dihydro-8H-pyrrolo[3,2-
e]-s-triazolo[1,5-a]pyrimidine
15 g of piperidine and 12 g of piperidine were dissolved in 200 ml of ethanol and heated under reflux for 5 hours. After refluxing, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 200 ml of chloroform. This chloroform solution was washed with 30 ml of water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was
-8-isoamyl recrystallized from 150ml of hexane-
5-Methyl-2-(1-piperidino)methyl-
6,7-dihydro-8H-pyrrolo[3,2-e]-
s-triazolo[1.5-a]pyrimidine was obtained.

Yield 10.5 g, yield 40%, melting point 93-95 °C NMR (δ, _CDCl3 ) 3.97 2H ( t , 7 Hz), 3.79 2H ( t , 9 Hz),
3.76 2H s , 3.00 2H ( t , 9Hz), 2.60~2.45
4H m , 2.36 3H s , 1.70~1.50 9H m , 0.97 6H
( d , 7Hz) Example 6 8-n-butyl-2-[1-(N-2-hydroxyethyl)piperazino]methyl-5-methyl-
6,7-dihydro-8H-pyrrolo[3,2-
e]-s-triazolo[1,5-a]pyrimidine 8-n-butyl-2-chloromethyl-5-methyl-6,7-dihydro-8H-pyrrolo[3,2-
e]-s-triazolo[1,5-a]pyrimidine
10 g of N-(2-hydroxyethyl)piperazine and 6 g of N-(2-hydroxyethyl)piperazine were dissolved in 100 ml of ethanol and heated under reflux for 5 hours. After refluxing, the solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of chloroform. This chloroform solution was washed with 20 ml of water and then dried over anhydrous sodium sulfate.
The residue obtained by distilling off the solvent under reduced pressure was diluted with 100 ml of n-hexane.
Recrystallized from 8-n-butyl-2-[1-(N-2
-hydroxyethyl)piperazino]methyl-5-
Methyl-6,7-dihydro-8H-pyrrolo[3.
2-e]-s-triazolo[1.5-a]pyrimidine was obtained.

Yield 8.4 g, yield 56%, melting point 164-165 °C NMR (δ, _CDCl3 ) 4.08 2H ( t , 7 Hz), 3.85 2H ( t , 9 Hz),
3.81 2H s , 3.59 2H ( t , 7Hz), 3.10 2H
( t , 9Hz), 2.80-2.20 11H m , 2.36 3H s ,
1.80-1.20 4H m , 0.96 3H ( t , 7Hz) Example 7 8-isoamyl-5-methyl-2-(N-methyl-N-phenyl)aminomethyl-6,7-dihydro-8H-pyrrolo[3. 2-e]-s-triazolo[1,5-a]pyrimidine 2-chloromethyl-8-isoamyl-5-methyl-6,7-dihydro-8H-pyrrolo[3,2-
e]-s-triazolo[1,5-a]pyrimidine
20 g of N-methylaniline, 7 g of triethylamine, and 7 g of triethylamine were dissolved in 200 ml of ethanol and heated under reflux for 10 hours. After refluxing, the solvent was distilled off under reduced pressure, and the residue was dissolved in 200 ml of chloroform. This chloroform solution was washed with 50 ml of water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 8-isoamyl-5.
-Methyl-2-(N-methyl-N-phenyl)aminomethyl-6,7-dihydro-8H-pyrrolo[3,2-e]-s-triazolo[1,5-a]pyrimidine was obtained.

Yield 8.4 g, yield 36%, melting point 91-101 °C NMR (δ, _CDCl3 ) 7.26-6.72 5H m , 4.67 2H s , 4.09 2H ( t ,
7Hz), 3.80 2H ( t , 9Hz), 3.19 3H s , 2.95
2H ( t , 9Hz) 2.36 3H s , 1.70~1.40 3H
m , 0.98 6H ( d , 7Hz) Example 8 8-isoamyl-2-(N-isoamyl-N-
phenyl)aminomethyl-5-methyl-6,7
-dihydro-8H-pyrrolo[3.2-e]-s-
Triazolo[1,5-a]pyrimidine 2-chloromethyl-8-isoamyl-5-methyl-6,7-dihydro-8H-pyrrolo[3,2-
e]-s-triazolo[1,5-a]pyrimidine
20 g of N-isoamylaniline, 11 g of N-isoamylaniline, and 9 g of triethylamine were dissolved in 300 ml of ethanol and heated under reflux for 10 hours. After refluxing, the solvent was distilled off under reduced pressure, and the residue was dissolved in 200 ml of chloroform. This chloroform solution was washed with 50 ml of water and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 8-isoamyl-2-
(N-isoamyl-N-phenyl)aminomethyl-6,7-dihydro-8H-pyrrolo[3,2-
e]-s-triazolo[1.5-a]pyrimidine was obtained.

Yield 7.3 g, yield 30%, melting point 109-110 °C NMR (δ, _CDCl3 ) 7.26-6.50 5H m , 4.63 2H s , 3.99 2H ( t ,
7Hz), 3.79 2H ( t , 9Hz), 3.52 2H ( t ,
7Hz), 3.06 2H ( t , 9Hz), 2.33 3H s , 1.75
~1.30 6H m , 0.96 6H ( d , 7Hz), 0.90 6H
( d , 7Hz)

Claims (1)

[Claims] 1 General formula (I) (In the formula, R ₁ is a straight chain or branched alkyl group having 1 to 6 carbon atoms, R ₂ and R ₃ are the same or different straight chain or branched alkyl groups having 1 to 6 carbon atoms, phenyl group, substituted A new pyrrolo[3.2-e]-s-triazolo[1.
5-a] Pyrimidine derivative.