JPS59164783A - Triazole disulfide derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R is H, phenyl; R' is H, methyl, pyridyl, or phenyl which may be substituted with halogen, methyl or methoxy; n is 0 or 1; where the cases where R and R' are Hs at a time and n is zero are excluded). EXAMPLE:Bis(s-phenyl-1,2,4-triazol-3yl) disulfide. USE:A remedy for hypertension: it has dopa decarboxylase-inhibiting and hypotensive actions as well as shows effects in treatment for Parkinson's disease in combination with L-dopa. It is orally administered in a dose of 10-100mg/adult/ day. PREPARATION:The reaction of a compound of formula II with an oxidizing agent such as hydrogen peroxide or iodine gives a compound of formula I where n is 0. Or the reaction between a compound of formula II, 3,5-dimercapto-1,2,4- triazole and an oxidizing agent gives another compound of formula I where n is 1.

Description

Detailed Description of the Invention The present invention is based on the general formula (wherein R is a hydrogen atom or a phenyl group, and R' is substituted with a hydrogen atom, a methyl group, a pyridyl group, or a halodane atom, a methyl group, or a methoxy group). The present invention relates to a method for producing a compound represented by the formula (optionally containing a phenyl group, D represents O or 1), and a therapeutic agent for hypertension containing the compound as an active ingredient.

Among the compounds according to the present invention, bis-1,2,4-triazole disulfide has ahθm, Bθr, 19579
No. 0 [202-3] and US Pat. No. 2,763,661, but nothing is known about its biological activity.

The present inventors have discovered that triazole disulfides represented by the general formula (1) have excellent decarboxylase inhibitory activity.

By inhibiting dono-f decarboxylase, the compound of the present invention can be applied to people with hypertension 7 to lower blood pressure, and when used in combination with dopa in the treatment of Parkinson's disease, it can enhance the effect of dopa. be able to.

Among the compounds of the present invention, in the general formula (1), n==
The compound Q can be produced by reacting a compound represented by the general formula (wherein R and R' have the same meanings as above) with an oxidizing agent such as hydrogen peroxide or iodine. , bifurcated, n-
1 is produced by reacting the compound represented by the formula (It) with 3,5-dimercapto-1,2,4-triazole and hydrogen peroxide or iodine. The reaction is usually carried out in an inert solvent at 0 to 50°C, preferably at 1
It is carried out at room temperature of 0-30°C for 0.5-5 hours.

Methanol, ethanol, acetone, water, etc. are used as the inert solvent.

Similarly, the structure of the compound of the present invention is based on Elemental Analyzer R, NMR1MA.
It was determined from the results of spectrum analysis such as SE+.

Next, the method for producing the compound of the present invention will be explained in more detail with reference to Examples.

4 Example 1 Compound No. 2 4.7f of 2-phenyl-3-mercapto-1,2,4-triazole was dissolved in 100 g of ethanol, and 27 g of IN-iodine and potassium iodide solution were added thereto under stirring. . After stirring for a minute at room temperature, 500 g of water was added, and the mixture was extracted twice with 100 g of ethyl acetate.

The organic layer was washed successively with a saturated aqueous sodium carbonate solution and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

The residue was recrystallized from ethanol to give bis(2-phenyl-
1,2,4-triazol-3-yl) disulfide 1
．． I got 02.

Yield: 2 ethyl Melting point: 131.5-132.5°C Example 2
Compound number 4 5-(4-methylphenyl)-3-mercapto-1,2
, 1.91 r of 4-triazole was dissolved in a mixed solvent of 30 ethanol and 30 a7thone, and a solution prepared by dissolving 30 t of hydrogen peroxide (2.83 F) in 10 d K of water was added to the mixture under water cooling while stirring. . After the addition was completed, the precipitated crystals were stirred at room temperature for several minutes, filtered, washed with water, and recrystallized from pyridine to give bis(:5-(4-methylphenyl)-1,2
,4-)lyazol-3-yl]disulfide 1.2f
I got it. Yield 62% Melting point 223-224℃ Example 3
Compound No. 7 5-(2-pyridyl)-3-mercapto-1,2゜4-
Dissolve triazole 0.89F in methanol 40-
A solution prepared by dissolving 2 liters of soda in 5 d of water was added thereto, and 0.64 ml of iodine was added at room temperature. The mixture was stirred at room temperature for several hours until the precipitation of crystals was completed, and the resulting crystals were washed with water and methanol to give bis[5-(2-pyridyl)-1,2,4-)lyazol-3-yl. ] Disulfide 0.64 f was obtained.

Yield 72% Melting point 262-264°C Example 4 Compound No. 10 Dithiourazole 2.8? , 3-mercapto-1°2.
Add 70 mg of water to 8.5 f of 4-triazole, and add 11-mg of water to 4.7 f of hydrogen peroxide solution while stirring under water cooling.
The added aqueous solution was added dropwise over a period of 5 hours. The generated crystals were collected, washed with an aqueous solution of IN-hydrocarbon soda and water, and then fractionated and recrystallized from ethanol repeatedly to obtain 3,5-G (
1,2,4-)riazol-3-yldithio) -1,
2,4-) Riazole 1v was obtained.

Melting point: 194-196℃ Representative examples of the compounds of the present invention are shown in Table 1.

-10 The compound of the present invention has dopa decarboxylase 1F activity and a blood pressure lowering effect, and also has a combined effect with L-dopa in the treatment of Parkinson's disease, and is extremely useful medically.

The compound of the present invention can be administered orally or parenterally, and can be formulated into various dosage forms depending on the method of administration.

In the case of oral administration, the dosage is 10 to 100 per day for adults.

Test examples showing the effectiveness of the compounds of the present invention are shown below.

Test example 1 Dono! Decarboxylase inhibition! Effect test: Weight approx. 30
02 male Sprague Dawley
After decapitation of the ey) type rats, the kidneys were removed, washed with a 0.25M sucrose solution, and triturated with the addition of 3 times the amount of cold distilled water. This ground mixture was centrifuged at 78,000 x t at 4°C for 6 minutes, and the supernatant was used as a crude fermented purple solution of dopa decarboxylase.

The method of Hamao Umezawa et al. [J, Antibio et al.
tics, 28. '947-952 (1975)
The enzyme inhibitory activity of the test compound was determined according to the following.

Test Example 2 Antihypertensive effect α-methyldopa, a commercially available antihypertensive agent, was used as a control compound. Spontaneous hypertensive males (8HR) aged 9 to 12 weeks and weighing 200 to 300 tons were used to test the test compound at 60 μ/K.
7 kg of f~10 was administered intraperitoneally (ip) twice, and blood pressure was measured non-invasively by a production measurement method 3.6 hours after the administration. Three SHR animals were used for each administration, and the average value was taken as the blood pressure value for the dose, and the blood pressure reduction rate (Q) was determined from the blood pressure value before administration of the test compound.

The results are shown in Table 3.

In addition, the antihypertensive effect of compounds numbered below, which are the basic structures of the compounds of the present invention, was investigated by oral administration (pO) of 100 to 50 ilv/kg using SHR and DOA hypertensive rats (DHR), which are one of the experimental hypertensive rats. The results are shown in Table 4.

Table 4 Test Example 3 Blood pressure lowering effect due to combination with L-dopa: D according to the usual method
HR was created and the blood pressure was stabilized at approximately 200 mH5'.
Using HR, after intramembrane administration of Compound No. 12 in an insufficient amount (4 in 10 kg) to exhibit a blood pressure lowering effect, an amount that does not itself have any effect on blood pressure after addition ( 20
L-dopa (my/Kp) was administered intraperitoneally, and blood pressure was measured non-invasively 1, 2, and 3.4 hours after administration.

The results are shown in Table 5.

Table 5 Test Example 4, Sex test results of typical examples of the compounds of the present invention by oral administration to ddY mice and intraperitoneal administration to Sprague-Dawley rats are shown in Table 6. Shown below is 1.

15- Table 6 =16- Continuation of page 1 0 shots: Eiji Takeuchi 25-30 Momohamacho, Hiratsuka City 0 shots Mikado Takebayashi 823 Kamomiya, Odawara City 0 shots Akira Kusase Yu 2-6 Koma, Oiso-machi, Naka-gun, Kanagawa Prefecture 23

Claims (3)

[Claims] (1) General formula (wherein R is a hydrogen atom or a phenyl group, R' is a hydrogen atom, a methyl group, a pyridyl group, or a phenyl it, nu which may be substituted with a halodane atom, a methyl group, or a methoxy group) or 1, except when R and R' are both hydrogen atoms and n=Q). (2) General formula (wherein R represents a hydrogen atom or a phenyl group, and R' represents a phenyl group optionally substituted with a hydrogen atom, methyl group, pyridyl group, or herodane atom, methyl group, or methoxy group) However, this excludes the case where R and R' are both hydrogen atoms. A method for producing a compound represented by (3) General formula (wherein R represents a hydrogen atom or a phenyl group, R' represents a phenyl group optionally substituted with a hydrogen atom, a methyl group, a pyridyl group, a norodane atom, a methyl group, or a methoxy group) .) and 3,5-dimerkanoto cape: 1.2.4-) riazole ゛≠
A method for producing a compound represented by the general formula (wherein R and R' have the same meanings as above), which comprises reacting with an oxidizing agent.