JPH037279A - 2-thiopyrancarbothioamide derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is H or 1-6C alkyl; R<2> is H, 1-6C alkyl, halogen, 1-6C alkoxy, carboxyl, 2-7C alkoxycarbonyl, carbamoyl, (phenyl substituted) 1-6C alkylaminoearbonyl, 2-6C dialkylaminocarbonyl, guanidinocarbonyl, cyano, nitro, sulfo, sulfamoyl or trifluoromethyl]. EXAMPLE:N-methyl-2-(3-chlorophenyl)-tetrahydrothiopyran-2-carbothioami de-1- oxide. USE:Giving vasodilator or vasodepressor activity, thus useful as a medicine for hypertension therapy. PREPARATION:Using both a compound of formula II and thiourea as starting materials, a compound of formula III is formed from the product, and through several processes including reaction of the compound of the formula III with 1-bromo-4-chlorobutane, the objective compound of the formula I can be obtained.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application J The present invention relates to a novel 2-thiopyrancarbothioamide derivative having antihypertensive activity.

[Prior art and problems to be solved by the invention] Conventionally,
Various compounds have been proposed as having antihypertensive effects. For example, thioformamide derivatives containing heterocyclic groups such as pyridine and quinoline may cause spontaneous hypertension.
It is known that the arterial pressure of (SHR) can be reduced (Japanese Patent Application Laid-open Nos. 57-42687 and 58-38281).
No. 59-7188 and No. 59-232281).

However, the number of compounds that can be put to practical use as antihypertensive agents is not necessarily sufficient, and there is a desire to develop antihypertensive agents with even more effective activity.

[Means for Solving the Problems] Therefore, the present inventors conducted extensive studies in order to provide a new compound having good antihypertensive effects. The inventors have discovered that the desired object can be achieved by -thiovirane carbothioamide derivatives, and have completed the present invention.

That is, the gist of the present invention is the following general formula (I) (wherein R1 represents a hydrogen atom or a 01-C6 alkyl group, R2 represents a hydrogen atom, a 01-C6 alkyl group, a halogen atom, a 01-C6 alkoxy group, carboxyl group, 02-C7 alkoxycarbonyl group, carbamoyl group, 01-C6 alkylaminocarbonyl group optionally substituted with phenyl group, 02-C6 dialkylaminocarbonyl group, guanidinocarbonyl group, cyano group, nitro group, sulfo group, sulfamoyl group or trifluoromethyl group).

To explain the present invention below, the 2-thioviranecarbothioamide derivative of the present invention is represented by the general formula (I).

In the formula, R1 is a hydrogen atom, a methyl group, an ethyl group, n
-propyl group, 1so-propyl group, n-butyl group, n
- Represents a straight chain or branched alkyl group having 1 to 6 carbon atoms such as hexyl group, preferably a lower alkyl group having 1 to 3 carbon atoms. R2 is a hydrogen atom; a straight or branched alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, a 1so-propyl group, an n-butyl group, or an n-hexyl group; a chlorine atom , halogen atoms such as fluorine and bromine atoms; alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, and butoxy; carboxyl groups; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl Alkoxycarbonyl group having 2 to 7 carbon atoms in total; carbamoyl group: 01-C6 alkylaminocarbonyl group optionally substituted with a phenyl group such as methylaminocarbonyl group, ethylaminocarbonyl group, benzylaminocarbonyl group, etc. ; 02-C6 dialkylaminocarbonyl group such as dimethylaminocarbonyl group and diethylaminocarbonyl group; guanidinocarbonyl group;
Cyano group: represents a nitro group; a sulfo group; a sulfamoyl group: or a trifluoromethyl group, preferably a halogen atom, a cyano group, or a trifluoromethyl group.

Specific examples of such compounds of the present invention include compounds shown in Table 1 below.

Table 1 Next, a method for producing the compound of the present invention will be explained.

The compound of the present invention can be produced, for example, by the following route.

(IV) (V) (■) (1) (In the above formula, R1 and R2 are as defined above, and X is a halogen atom, -〇SO□CH3, -oso -
@) - Represents CH3, etc. ) That is, thiourea and the above formula (
II) The compound shown in methanol, ethanol,
in a polar solvent such as N,N-dimethylformamide at 0°C.
By reacting at ~100°C for several minutes to several hours,
An isothiourea represented by the above formula (111) is obtained.

By reacting this isothiourea (III) in an aqueous solution such as sodium hydroxide or potassium hydroxide at room temperature to 100°C for several minutes to several hours, the thiol represented by the above formula (IV) can be obtained.

Thiol (IV) may be isolated and purified, or may be subjected to the next reaction without being isolated.

Thiol (IV) and 1-bromo-4 obtained in the above reaction
- Chlorobutane in water, methanol, ethanol, N.

By reacting in N-dimethylformamide or a mixed solvent thereof in the presence of a base such as sodium hydroxide or potassium hydroxide at 0°C to 100°C for several minutes to more than ten hours, the above formula (V) can be obtained. The indicated sulfide is obtained.

The sulfide (V) obtained in the above reaction is treated with an oxidizing agent such as hydrogen peroxide, peracetic acid, perbenzoic acid, meta-chloroperbenzoic acid, sodium metaperiodate, bromine, or N-bromosuccinimide in water or methanol. , in a polar solvent such as ethanol, acetic acid, or a mixed solvent thereof, or in a halogenated solvent such as methylene chloride, chloroform, carbon tetrachloride, etc., at 0°C.
The sulfoxide represented by the above formula (VI) can be obtained by reacting at room temperature for several minutes to over ten hours, but in this reaction, the sulfide (V) is particularly
It is preferable to react chloroperbenzoic acid in methylene chloride under water cooling for several tens of minutes.

The sulfoxide (VI) obtained in the above reaction is mixed with a suitable base such as potassium tert-butoxide, sodium hydride, etc. in a polar solvent such as tetrahydrofuran.
A thiopyran represented by the above formula (■) can be obtained by reacting at a temperature of C to 60°C for several minutes to several hours.

Thiopyran (■) obtained in the above reaction and carbon disulfide are reacted in a polar solvent such as tetrahydrofuran or N,N-dimethylformamide at 06C to 50°C for several minutes to several hours, and the resulting reaction solution is obtained. Add methyl iodide to 0
The diothiester represented by the above formula (■) can be obtained by reacting at a temperature of .degree. C. to 50.degree. C. for several minutes to several hours.

The diothiester (■) obtained in the above reaction and ammonia, or the following general formula and ammonia, or the following general formula (IX)
) H2N-R1, , , , , , , (IX) (wherein,
R1 is as defined above. ) in water, a polar solvent such as methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, and ether, or a mixed solvent thereof, an aromatic hydrocarbon such as benzene, toluene, xylene, or no solvent. 14
By reacting at 0°C for several minutes to over ten hours, the compound of the present invention represented by the above formula (I) can be obtained.

The thus obtained compound (I) of the present invention has four types of spatial isomers because an oxygen atom is bonded to the sulfur atom of the thiopyran ring. However, in the present invention, these isomers are not necessary. It may be separated or divided depending on the situation.

The 2-thioviranecarbothioamide derivatives of the present invention have vasodilatory and blood pressure lowering effects and are therefore useful for the treatment of hypertension.

When using the compound according to the present invention as an antihypertensive agent,
It is administered orally or parenterally to humans using conventional methods. Dosage forms for oral administration include granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions,
Examples include suspensions and solutions. In addition, dosage forms for parenteral administration include injections, suppositories, transdermal preparations, and the like.

The compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, in the above dosage form, a solid or liquid pharmaceutical carrier or excipient, a stabilizer, a lubricant, a sweetener, a preservative, It is included along with commonly used pharmaceutical additives such as suspending agents.

Examples of solid carriers that can be used include lactose, china clay, sucrose, crystalline cellulose, cornstarch, talc, agar,
Examples include pectin, acacia, stearic acid, magnesium stearate, lecithin, and sodium chloride.

Examples of liquid carriers include syrup, glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol,
Examples include benzyl alcohol, propylene glycol, water and the like.

When the compound of the present invention is used orally, the dosage for adults is 0.01 mg to 1000 mg (preferably 0.1 mg to 100 mg) per day, but depending on the age,
It is more preferable to increase or decrease the amount as appropriate depending on gender, pathological condition, symptoms, presence or absence of simultaneous treatment, etc. Further, the administration frequency may be once a day or divided into several times a day at appropriate intervals.

When producing solid preparations, excipients include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, and the like. In the case of liquid preparations for oral administration, such as syrups, lactose, suspensions or solutions, the above-mentioned commonly used liquid carriers are combined with suitable adjuvants such as wetting agents, suspending agents, sweetening agents, etc.
Used with fragrances, colorants, or preservatives.

[Example] Hereinafter, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to the following examples unless it exceeds the gist thereof.

Example I Synthesis of N-methyl-2-(3-chlorophenyl)-tetrahydrothiopyran-2-carbothioamide-1-oxide (Compound No. 35 in Table 1) e (1) S-(3-chlorobenzyl )-Synthesis of thiuronium hydrochloride e 3-chlorobenzyl chloride 100g (0,621m
After dissolving ol) in 300 ml of ethanol, 55 ml of thiourea
g (0,723 mol) and reflux with stirring. When a solid precipitated from the reaction solution, 100 ml of ethanol was added, and the reflux was continued. After 5 hours, the reaction solution was cooled and the precipitated crystals were counted to obtain 135 g (yield: 91.5%) of the above-mentioned target product. Obtained.

(2) Synthesis of 3-''lolobenzyl-4-chlorobutyl sulfide e 30 g (0,126 mol) of the 5-(3-chlorobenzyl)-thiuronium salt obtained in (1) above was mixed with 50 g of water.
ml, 28 ml of 10N sodium hydroxide was added, and the mixture was heated at 80°C for 165 hours.

Add 15 liters of sodium hydroxide to the above reaction solution under water cooling.
m1, then 1-bromo-4-chlorobutane 12
8 mmol was added and stirred at room temperature overnight.

The reaction solution was extracted with 500 ml of dichloromethane, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed from the reaction solution, and the resulting solution was concentrated and purified by silica gel column chromatography.Elution solvent: dichloromethane), the above target product 36
g (100% yield) was obtained.

(3) Synthesis of 3-chlorobenzyl-4-chlorobutyl sulfoxide e After dissolving 36 g (0,126 mol) of 3-chlorobenzyl-4-chlorobutyl sulfide obtained in (2) above in 200 ml of dichloromethane, the reaction system 24 g of meta-chloroperbenzoic acid while stirring and keeping the temperature below 15°C.
(0,126 mol) was added. After addition of meta-chloroperbenzoic acid, the mixture was reacted for another 10 minutes, and then 250 ml of 10% aqueous sodium bicarbonate solution was added, followed by washing with saturated brine and drying over anhydrous sodium sulfate. After concentrating the solution obtained by separating the anhydrous sodium sulfate, it was purified by silica gel column chromatography. Elution solvent: hexane:ethyl acetate = 1:1, then ethyl acetate), 21.3 g of the above target product (yield: 63. 7%).

(4) In the synthesis of methyl-2-(3-chlorophenyl)-tetrahydrothiopyran-2-carbodithioate-1-oxide, the above-mentioned target 8.
7 g (yield 33.0%) was obtained.

(5) Synthesis of N-methyl-2-(3-chlorophenyl)-tetrahydrothiopyran-2-carbothioamide-1-oxide e 3-chlorobenzyl-4-chlorobutyl sulfoxide obtained in (3) above 21. 2 g (0.08 mol)
After dissolving in 60ml of tetrahydrofuran, the reaction system was
A solution of 18.5 g (0,165 mol) of potassium t-butoxy in 60 ml of tetrahydrofuran was added dropwise to the reaction solution while keeping the temperature below °C. After the dropwise addition, the reaction was carried out for 10 minutes, and 14 ml of carbon disulfide (0,24
A solution of mol) in 15 ml of tetrahydrofuran was added dropwise to the reaction system while keeping the temperature below 10°C. After finishing dropping,
After reacting for 10 minutes, add 14 ml of methyl iodide (0,2
3 mol) was added dropwise in the same manner, and the reaction was further continued for 10 minutes.

After the reaction is complete, the solvent is distilled off, and the resulting residue is mixed with 200% water.
The precipitated crystals were added to 15ml of ethyl acetate and 0.65g (2mmol) of the methyl-2-(3-chlorophenyl)-tetrahydrothiopyran-2-carbodithioate-1-oxide obtained in (4) above. 40
% methylamine-methanol solution was added thereto, and the mixture was stirred at room temperature for 30 minutes. The residue obtained by distilling off the solvent from this homogeneous solution was suspended and washed with 1 ml of acetonitrile, and the crystals were crushed to obtain 400 mg of the above-mentioned target product (yield: 64
．． 1%).

Melting point (m, p, ): 230-231°C Example 2 The compounds in Table 2 below (compound No.
, corresponds to Table 1) were synthesized.

Table 2 Test Example 10 mg/kg of the compound of the present invention was orally administered to spontaneously hypertensive rats (OKAMOTO-AOKI strain) with an average blood pressure of 150 mmHg or higher.
K., Kato H. and Takayanagi
K., Japanese Journal of
Pharmacology.

Blood pressure and heart rate were measured 2 hours after administration by the direct method described in Voi, 25.25 (1975). The results are shown in Table 3 below.

Table 3 [Effect of the invention] 2-thiopyrancarbothioamide derivatives of the present invention is a new compound, It has an excellent antihypertensive effect.

Claims (2)

[Claims] (1) The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (I) (In the formula, R^1 represents a hydrogen atom or an alkyl group of C_1 to C_6, and R^2 represents hydrogen atom, an alkyl group of C_1 to C_6, a halogen atom, an alkoxy group of C_1 to C_6, a carboxyl group, an alkoxycarbonyl group of C_2 to C_7, a carbamoyl group, an alkylaminocarbonyl group of C_1 to C_6 which may be substituted with a phenyl group , C_2 to C_6 dialkylaminocarbonyl group, guanidinocarbonyl group, cyano group, nitro group, sulfo group, sulfamoyl group or trifluoromethyl group). (2) In general formula (I), R^1 has 1 to 3 carbon atoms
2 according to claim 1, wherein R^2 is a halogen atom, a cyano group or a trifluoromethyl group.
-Thiopyrancarbothioamide derivative