JPS6153343B2 - - Google Patents

Description

Detailed Description of the Invention The present invention relates to a sulfur-containing compound represented by the following general formula [] and its salts. [In the formula, R ¹ represents a hydroxy group or a lower alkanoyloxy group. R ² represents a lower alkyl group or a lower alkyl-substituted phenyl group. Z is 1-3
represents a straight-chain or branched alkylene having 5 carbon atoms. same as below. ] The compound of the present invention [ ] is an S-acyl derivative of mercaptoacyl amino acid, which is an angiotensin-converting enzyme inhibitor effective for hypertension symptoms, and undergoes enzymatic and/or chemical hydrolysis when administered to humans or animals. It releases mercaptoacyl amino acids, which have proven medicinal efficacy, at the site where they should exert their activity. Since mercaptoacylamino acids contain sulfhydryl groups in their molecules, they are susceptible to reactions such as oxidation during preparation or over time, and therefore have problems such as decreased activity and short duration. On the other hand, by protecting the sulfhydryl group with an acyl group, especially a benzoyl group, it is possible to prolong the action and at the same time increase the lipophilicity and thus improve its absorption properties. However, since the conventionally known S-benzoyl derivatives are rapidly deacylated by hydrolysis reaction or metabolism in the living body after being absorbed, it is not possible to extend the duration to a desirable extent. Therefore, in the present invention, in order to achieve the purpose of sustaining the effect for as long as possible, various substituents were introduced into the benzoyl group as an acyl group to protect the sulfhydryl group of the mercaptoacylamino acid. As a result, S-
It has been found that it can last even longer than benzoyl derivatives and is extremely suitable for protecting sulfhydryl groups. In addition, since the unstable sulfhydryl group of the compound of the present invention is protected with an acyl or alkyl group, it has the feature that the potency is less likely to decrease due to oxidation, etc.
The formulation is more stable than conventional antihypertensive agents containing mercaptoacyl amino acids, and does not degrade during the formulation process or over time, resulting in a decrease in potency or generation of off-flavors.

The compound of the present invention [] can be synthesized, for example, by the following methods A and B.

(A) General formula R ² -S-Z-CO-Y [] [In the formula, Y represents a hydroxyl group or a halogen atom. same as below. ] Compounds and general formula The compound of the present invention represented by the general formula [ ] can be obtained from the compound represented by the formula [ ] by a general method such as the Schotten-Baumann reaction or the mixed acid anhydride method.

(B) Compound represented by the general formula R ² -Y [] and the general formula The compound of the present invention represented by the general formula [ ] can be obtained from the compound represented by the formula [ ] by a general method such as the Schotten-Baumann reaction or the mixed acid anhydride method.

The compound of the present invention represented by the general formula [ ] synthesized by the methods A and B above may be combined with commonly used pharmaceutical salts such as sodium, potassium, calcium, aluminum, ammonium, diethylamine, and triethanolamine, if necessary. can do. Since the compound of the present invention [ ] has one or more asymmetric carbon atoms, stereoisomers exist. All of these are included within the scope of the compounds of the present invention. Examples are shown below.

Example 1 5-(2-hydroxyphenyl)-1-(S-pivaloyl-3-mercaptopropanoyl)-2
-Production of pyrrolidinecarboxylic acid 2.4g of 5-(2-hydroxyphenyl)-2-pyrrolidinecarboxylic acid hydrochloride and sodium carbonate
Dissolve 2.1g in 50ml of water and add S while stirring under ice cooling.
- 1.8 g of pivaloyl-3-mercaptopropanoyl chloride is added dropwise. After completion of the dropwise addition, the mixture was stirred for 1 hour under ice-cooling and further stirred at room temperature for 1 hour. This reaction solution was washed with ethyl acetate, acidified with concentrated hydrochloric acid, and the precipitated crystals were collected to obtain 3.6 g of the title compound (yield 91%).
get.

Melting point 195-196℃ (ethyl acetate-benzene) IR 3180, 1719, 1676, 1616, 1596, 1448,
1247 Example 2 5-(2-hydroxyphenyl)-1-[(2s)-
Production of S-(4-methylbenzoyl)-3-mercapto-2-methylpropanoyl]-2-pyrrolidinecarboxylic acid 5-(2-hydroxyphenyl)-1-[(2s)-
3-Mercapto-2-methylpropanoyl]-2
-Pyrrolidinecarboxylic acid (melting point 241-242℃,
[α] ²⁸ _D -22.0゜(c=1.1, methanol)) 3.1g
and 3.5 g of potassium carbonate were dissolved in 70 ml of water, 1.6 g of p-toluoyl chloride was added dropwise with stirring under ice cooling, and the title compound was prepared in the same manner as in Example 1.
Obtain 4.0 g (94% yield).

Melting point 183-184°C (ethyl acetate-benzene) [α] ²⁵ _D -10.9° (c = 1.0, methanol) IR 3330, 1714, 1663, 1621, 1602, 1462, 910 Example 3 5-(2-acetoxyph) enyl)-1-[(2s)-
Production of S-(4-methylbenzoyl)-3-mercapto-2-methylpropanoyl]-2-pyrrolidinecarboxylic acid A suspension of 0.6 g of 50% sodium hydride in 15 ml of anhydrous N,N-dimethylformamide under a nitrogen atmosphere 5-(2-hydroxyphenyl)-1-[(2s)
A solution of 2.1 g of -S-(4-methylbenzoyl)-3-mercapto-2-mercapropanoyl]-2-pyrrolidinecarboxylic acid in 15 ml of anhydrous N,N-dimethylformamide is added dropwise and stirred at room temperature for 30 minutes.
To this was added dropwise 0.6 g of acetyl chloride, and after further stirring at room temperature for 3 hours, 0.4 ml of acetic acid was added and concentrated under reduced pressure. Add an aqueous potassium carbonate solution and ether to the concentrate, separate the aqueous layer, make it acidic with concentrated hydrochloric acid, and then extract with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and the resulting oil is purified by silica gel column chromatography to obtain 1.8 g (yield: 77%) of the title compound.

Example 4 5-(2-hydroxyphenyl)-1-[S-(4
-Methylbenzoyl)-3-mercaptopropanoyl]-2-pyrrolidinecarboxylic acid Production of 5-(2-hydroxyphenyl)-1-(3-mercaptopropanoyl)-2-pyrrolidinecarboxylic acid (melting point 197-198°C (Decomposition), [α] ²⁵ _D +34.7° (c = 0.5, methanol)) 2.9 g and triethylamine 2.2 g were dissolved in anhydrous acetone 30 ml, and 1.5 g of p-toluoyl chloride was added dropwise while stirring under ice cooling. do. After dropping, cool on ice for 1 hour, then at room temperature for 1 hour.
After stirring for an hour, concentrate under reduced pressure. Dissolve the residue in ethyl acetate, filter out insoluble matter, and wash the solution with water and saturated brine. The organic layer was dehydrated over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting oil was purified using silica gel column chromatography to obtain 3.1 g of the title compound (yield:
75%).

[α] ²⁵ _D +42.5° (c=0.5, methanol) TLC (Rf value) 0.63 [Ethyl acetate-chloroform-acetic acid (7:5:1)/ _SiO2 ] IR ( _CHCI3 , cm ^-1 ) 1723 , 1645, 1605, 1175,
913, 826 FIG. 1 shows the results of pharmacological tests on representative compounds of the present invention and their salts when used as antihypertensive agents. As is clear from FIG. 1, the compound of the present invention exhibited a long-lasting and useful antihypertensive effect and had excellent stability.

Pharmacological testing It has recently been revealed that compounds that inhibit angiotensin-converting enzyme can be used to treat not only renal hypertension but also essential hypertension.
The compounds of the present invention were evaluated as antihypertensive agents by the following method.

Experimental method Animals were male Wistar rats (body weight 200~
300g) was used. Polyethylene cannulae were inserted into the carotid artery and jugular vein under ether anesthesia, and the carotid artery cannula was connected to an electric sphygmomanometer and the jugular vein cannula to a continuous infusion device. After complete recovery from anesthesia, administer angiotensin via continuous infusion device.
300 ng/Kg was injected intravenously, and changes in blood pressure increase at that time were recorded using a polygraph (Nihon Kohden, RM-150). The compound of the present invention was suspended in 0.5% tragacanth solution and administered orally at a rate of 0.3 ml per 100 g of body weight, and the pressor response caused by intravenous injection of angiotensin was measured over time. Angiotensin converting enzyme inhibitory activity was expressed as angiotensin pressor response inhibition rate (%).

Experimental Results Similar to known antihypertensive mercaptoacyl amino acids, the compound of the present invention suppressed angiotensin pressor response when orally administered to unanesthetized rats, and this was due to its mechanism of inhibiting angiotensin converting enzyme. The compounds of the present invention are derivatives of mercaptoacyl amino acids, and when equimolar amounts of these compounds were orally administered to compare their angiotensin pressor response inhibitory effects, the compounds of the present invention were well absorbed into the gastrointestinal wall and were found to be effective at the site of onset of action. Because it is gradually hydrolyzed, it has a longer-lasting effect and has been recognized as an advantage as an antihypertensive agent.

Stability Test The stability of a mercaptoacylamino acid and its S-acyl compound in a methanol solution was compared.

Storage conditions: room temperature, 1 month Experimental results: S-acyl compounds were more stable than mercaptoacylamino acids.

Next, the compounds used in the test are shown.

Compound A: 5-(2-hydroxyphenyl)-1-
[(2s)-3-mercapto-2-methylpropanoyl]-2-pyrrolidinecarboxylic acid compound B: 1-[(2s)-S-benzoyl-3-mercapto-2-methylpropanoyl]-5-(2
-hydroxyphenyl)-2-pyrrolidinecarboxylic acid compound C: 5-(2-hydroxyphenyl)-1-
[(2s)-S-(4-methylbenzoyl)-3-mercapto-2-methylpropanoyl]-2-pyrrolidinecarboxylic acid As is clear from the above pharmacological tests, the compound of the present invention [] has a sustained hypotensive effect. It is useful as a drug. In that case, it may optionally be combined with a diuretic, as is currently common practice. The administration form may be either oral or parenteral administration, and therapeutic preparations include tablets, capsules, granules, powders, suppositories, and injections. In addition to the usual fillers, especially in the treatment of hypertension, these preparations can also contain antihypertensive agents such as reserpine, alpha-methyldopa, guanethidine, clonidine or hydralazine. Although the dosage varies depending on symptoms, administration method, etc., it is usually 1 to 5,000 mg per day, preferably 10 to 1,000 mg per day, which can be administered once or divided into several doses.

Next, the composition of the preparation will be illustrated.

(1) Oral medication (a) Tablet 5-(2-hydroxyphenyl)-1- [(2s)
-S-(4-methylbenzoyl)-3-mercapto-2-methylpropanoyl]-2-pyrrolidinecarboxylic acid 30mg Lactose 150mg Crystalline cellulose 50mg Carboxymethyl cellulose calcium 7mg Magnesium stearate 3mg Total 240mg (b) Granules 5- (2-hydroxyphenyl)-1-[(2s)
-S-(4-methylbenzoyl)-3-mercapto-2-methylpropanoyl]-2-pyrrolidinecarboxylic acid 30mg Polyvinylpyrrolidone 25mg Lactose 385mg Hydroxypropyl cellulose 50mg Talc 10mg Total 500mg (c) Powder 5-(2 -hydroxyphenyl)-1-[(2s)
-S-(4-methylbenzoyl)-3-mercapto-2-methylpropanoyl]-2-pyrrolidinecarboxylic acid 30mg Lactose 500mg Starch 440mg Colloidal silica 30mg Total 1000mg (d) Capsules 5-(2-hydroxyphenyl) )-1-[(2s)
-S-(4-methylbenzoyl)-3-mercapto-2-methylpropanoyl]-2-pyrrolidinecarboxylic acid 30mg Lactose 102mg Crystalline cellulose 56mg Colloidal silica 2mg Total 190mg 5-(2-hydroxyphenyl)-1- [(2s)
-S-(4-Methylbenzoyl)-3-mercapto-2-methylpropanoyl]-2-pyrrolidinecarboxylic acid 30mg Glycerin 349.98mg Butyl paraoxybenzoate 0.02mg Total 380mg (2) Injection 5-(2-hydroxyphenzoyl) enyl)-1-[(2s)
-S-(4-methylbenzoyl)-3-mercapto-2-methylpropanoyl]-2-pyrrolidinecarboxylic acid aqueous solution (pH 6.5-7.0) containing 1-30 mg per ml.

[Brief explanation of the drawing]

FIG. 1 is a graph showing changes in the antihypertensive effects of the compounds according to the present invention and comparative compounds over time. In the figure, the inhibition rate on the vertical axis is the inhibition rate of the pressor reaction by angiotensin.

Claims (1)

[Claims] 1. Compounds represented by the following general formula [] and salts thereof. [In the formula, R ¹ represents a hydroxy group or a lower alkanoyloxy group. R ² represents a lower alkyl group or a lower alkyl-substituted phenyl group. Z is 1-3
represents a straight-chain or branched alkylene having 5 carbon atoms. ]