JPH0121815B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a therapeutic agent for hypertension, and more specifically, the present invention relates to a therapeutic agent for hypertension, and more specifically, (However, R ¹ is a lower alkyl group, R ² is a lower alkyl group, R ³ is a phenyl-substituted lower alkyl group, R ⁴
represents a hydrogen atom or a lower alkyl group. ) The present invention relates to a therapeutic agent for hypertension comprising a novel 2-oxo-imidazolidine derivative or a pharmacologically acceptable salt thereof as an active ingredient. Angiotensinogen in plasma is broken down by the enzyme renin to angiotensin, which is converted by angiothesicin-converting enzyme (hereinafter referred to as ACE) to angiotensin, which is a pressor active substance and is a cause of various types of hypertension in mammals. It is known that It is also known that ACE inactivates bradykinin, an antihypertensive active substance, without degrading it, thereby causing an increase in blood pressure. Therefore, in recent years, various studies have been conducted on ACE inhibitors based on the idea that inhibiting ACE activity can prevent the formation of angiotensin and the degradation of bradykinin caused by ACE, and can be used effectively in the treatment of hypertensive patients. being done. Under these circumstances, the present inventors have conducted various studies and found that a novel 2-oxo-imidazolidine derivative represented by the general formula () has excellent ACE inhibitory activity and is therefore useful as a therapeutic agent for hypertension. I discovered that. For example, in vivo ACE testing using rats administered intravenously with angiotensin.
When the inhibitory activity was investigated, it was found that (4S) according to the present invention
-1-methyl-3-{(2S)-2-[N-((1S)
-1-Ethoxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid inhibited ACE activity by 60% at a dose of 1.0 mg/Kg. Furthermore, when the test compound was orally administered to spontaneously hypertensive rats, (4S)-1-methyl-3-{(2S)-2-
[N-((1S)-1-ethoxycarbonyl-3-
phenylpropyl)amino]propionyl}-2
-oxo-imidazolidine-4-carboxylic acid is 3
A dose of mg/Kg was able to reduce the blood pressure of the rats by approximately 45 mmHg over a period of 6 hours.
Furthermore, the toxicity of the compound () according to the present invention is extremely low. As mentioned above, the compound () or a pharmacologically acceptable salt thereof according to the present invention can be effectively used to alleviate hypertension in mammals. In the compound according to the present invention, in the general formula (), for example, R ¹ is a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, or isobutyl group. and R ² is a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, or isobutyl group,
R ³ is a phenyl-substituted lower alkyl group such as a benzyl group, phenethyl group, phenylpropyl group, or phenylbutyl group, and R ⁴ is a hydrogen atom or a methyl group, ethyl group, n-propyl group, isopropyl group, or n-butyl group. , carbon number 1 such as isobutyl group
-4 lower alkyl groups are mentioned. Among these, preferred compounds include general formula () in which R ¹ is an alkyl group having 1 to 4 carbon atoms, R ² is an alkyl group having 1 to 4 carbon atoms, and R ³ is an alkyl group having 4 to 8 carbon atoms. A straight chain or branched alkyl group, benzyl group or phenethyl group,
Examples include compounds in which R ⁴ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. More preferred compounds include R ¹ being a methyl group or n-butyl group;
R ² is a methyl group or ethyl group, R ³ is a benzyl group or phenethyl group, R ⁴ is a hydrogen atom,
Examples include compounds that are ethyl or n-butyl groups. Even more preferable compounds include R ¹
is a methyl group, R ² is a methyl group, R ³ is a phenethyl group, and R ⁴ is a hydrogen atom or an ethyl group. Since the compound () according to the present invention has three asymmetric carbon atoms in the molecule, it exists as four diastereoisomers or eight types of optical isomers.
The present invention includes any isomers.
However, among these optical isomers, compounds suitable for pharmaceutical use include the 4-position of the oxoimidazolidine ring and the formula -NH-
Examples include compounds in which the 2-position carbon atoms of the amino acid moiety represented by CH(R ³ )COOR ⁴ are all in the S configuration. Furthermore, compounds suitable for medicinal use include:
4 of the oxoimidazoline ring in compound ()
A compound in which the carbon atom at position 2 of the alkanoyl moiety represented by the formula -COCH(R ² )- and the carbon atom at position 2 of the amino acid moiety represented by the formula -NH-CH(R ³ )COOR ⁴ are all in the S-configuration. can be mentioned. The compound () according to the present invention is a free acid (and/
It can be used for pharmaceutical purposes in any form (or free base) or its pharmacologically acceptable salts, and salts can be formed with organic and inorganic acids or organic and inorganic bases. Pharmaceutically acceptable salts of the compound () include, for example, organic acid addition salts such as succinate, maleate, fumarate, methanesulfonate; hydrochloride, hydrobromide, sulfate; Inorganic acid addition salts such as phosphates; salts with organic bases such as lysine salts and ornithine salts; sodium salts, potassium salts, calcium salts,
Salts with inorganic bases such as magnesium salts may be mentioned. The dosage of the compound () or a pharmacologically acceptable salt thereof according to the present invention varies depending on the degree of disease, age, weight and condition of the patient, and other factors, but is usually 1 to 1000 mg/day. body, preferably 10 to 500 mg/body. Furthermore, the compound () or a pharmacologically acceptable salt thereof can be combined with or mixed with a pharmaceutical excipient suitable for oral or parenteral administration to be used as a pharmaceutical preparation containing the same compound. As excipients, for example, starch, lactose, glucose, potassium phosphate, corn starch, gum arabic, stearic acid, and other commonly used pharmaceutical excipients can be used. These pharmaceutical preparations can be solid preparations such as tablets, pills, capsules, and suppositories, and liquid preparations such as solutions, suspensions, and emulsions, and these preparations may be sterilized. Furthermore, it may contain auxiliary agents such as stabilizers, wetting agents, and emulsifiers. The compound () according to the present invention has the general formula (However, R ⁵ represents a protective group that can be removed by acid treatment or catalytic reduction, R ⁶ represents a lower alkyl group or a protective group that can be removed by acid treatment or catalytic reduction, and R ¹ , R ² and R ³ are It has the same meaning as above.) It can be produced by acid treatment and/or catalytic reduction of the compound shown. In the above compound (), suitable examples of the protecting group (R ⁵ and/or R ⁶ ) include a tert.-butyl group and a benzyl group. as a protecting group
When a tert.-butyl group is used, removal of the tert.-butyl group can be easily carried out, for example, by contacting the compound () in a suitable solvent with an acid. As the acid, for example, hydrogen chloride, hydrogen bromide, hydrogen fluoride, trifluoroacetic acid, etc. can be suitably used. Further, as the solvent, it is preferable to use, for example, dioxane, tetrahydrofuran, ethyl acetate, or the like. This reaction is preferably carried out at a temperature of 0°C to 50°C, particularly 20°C to 30°C. On the other hand, when a benzyl group is used as the protecting group (R ⁵ and/or R ⁶ ), the benzyl group can be removed by catalytic reduction. This catalytic reduction can be carried out in a suitable solvent in the presence of a catalyst and under a flow of hydrogen gas. Preferred examples of the catalyst include palladium black, palladium on carbon, and platinum oxide. As the solvent, lower alkanols such as methanol, ethanol, and propanol can be suitably used. This reaction is
It is preferable to carry out shaking at 20°C to 40°C and under 1 to 5 atmospheres. For example, this reaction proceeds suitably at normal temperature and normal pressure. In the above reaction, an optically active form of the compound () or a mixture thereof may be used. Since the above reaction proceeds without ceramization, the optically active form of compound () or a mixture thereof can be easily obtained by using the corresponding optically active form of compound () or a mixture thereof. Further, the compound () according to the present invention can be easily converted into a pharmacologically acceptable salt thereof by a conventional method, for example, by treatment with a base or an acid. The compound () used in producing the compound () according to the present invention is also a new compound, and can be produced, for example, by the method shown in the reaction formula below. (In the above formula, X represents a halogen atom, an alkylsulfonyloxy group, or an allylsulfonyloxy group, and R ¹ , R ² , R ³ , R ⁵ and R ⁶ have the same meanings as above.) In the above reaction formula, For example, the compound () is 3
-Benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylic acid (Justus Liebitz Annaren der Chemy., vol. 529, 1
(1937)) with an alcohol represented by R ⁵ -OH (where R ⁵ has the same meaning as above) to form 3-benzyloxycarbonyl-2-
oxo-imidazolidine-4-carboxylic acid ester, and the ester is R ¹ -X' (however, X' represents a halogen atom, and R ¹ has the same meaning as above)
1-Substituted-3-benzyloxycarbonyl-2-oxo-
As imidazolidine-4-carboxylic acid ester,
It can then be produced by subjecting the compound to catalytic reduction. The starting compound, ie, 3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylic acid, can be used in either its racemic form or its optically active form. In addition, since all of the above reactions proceed without racemization, the optically active form of compound () is the corresponding 3
It can be easily obtained by using an optically active form of -benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylic acid. According to method A, compound () can be produced by subjecting compound () to a condensation reaction with a reactive derivative of compound (). The condensation reaction between compound () and a reactive derivative of compound () (e.g., succinimide ester, benzotriazole ester) is carried out using a base (e.g., tert.-butoxy) in a suitable solvent (e.g., tetrahydrofuran, dioxane, methylene chloride). potassium, sodium ethylate) -60℃~20℃, especially -40℃~
Preferably, it is carried out at 0°C. In this reaction, the reactive derivative of compound () and () may be either an optically active form or a mixture thereof, and the optically active form of compound () may be the optically active form of compound () or (). By doing so, it can be obtained without racemization. Furthermore, the compound () is _NH2
-CH(R ² )-COOR ⁷ ( ) (wherein R ⁷ represents a tert.-butyl group or a benzyl group, and R ² has the same ^meaning as above) is converted into an amino acid ester represented by )-COOR ⁶ () (where X represents a halogen atom, an alkylsulfonyloxy group, or an allylsulfonyloxy group, and R ³ and R ⁶ have the same meanings as above), or ⁷ OOC−CH(R ² )−X()(shi,
NH ² CH(R ^{3 )} _-
R ⁷ OOC-CH(R ² )-NH-CH(R ³ )-COOR by reacting with a compound represented by COOR ⁶ () (where R ³ and R ⁶ have the same meanings as above) by a conventional method. ⁶
(XI) (wherein R ² , R ³ , R ⁶ and R ⁷ have the same meanings as above), and then removing the protecting group (R ⁷ ) from the compound. can. If compound (XI) obtained in this reaction is a mixture of two isomers,
These isomers can be separated into individual isomers by silica gel chromatography and/or fractional crystallization. The fractional crystallization method can be carried out by first converting compound (XI) into a salt with maleic acid, and then collecting the poorly soluble isomer from the reaction mixture. In this fractional crystallization method, a compound in which the asymmetric carbon atom at the 2-position of the fatty acid moiety and the 2-position asymmetric carbon atom of the amino acid moiety of compound (XI) are both in the S configuration is formed as a sparingly soluble diastereoisomeric salt.
Removal of the protecting group of compound (XI) can be easily carried out by acid treatment or catalytic reduction of compound (XI). On the other hand, according to Method B, compound () is produced by subjecting compound () to a condensation reaction with a reactive derivative of compound () to form compound ();
can be produced by condensation reaction with compound (). The condensation reaction between compound () and a reactive derivative of compound () (e.g., acid chloride, acid bromide) is carried out using a deoxidizing agent (e.g.,
-60°C to 20°C, especially -40°C to 0°C
It is preferable to carry out. The second step, that is, the condensation reaction between compound () and compound (), is carried out using a deoxidizing agent (e.g., potassium carbonate, sodium carbonate, sodium bicarbonate) in a suitable solvent (e.g., hexamethylphosphoric acid triamide, dimethylformamide, tetrahydrofuran). , 0°C to 80°C, especially 20°C to
Preferably it is carried out at 50°C. In the above reaction, compounds (), (), and () can be either ceramiforms or optically active forms thereof. Further, when the compound () obtained by these reactions is a mixture of isomers, the compound () can be separated into each isomer by silica gel chromatography. In addition, amino acids in which R ³ is a phenethyl group in the general formula () are J.Med.Chem., 11 , 1258,
(1968) can be produced according to the method described in
The optically active form of this amino acid can also be produced by enzymatically resolving the racemic form with aminoacylase. Experimental example 1 <ACE inhibitory activity (in vitro test)> Add 50μ of hipryl-histidyl-leucine (substrate) at 0.01 molar concentration and 0 to 100μ of the sample solution to 300μ of 0.2M Tris-HCl buffer containing 0.2M of sodium chloride/water. The total size is 450μ. Then, 50μ of angiotensyl converting enzyme (ACE) isolated from pig kidney cortex is added to the mixture and left at 37°C for 20 minutes. The amount of histidyl-leucine obtained by the reaction between the substrate and ACE was measured by a microbial assay using Leuconostocmesenteroides P-60 to determine the ACE inhibitory activity of the sample. The results are shown in Table 1 below.

[Table] Experimental Example 2 <ACE inhibitory activity (in vivo test)> Normotensive rats and normotensive cats were anesthetized with urethane (1.2g/Kg, SC), and then angiotensin (rats: 300ng/Kg, cats: 600n)
g/Kg) into the jugular vein for rats and the femoral vein for cats. The increase in blood pressure due to angiotensin administration is measured using a pressure transducer connected to the carotid artery. 10 minutes after administration of angiotensin, the specimen (dose 10 γ/Kg) is administered intravenously, and 10 minutes after administration of the specimen, angiotensin (rat: 300 ng/Kg, cat: 600 ng/Kg) is administered intravenously over time. The ACE inhibitory activity of the sample is
The increase in blood pressure caused by the administration of angiotensin was measured before and after the administration of the sample, and was calculated using the following formula.
The inhibitory effect on ACE activity (%) was determined. The results are shown in Table 2 below. ACE activity inhibitory effect (%) = P ₁ - P ₂ / P ₁ × 100 P ₁ : Increase in blood pressure due to angiotensin before administration of sample (ΔmmHg) P ₂ : Increase in blood pressure due to angiotensin after administration of sample (ΔmmHg)

[Table] Experimental example 3 <ACE inhibitory activity (in vivo test)> Normotensive rats treated with urethane (1.2g/Kg, SC)
anesthetized with angiotensin (300n).
g/Kg) into the rat jugular vein. The increase in blood pressure due to angiotensin administration is measured using a pressure transducer connected to the carotid artery. 10 minutes after administration of angiotensin, the specimen (dose: 1 mg/Kg) is administered orally, and 30 minutes after administration of the specimen, angiotensin (300 ng/Kg) is administered intravenously over time. The ACE inhibitory activity of the sample was determined by measuring the increase in blood pressure caused by the administration of angiotensin before and after administering the sample, and the ACE activity inhibitory effect (%) was determined in the same manner as in Experimental Example 2. The results are shown in Table 3 below.

[Table] Experimental Example 4 <Hypertensive effect on SHR> A sample (dose: 3 mg/Kg) is suspended in an aqueous carboxymethylcellulose solution and orally administered to spontaneously hypertensive rats (SHR) that have been fasted overnight.
Systolic blood pressure in rats was determined by the Thael plethysmograph method (The Journal of Laboratory and Clinic Medicine, 78 , 957 (1971)).
It was measured by The antihypertensive effect of the test compound was determined by the level of decrease in blood pressure. The results are shown in Table 4.

[Table] Experimental Example 5 <ACE inhibitory activity (in vivo test)> It was carried out in the same manner as Experimental Example 3, except that the specimen was orally administered at doses of 0.2, 0.5, 1.0, and 2.0 mg/Kg. The ACE inhibitory activity of the sample is 50% effective dose ( _ED50 ),
In other words, the increase in blood pressure caused by angiotensin is reduced by 50%.
Expressed as the dose required to suppress the effect. <Acute toxicity> A 0.5% carboxymethyl cellulose/sodium suspension of the sample was administered to ddy male mice (body weight: 18 to
(22g) was orally administered. The 50% lethal dose (LD ₅₀ ) of the sample was calculated by the probit method from the number of mice that died within 5 days after administration. <Results> The results are shown in Table 5 below.

【table】

【table】

[Preparation of raw material compound ()]

(1-a) L-alanine benzyl ester 21.7
A mixture of 33.0 g of 2-bromo-4-phenyl-n-butyric acid ethyl ester, 20.2 g of anhydrous potassium carbonate, and 60 ml of hexamethylphosphoric acid triamide was stirred at room temperature for 3 days. Ether is added to the reaction mixture and the ether layer is separated. After drying the ether solution, the solvent is distilled off. The residue is subjected to silica gel column chromatography (solvent: toluene:ethyl acetate = 10::1), and a fraction containing the target compound is collected. The collected liquid is concentrated under reduced pressure to remove the solvent. The residue and 11.0 g of maleic acid are dissolved in ethyl acetate, and isopropyl ether is added to the solution. By filtering the precipitated crystals, (2S)-2-[N-((1S)-
1-ethoxycarbonyl-3-phenylpropyl)amino]propionic acid benzyl ester
21.2 g of maleate salt are obtained. Yield: 36.1% (1-b) (2S)-2-[N-((1S)-1-
ethoxycarbonyl-3-phenylpropyl)
Add potassium carbonate aqueous solution to 21.2 g of amino] propionic acid benzyl ester maleate,
The mixture is extracted with ether. The extract is washed with brine, dried, and the solvent is distilled off. Dissolve the residue in 250 ml of ethanol and add 200 mg of palladium black to the solution. The mixture was shaken in a hydrogen gas stream at room temperature and pressure for 2 hours. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove the solvent.
By crystallizing the residue with ether,
9.86 g of (2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino]propionic acid is obtained as colorless crystals. Yield: 80.8% MP150-152℃ [α] ¹⁷ _D +17.6゜ (C=1, ethanol) IRν ^nujol _nax (cm ^-1 ): 1745, 1600 Mass (m/e): 279 (M ⁺ ) ( 2-a) L-alanine benzyl ester 6.05
g, 2-bromo-4-phenyl-n-butyric acid n-
A mixture of 10.1 g of butyl ester, 4.9 g of potassium carbonate and 20 ml of hexamethylphosphoric triamide is stirred at room temperature for 3 days. Add 100 ml of ether and 40 ml of water to the reaction mixture, and separate the ether layer. The ether solution is washed with water, dried, and the solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent, toluene: ethyl acetate =
13:1), (2S)-2-[N
-((1S)-1-n-butoxycarbonyl-3
2.6 g of -phenylpropyl)amino]propionic acid benzyl ester are obtained as a colorless viscous oil. Yield: 19.4% IRν ^film _nax (cm ^-1 ): 3320, 1735 Mass (m/e): 397 (M ⁺ ) (2-b) (2S)-2-[N-((1S)-1-
n-Butoxycarbonyl-3-phenylpropyl)amino]propionic acid benzyl ester
Dissolve 2.6 g in 40 ml of methanol, and add 50 mg of palladium black to the solution. The mixture is shaken in a hydrogen gas stream at room temperature and pressure. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove the solvent.
The residue was subjected to silica gel chromatography (solvent,
By purifying with chloroform:ethanol=15:1), (2S)-2-[N-((1S)-
1.29 g of 1-n-butoxycarbonyl-3-phenylpropyl)amino]propionic acid is obtained as colorless crystals. Yield: 64.2% MP156-158℃ [α] ²³ _D +8.5゜ (C=0.5, ethanol) IRν ^nujol _nax (cm ^-1 ): 1740, 1600 Mass (m/e): 307 (M ⁺ )

Claims (1)

[Claims] 1. General formula (However, R ¹ is a lower alkyl group, R ₂ is a lower alkyl group, R ³ is a phenyl-substituted lower alkyl group, R ⁴
represents a hydrogen atom or a lower alkyl group. ) A therapeutic agent for hypertension comprising a 2-oxo-imidazolidine derivative or a pharmacologically acceptable salt thereof as an active ingredient.