KR950007100B1 - Anti hypertension agent - Google Patents

Abstract

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Description

Blood pressure lowering agents

The present invention relates to a blood pressure lowering agent.

More specifically, the present invention relates to a novel blood pressure lowering agent comprising a phenoxyacetic acid derivative of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

Wherein R is a lower alkyl group, or lower alkoxy-substituted lower alkyl group, and X is a halogen atom.

Hypertension is a disease in which blood pressure rises due to increased resistance of peripheral resistance vessels accompanied by functional or organic changes, and is generally classified into two categories, essential hypertension and secondary hypertension, depending on its origin. To date, antihypertensive agents that have been used to treat these hypertensives include, for example, adrenaline, including vasodilators (e.g. hydralazine, etc.), α-blockers (e.g., prazosin, etc.), and β-blockers (e.g., pindrol, etc.) Receptor blockers, angiotensin converting enzyme inhibitors such as captopril and the like, calcium antagonists such as nifedipine and diuretics such as hydrochlorothiazide are known.

The phenoxyacetic acid derivatives of the general formula (I) and the pharmaceutically acceptable salts thereof, which are the active ingredients of the blood pressure lowering agent of the present invention, are novel compounds and have excellent blood pressure lowering activity. For example, in the present invention, spontaneously hypertensive rats fastened with phenoxyacetic acid derivatives overnight (hereinafter referred to as SHR, about 40 weeks of age) are administered orally once at a dose of 200 mg / kg and its blood pressure enhancing activity When evaluated, the test compound (herein, [2,3-dichloro-4- (1-ethoxymethyl-5-pyrazolylcarbonyl) phenoxy] acetic acid, [2,3-dichloro-4- as an active ingredient In the administration group (1-ethyl-5-pyrazolylcarbonyl) phenoxy] acetic acid, etc.), the systolic pressure of rats showed a drop of about 13% after 2 hours of administration compared to the systolic pressure before administration.

Suitable examples of phenoxyacetic acid derivatives useful as active ingredients of the blood pressure lowering agent of the present invention include lower alkyl groups having 1 to 6 carbon atoms, lower alkoxy groups having 1 to 6 alkoxy groups, and X being a halogen atom (e.g., Chlorine or bromine atom), a preferred compound of which R is an alkyl group having 1 to 3 carbon atoms substituted by an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, X Is a compound of formula (I) wherein is a chlorine atom.

Particularly preferred compounds are those of the general formula (I) wherein R is an ethyl group or an ethoxymethyl group, X is a chlorine atom, and more particularly [2,3-dichloro-4- (1-ethoxymethyl-5- Pyrazolyl-carbonyl) phenoxy] acetic acid, [2,3-dichloro-4- (1-ethyl-5-pyrazolylcarbonyl) -phenoxy] acetic acid.

Since the penoxyacetic acid derivative of Formula (I) of the present invention and the pharmaceutically acceptable salt thereof have excellent blood pressure lowering activity, treatment and prevention of essential hypertension and secondary hypertension (eg, renal hypertension, endocrine hypertension) , Cardiovascular hypertension, hypertension with pregnancy, hypertension with acute stress, drug-induced hypertension, and alcoholic hypertension and other hypertensions).

The phenoxyacetic acid derivative (I) of the present invention may be used in free form or in the form of a pharmaceutically acceptable salt thereof. Suitable examples of pharmaceutically acceptable salts of compound (I) include alkali metal salts (e.g., sodium salts, potassium Salts), alkaline earth metal salts (e.g. calcium salts), inorganic acid salts (e.g. hydrochloride, hydrobromide, etc.) and organic acid salts (e.g. methanesulfonate, oxalate, etc.).

Blood pressure lowering agents of the present invention can be administered orally or parenterally. For oral administration, the antihypertensive agents of the present invention may be used in the form of pharmaceutical preparations which may contain pharmaceutical carriers suitable for oral administration, such as excipients, binders, disintegrants and wetting agents. Pharmaceutical carriers include, for example, starch, lactose, glucose, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, sugar, corn starch, polyethylene glycol, talc, potassium phosphate, magnesium stearate, and other conventional excipients, Binders, disintegrants, wetting agents, and the like. Pharmaceutical formulations can be used in solid dosage forms (e.g. tablets, powders, capsules, granules, etc.) or in liquid dosage forms (e.g. solutions, suspensions, emulsions, syrups, elixirs, etc.). For parenteral administration, the pharmaceutical preparations are preferably used in the form of injections. Suitable examples of solvents for injection are distilled water for injection, vegetable oil, propylene glycol and the like. Pharmaceutical formulations for injection may also contain stable solubilizers, buffers, stabilizers and the like.

The dose of the compound (I) or pharmaceutically acceptable salt of the lowering blood pressure of the present invention may vary depending on the route of administration, the age, weight or health condition of the patient and the type of disease to be treated. In general, the preferred dose of compound (I) or a salt thereof is usually in the range of 1 to 200 mg / kg / day, in particular 3 to 100 mg / kg / day.

The phenoxyacetic acid derivative (I) is, for example, after reacting a phenol derivative of the general formula (II) with an acetic acid compound of the general formula (III) to obtain a phenoxyacetic acid ester derivative of the general formula (I '), Phenoxyacetic acid ester derivatives can be prepared by hydrolysis in a conventional manner:

Y-CH2COOR ¹ (Ⅱ)

Wherein Y is a halogen atom; R ¹ is a lower alkyl group; R and X are as defined above.

The invention is illustrated by, but not limited to, the following experiments and preparation methods.

[Experiment]

[Test Compound]

[Experiment 1]

[Blood pressure lowering activity in SHR by single dose of test compound]

[Methods and Results]

1 ml volume per 100 g body weight of the rats per SHR (about 40 weeks old, 4 to 6 rats / group) fasted overnight of a suspension of test compound in water containing a small amount of Tween 80 (dose of test compound 200 mg / kg). The blood pressure is measured noninvasively by the Taeil-press method before and after administration of the test compound, and the rate of blood pressure change 2 hours after administration of the test compound to the blood pressure before administration of the test compound is evaluated. For both Test Compound Nos. (1) and (2), the rate of change in blood pressure is about -13%.

[Experiment 2]

[Blood Drop Activity for Progressive Hypertension of DOCA-Inflammated Rats]

[Methods and Results]

The left kidney was taken from male SD rats (6 weeks after birth, about 200 g body weight, 10 rats / group), and one week later, silicon resin containing 150 mg / kg of deoxycorticosterone acetic acid (DOCA) was subjected to ether anesthesia. Into the subcutaneous tissue of the rat's back. After operation, the rats are fed with water containing 1% sodium chloride and 0.2% potassium chloride as drinking water to make DOCA-salt rats. From the day following the operation of inserting the DOCA-containing silicon resin, a suspension of test compound (I) in water containing a small amount of Tween 80 was added once daily for 4 weeks to the test compound-administered group 10 mg / day. Oral administration in a volume of kg (dose of test compound: 50 mg / kg / day). In addition, the same amount of water containing a small amount of Tween 80 in place of the suspension of test compound (I) is administered to the control group. In both groups, the systolic pressure of rats is measured by the tail-press method once a week until the fourth week. The results are shown in Table 1 below.

TABLE 1

(*: P <0.05)

As shown in Table 1, the elevated blood pressure of rats in the test compound-administered group is significantly inhibited from 2 weeks of administration compared to the control group.

[Experiment 3]

Blood Pressure Drop Activity in SHR

[Methods and Results]

Test compound (1) in water containing a small amount of Tween 80 was added to the suspension once a day for 4 weeks for SHR rats (5 weeks postnatal: about 100 g body weight, 10 rats / group) of the test compound-administered group. Oral administration in a volume of ml / kg (dose of test compound: 100 mg / kg / day). In addition, the same amount of water containing a small amount of Tween 80 is administered to rats of the control group instead of a suspension of test compound (1). In both groups, the systolic pressure of rats is measured by the tail-press method once a week until the fifth week. The results are shown in Table 2 below.

TABLE 2

(**: P <0.01)

As shown in Table 2, the elevated blood pressure of rats in the test compound-administered group is significantly inhibited from 1 week of administration compared to the control group.

[Experiment 4]

Blood Pressure Drop Activity in SHR with Chronic Hypertension

[Methods and Results]

Using SHR with chronic hypertension (chronic-SHR, 18 weeks old, body weight 300-375 g, 8 rats / group), in the same manner as in Experiment 3, except that the administration period of test compound (1) was 3 weeks Measured until 3 weeks after administration of systolic pressure. The results are shown in Table 3 below.

TABLE 3

(*: P <0.05)

As shown in Table 3, the blood pressure of rats in the test compound-administered group dropped significantly from week 1 of administration compared to the blood pressure of rats in the control group.

[Experiment 5]

Blood Pressure Drop Activity in DOCA-Salt Rats with Chronic Hypertension

[Methods and Results]

DOCA-salt-impregnated rats with stable hypertension were obtained by feeding tap water instead of aqueous salt solution for 6 weeks to the DOCA-salt-impregnated rats used in Experiment 2. These chronic DOCA-salt hypertensive rats (8 rats / group) were used as in Experiment 3 except that the dose of Test Compound (1) was 50 mg / kg / day and the administration period was 3 weeks, and the systolic pressure Measured until 4 weeks after dosing. The results are shown in Table 4 below.

TABLE 4

(*: P <0.05)

As shown in Table 4, the blood pressure of rats in the test compound-administered group dropped significantly from the second week of administration compared to the blood pressure of rats in the control group.

Preparation Example 1

(1) 2,3-dichloro-4- (1-ethyl-5-pyrazolylcarbonyl) -phenol (2,12 g), ethyl bromoacetate (1.61 g) and potassium carbonate (2.36 g) were added to acetone (80 ml). ) And the mixture is refluxed for 1.5 h. The reaction mixture is filtered and the solvent is distilled off from the filtrate. The residue is dissolved in benzene and treated with octane, after which the solvent is further distilled off. The residue was recrystallized from isopropyl ether to colorless [2,3-dichloro-4- (1-ethyl-5-pyrazolylcarbonyl) -phenoxy] acetic acid ethyl ester (2.20 g) having a melting point of 79 to 81 ° C. Obtained as a crystal.

(2) To a suspension of the product (1.6 g) in ethanol (25 ml) is added 10% aqueous sodium hydroxide solution (15 ml) and the mixture is stirred at room temperature for 1 hour. Ethanol is distilled off from the reaction solution and the mixture is adjusted to pH 1-2 with 10% hydrochloric acid. The precipitated crystals are collected by filtration. The crystals were washed successively with water and isopropyl alcohol and dried to [2,3-dichloro-4- (1-ethyl-5-pyrazolyl carbonyl) phenoxy] acetic acid (1.40 g) (melting point: 203 to 203). 204 ° C.).

Mass (m / e): 342 (M ⁺ )

Melting point of its sodium salt and monohydrate: 243.5 to 245.5 ° C

[Production Examples 2 to 6]

The compounds of Table 5 below are obtained by treating the corresponding starting materials in the same manner as in Example 1.

TABLE 5

Claims (6)

An antihypertensive agent comprising a penoxyacetic acid derivative of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with a pharmaceutically acceptable carrier or diluent in an effective amount for lowering blood pressure.

Wherein R is a lower alkyl group or a lower alkoxy-substituted lower alkyl group and X is a halogen atom. The antihypertensive agent according to claim 1, wherein the active ingredient comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is a chlorine atom. The compound of formula (I) according to claim 2, or a pharmaceutical thereof, wherein R is an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 3 carbon atoms substituted by an alkoxy group having 1 to 3 carbon atoms as an active ingredient. An antihypertensive agent comprising an acceptable salt. The antihypertensive agent according to claim 2, wherein the active ingredient comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is an ethyl group or an ethoxymethyl group. 2. The antihypertensive agent of claim 1, wherein the active ingredient is [2,3-dichloro-4- (1-ethoxymethyl-5-pyrazolylcarbonyl) phenoxy] acetic acid or a pharmaceutically acceptable salt thereof. The antihypertensive agent according to claim 1, wherein the active ingredient is [2,3-dichloro-4- (1-ethyl-5-pyrazolylcarbonyl) phenoxy] acetic acid or a pharmaceutically acceptable salt thereof.