JPH0629187B2 - Nephropathy treatment - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel therapeutic agent for renal disorders.

[Prior art]

The kidney is an important organ that maintains the normality of body fluids by controlling water and salt, but it is known that renal blood flow decreases and renal excretion of salt, especially Na, is impaired if renal function is impaired. [Clinical Pharmacology, Volume 8, Diuretics / Infusions, pp. 54-55 (1966, published by Nakayama Shoten).

Therefore, the action of increasing renal blood flow and excretion of Na is a useful action for the treatment of renal disorders.

[Structure and Effect of Invention]

The present invention has the general formula (Wherein R ¹ represents a lower alkyl group, R ² represents a lower alkyl group, R ³ represents a phenyl-substituted lower alkyl group, and R ⁴ represents a hydrogen atom or a lower alkyl group). An agent for treating renal disorders, which comprises an oxo-imidazolidine derivative or a pharmacologically acceptable salt thereof as an active ingredient.

The 2-oxo-imidazolidine derivative or its pharmacologically acceptable salt, which is the active ingredient of the present invention, has an excellent renal blood flow increasing action and Na excretion increasing action. For example, (4S) -1-methyl-3-{(2S) -2- [N-
((1S) -1-carboxy-3-phenylpropyl)
When 10 μg / kg of [amino] propionyl} -2-oxo-imidazolidine-4-carboxylic acid was intravenously administered to anesthetized Beagle dogs, renal blood flow and Na excretion increased remarkably.
In addition, there was virtually no increase in K excretion, and the urinary Na / K ratio also increased. In addition, (4S) -1-Melch-3-{(2S)
-2- [N-((1S) -1-ethoxycarbonyl-3
-Phenylpropyl) amino] propionyl} -2-oxo-imidazolidine-4-carboxylic acid 10 mg / kg administered intraduodenally produces the same effects as above, and is particularly excellent in that the effects last for a long time. It showed the characteristic.

Further, the toxicity of the compound (I) is extremely low, and for example, (4S) -1-methyl-3-{(2S) -2- [N-
((1S) -1-carboxy-3-phenylpropyl)
Amino] propionyl} -2-oxo-imidazolidine-4-carboxylic acid or (4S) -1-methyl-3-
Rats were administered {(2S) -2- [N-((1S) -1-ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2-oxo-imidazolidine-4-carboxylic acid at a dose of 5 g / kg. Oral administration was carried out for 5 days, and no rat deaths were observed even after 5 days of administration.

Examples of the compound which is the active ingredient of the present invention include compounds represented by the general formula (I)
In the above, for example, R ¹ is a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group and an isobutyl group, and R ² is a methyl group, an ethyl group, n -Propyl group, isopropyl group, n
A lower alkyl group having 1 to 4 carbon atoms such as a butyl group and an isobutyl group, R ³ is a phenyl-substituted lower alkyl group such as a benzyl group, a phenethyl group, a phenylpropyl group and a phenylbutyl group, and R ⁴ is hydrogen. Atom or methyl group, ethyl group, n-propyl group, isopropyl group, n-
Examples thereof include compounds having a lower alkyl group having 1 to 4 carbon atoms such as butyl group and isobutyl group.

Of these, preferred compounds include those in which R ¹ is a methyl group and R ² is a methyl group in the general formula (I),
Examples thereof include compounds in which R ³ is a phenethyl group and R ⁴ is a hydrogen atom or an ethyl group.

The compound (I), which is the active ingredient of the present invention, has 3 asymmetric carbon atoms in the molecule and therefore exists as 4 types of diastereoisomers or 8 types of optical isomers. Also includes isomers. However, among these optical isomers, compounds suitable for pharmaceutical use include compounds (I) at the 4-position of the oxoimidazolidine ring and the 2-position carbon of the amino acid moiety represented by the formula —NH—CH (R ³ ) COOR ^4. Compounds in which all atoms are in the S configuration are mentioned. Further, as a compound suitable for pharmaceutical use, in the compound (I), the 4-position of the oxoimidazolidine ring, the 2-position of the alkanoyl moiety represented by the formula —COH (R ² ) — and the formula —NH—CH (R ³ ) COO
The 2-position carbon atom of the amino acid portion represented by R ⁴ is S
The compounds are in the configuration.

The compound (I), which is the active ingredient of the present invention, can be used for medicinal use in any form of a free acid (and / or free base) or a pharmaceutically acceptable salt thereof. Salts can be formed with organic and inorganic bases. Examples of the pharmacologically acceptable salt of compound (I) include organic acid addition salts such as succinate, maleate, fumarate and methanesulfonate; hydrochloride, hydrobromide and sulfate. , Inorganic acid addition salts such as phosphates; salts with organic bases such as lysine salts and ornithine salts; salts with inorganic bases such as sodium salts, potassium salts, calcium salts and magnesium salts.

The compound (I) and the pharmaceutically acceptable salt thereof, which are the active ingredients of the present invention, are useful as a therapeutic agent for renal disorders because they have excellent renal blood flow increasing action and Na excretion increasing action as described above. And is useful for treating renal diseases such as edema, acute renal failure, progressive renal failure, and proliferative nephritis.

In addition, compound (I) or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and the dose may be the degree of disease, the age, weight and condition of the patient, or other factors. Orally, it is usually 0.1 to 100 mg / kg, preferably 0.5 to 50 mg / kg per day, although it depends on factors. Also, parenterally usually 0.001 to 10mg / k per day
g, preferably 0.005 to 5 mg / kg is suitable.

Furthermore, compound (I) or a pharmaceutically acceptable salt thereof can be used as a mixture with an excipient suitable for oral or parenteral administration. As such an excipient, for example, starch, lactose, glucose, potassium phosphate, corn starch, gum arabic, stearic acid and any other commonly used excipient can be used. These pharmaceutical preparations may be tablets, pills, capsules, solid preparations such as suppositories, liquid preparations such as solutions, suspensions and emulsions, and these preparations may be sterilized. May contain auxiliary agents such as stabilizers, wetting agents and emulsifiers.

Compound (I), which is the active ingredient of the present invention, is disclosed in JP-B-60-58233.
It can be produced by the method described in No.

Experimental Example 1 Male beagle dog (body weight 8 to 10.5 kg, 1 fasted for 18 hours)
Sodium pentobarbital (30 mg / kg, i.
v.) for anesthesia, and then continuously administer the drug (4.5 mg / kg / h
r, iv) to maintain the depth of anesthesia.

(4S) -1-Methyl-3-{(2S) -2- [N-
((1S) -1-carboxy-3-phenylpropyl)
Amino] propionyl} -2-oxo-imidazolidine-4-carboxylic acid sodium salt was intravenously administered at 10 μg / kg, and the renal blood flow was measured 10 minutes after the administration of the sample. In addition, excreted urine 20 minutes after the administration of the sample was collected, the concentrations of Na and K in the urine were measured, and the amount of excreted electrolyte and the Na / K ratio were calculated.

The renal blood flow was measured by mounting a probe of an electromagnetic flow meter on the left renal artery.

The results are shown in Table 1 below.

From the above table, the drug of the present invention has an excellent renal blood flow increasing action,
It is clear that it has a Na excretion increasing effect and a Na / K ratio increasing effect.

Experimental Example 2 A male beagle dog (body weight: 8) anesthetized in the same manner as in Experimental Example 1 above.
~ 10.5kg, 5 animals per group) (4S) -1-methyl-3-
{(2S) -2- [N- (1S) -1-ethoxycarbonyl-3-phenylpropyl) amino] propionyl}
2-oxo-imidazolidine-4-carboxylic acid / hydrochloride 10 mg / Kg was administered into the duodenum, renal blood flow was measured at 20-minute intervals after sample administration, and excreted urine was collected to collect urine. The concentrations of Na and K were measured, and their excretion amount and Na / K ratio were calculated.

The renal blood flow was measured by mounting a probe of an electromagnetic flow meter on the left renal artery.

The results are shown in Table 2 below.

From the above table, it is clear that the drug of the present invention has a continuous renal blood flow increasing action, Na excretion increasing action and Na / K ratio increasing action.

Example 1 <Production method> Lactose and corn starch are added to the main ingredient and mixed well, and then a solution of polyvinylpyrrolidone dissolved in purified water is added and kneaded to granulate. After drying the obtained granules, magnesium stearate is added and compressed to give tablets.

Example 2 <Manufacturing Method> A tablet is obtained by treating the above formulation in the same manner as in Example 1.

Example 3 <Production method> The main drug and sodium chloride are dissolved in distilled water for injection.
Then, the mixture is filtered with a filter having a pore size of 0.22 μm, filled into an ampoule and sterilized to obtain an injection.

Example 4 <Production method> Sodium chloride is dissolved in distilled water for injection, the main drug is added, and the mixture is dissolved in sodium hydrogen carbonate solution. Then pore size 0.
An injection is obtained by filtering with a 22 μm filter, filling an ampoule, and sterilizing.

Claims (1)

[Claims] 1. A general formula (Wherein R ¹ represents a lower alkyl group, R ² represents a lower alkyl group, R ³ represents a phenyl-substituted lower alkyl group, and R ⁴ represents a hydrogen atom or a lower alkyl group). A therapeutic agent for renal disorders, which comprises an oxo-imidazolidine derivative or a pharmacologically acceptable salt thereof as an active ingredient.