JPH06145064A - Medicine for improving edema - Google Patents

Abstract

PURPOSE:To provide a high-safety diuretics capable of promoting excretion of only water without promoting excretion of electrolytes. CONSTITUTION:N-methyl-L-tyrosylglycylglycyl-L-phenylalanyl-L-leucyl-L- arginyl- N<2>-methyl-L-arginyl-N-ethyl-D-leucinamide or its pharmaceutically permissible salt is, e.g. intramuscularly, orally, intrarectally or intranasally administrated so as to high safely improve edema by its water diuresis effect.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a diuretic for improving and treating edema.

[0002]

2. Description of the Related Art Conventionally, a large number of components have improved various edemas such as cardiac edema (congestive heart failure), renal edema, hepatic edema, pregnancy toxemia / pregnancy edema, and edema due to peripheral vascular disorder.
It is used as a diuretic to treat. Due to their mechanism of action, (1) thiazide diuretics, (2) loop diuretics, (3) aldosterone antagonists, (4) potassium-sparing diuretics, (5) osmotic diuretics, (6) carbonic acid It is classified as a dehydratase inhibitor.

These diuretics other than the osmotic diuretic are those which suppress the reabsorption of electrolytes, particularly sodium ions and chloride ions, mainly in the kidney to cause salt diuresis and reduce the amount of extracellular fluid. That is, as a result of inhibiting the transport of electrolytes in the renal tubule, a diuretic effect is exhibited.

[0004]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention Conventional diuretics that act on renal tubules all have a low side effect as a common side effect due to the mechanism of action that increases excretion of sodium ions into urine and increases urine output. Natriemia and dehydration are more likely to occur and the frequency is high. At the same time, urinary excretion of potassium ions is also increased, which is also reported to cause hypokalemia and potassium deficiency.

Further, side effects other than the above have been reported. Since thiazide diuretics also reduce uric acid excretion in the renal tubules, they cause hyperuricemia with a high frequency and are contraindicated for hyperuricemia / gout patients. In addition, side effects such as hypocalcemia, hypomagnesemia / magnesium deficiency, impaired glucose tolerance, hearing impairment, and hypochloremic alkalosis have been observed.

Loop diuretics include hypocalcemia, hyperuricemia, hypomagnesemia / magnesium deficiency,
Glucose intolerance, hearing loss, hypochloremic alkalosis, etc. have been reported.

[0007] Potassium-sparing diuretics have side effects such as hyperkalemia, endocrine disorders, metabolic acidosis, and blood disorders.

It is known that carbonic anhydrase has side effects such as hypochloremic alkalosis and kidney stone formation.

On the other hand, an osmotic diuretic raises the osmotic pressure in extracellular fluid and causes a movement of water from the inside of cells, and as a result, a diuretic action is expressed, but hyponatremia, hypochloremia, hemolysis and the like are caused. There are side effects. In patients with impaired renal function or cardiac function, heart failure, pulmonary edema, and high degree of dehydration are likely to occur, and careful administration is required.

While the use of conventional diuretics, especially loop diuretics, is becoming possible to treat most edemas,
Drugs with a strong diuretic effect are more likely to cause side effects,
There is a need for diuretics that are highly safe and highly effective. In particular, in the case of severe edema, the tendency of water retention is enhanced, and conventional diuretic treatment may cause hyponatremia, so only water excretion is increased without changing sodium excretion, Highly safe diuretics are craving.

Therefore, as a result of intensive studies on compounds having such requirements, the present invention was completed by finding that the peptide compounds shown below achieve their intended purposes as diuretics. Therefore, an object of the present invention is to provide a novel edema-improving / therapeutic agent and a diuretic agent.

The compound of the present invention is a compound described in JP-A-61-115097, which has an analgesic effect. The present invention has been completed by finding out that it also has an action and reaches the intended purpose as a diuretic.

[Means for Solving the Problems]

The compound used in the present invention is N-methyl-L-
Tyrosyl glycyl glycyl-L-phenylalanyl-L-leucyl-L-alkynyl-N ² -methyl-L
-Alkynyl-N-ethyl-D-leucinamide or a pharmacologically acceptable salt thereof, which is a peptide represented by the following chemical structural formula (I), and the present invention is the peptide or its pharmacologically acceptable salt. It is an edema-improving / therapeutic agent and a diuretic agent containing the resulting salt as an active ingredient.

CH ₃ Tyr-Gly-Gly-Phe-Leu-Arg-CH ₃ Arg-D-Leu-NHC ₂ H ₅ (I)

The amino acids constituting the peptide generally have a D-form and an L-form, but in the present specification, the L-form is used unless otherwise indicated as the D-form. Regarding the notation of each amino acid, the abbreviations that are commonly used in peptide chemistry are used.

Tyr: Tyrosine Gly: Glycine Phe: Phenylalanine Leu: Leucine Arg: Arginine

In the present invention, the pharmacologically acceptable salt means, for example, an inorganic acid addition salt such as hydrochloride, sulfate, hydrobromide, hydroiodide or perchlorate, and shu. Examples thereof include addition salts of organic acids such as acid salts, maleates, fumarates, succinates and methanesulfonates. Among these, the most preferable salt is the trihydrochloride (II) shown below. CH ₃ Tyr-Gly-Gly-Phe-Leu-Arg-CH ₃ Arg-D-Leu-NHC ₂ H ₅・ 3HCl (II)

Next, as a typical example of the peptide compound used in the present invention, N-methyl-L-tyrosyl glycyl glycyl-L-phenylalanyl-L-leucyl-L-alkynyl-N ² -methyl-L- Alginyl-N-ethyl-D-leucinamide trihydrochloride
The physicochemical properties of (II) are described.

(Physicochemical properties) Molecular formula: C ₅₀ H ₈₁ N ₁₅ O ₉ · 3HCl Molecular weight: 1145.69 Structural formula: CH ₃ Tyr-Gly-Gly-Phe-Leu-Arg-CH ₃ Arg-D-Le
u-NHC ₂ H ₅・ 3HCl Properties: White powder

Next, the method described in Example 1 of the above publication will be mentioned as a reference example of the production examples of the compound of the present invention.

[Reference example] (Production example) N-methyl-L-tyrosyl glycyl glycyl-L-phenylalanyl-L-leucyl-L-alkynyl-
Synthesis of N ² -methyl-L-alkynyl-N-ethyl-D-leucinamide (I)

1) Synthesis of Boc-D-Leu-NHC ₂ H ₅ 25 g of Boc-D-Leu-OH.H ₂ O was dissolved in 200 ml of THF and -20
After cooling to ℃, add 11 ml of N-methylmorpholine and 9.56 ml of ethyl chlorocarbonate. After 5 minutes, add 12.9 g of 70% ethylamine aqueous solution and stir at about -5 ° C for 2 hours. After concentration, the residue is dissolved in ethyl acetate, washed successively with aqueous sodium hydrogen carbonate solution and water, and concentrated to dryness to yield Boc-D-Leu-NHC.
₂ H ₅ 24.5 g are obtained.

Melting point: 103-106 ° C. TLC: Rf value 0.77 (ethyl acetate) Optical rotation: [α] _D = + 20.0 ° (C = 1, methanol) Elemental analysis value: C as C ₁₃ H ₂₆ N ₂ O ₃ H N theoretical value (%) 60.44 10.14 10.84 Actual value (%) 60.42 10.33 10.86

2) Synthesis of Z-CH ₃ Arg (Tos) -D-Leu-NHC ₂ H ₅ The method of P. Quitt et al. [Helvetica Chimica Acta, 32,327 (19
63)] and synthesized Z-CH ₃ Ar from H-Arg (Tos) -OH.
1.43 g of g (Tos) -OH [[α] _D = -15 ° (C = 1, dimethylformamide)] is dissolved in 15 ml of tetrahydrofuran.
After cooling to -30 ° C, add 0.33 ml of N-methylmorpholine and 0.29 ml of ethyl chlorocarbonate. 5 minutes later, CF ₃ COOH HD-Le
_{u-NHC 2 H 5 (Boc} -D-Leu-NHC 2 H 5 the presence of anisole, CF ₃ C
A solution of 817 mg (synthesized by treatment with OOH) and 0.83 ml of triethylamine in tetrahydrofuran (7 ml) is added, and the mixture is stirred at about -5 ° C for 2 hours. After concentration, the residue is dissolved in ethyl acetate, washed successively with aqueous sodium hydrogen carbonate and water, and concentrated to dryness to form a glassy Z-CH ₃ Arg (Tos) -D-Leu-NHC ₂ H ₅ 1.
58g is obtained.

TLC: Rf value 0.68 (methanol: chloroform, 1: 7) Optical rotation: [α] _D = 0 ± 0.5 ° (C = 1, methanol) Elemental analysis value: C ₃₀ H ₄₄ N ₆ O ₆ S CHN theoretical value (%) 58.42 7.19 13.63 measured value (%) 58.29 7.19 13.40

3) Boc-Arg (Tos) -CH ₃ Arg (Tos) -D-Leu-NHC
₂ H ₅ Synthesis _{Z-CH 3 Arg (Tos)} -D-Leu-NHC 2 CH which H ₅ was obtained by Pd-C presence catalytic reduction _{3 Arg (Tos) -D-Leu} -NHC 2 H 5 1.1 g, Boc-Arg (Tos)
Dissolve 983 mg of -OH and 372 mg of N-hydroxybenzotriazole in 4 ml of dimethylformamide. 520 mg of dicyclohexylcarbodiimide was added under ice cooling and kept in the refrigerator for 1 day.
Then stir at room temperature for 1 day. The precipitate was filtered off and concentrated, and the residue was subjected to silica gel column chromatography (CH ₃ OH: CH chlorine ₃ =
Elute 1:15) to purify glassy Boc-A
1.2 g of rg (Tos) -CH ₃ Arg (Tos) -D-Leu-NHC ₂ H ₅ are obtained.

TLC: Rf value 0.64 (methanol: chloroform, 1: 7) Optical rotation: [α] _D = -20.6 ° (C = 1, methanol) Elemental analysis value: C ₄₀ H ₆₄ N ₁₀ O ₉ S ₂ · CH ₂ theoretical value (%) as H ₂ O 52.72 7.30 15.37 Measured value (%) 52.82 7.22 15.06

4) Boc-Leu-Arg (Tos) -CH ₃ Arg (Tos) -D-Leu
-NHC ₂ H ₅ Synthesis Boc-Leu-OH H ₂ O 1.645 g was added to dimethylformamide 12 m
Dissolve in l, cool to -20 ° C and then add N-methylmorpholine 0.7
Add 26 ml and 0.631 ml of ethyl chlorocarbonate. CF ₃ after 5 minutes
COOH ・ H-Arg (Tos) -CH ₃ Arg (Tos) -D-Leu-NHC ₂ H ₅ [Boc-A
rg (Tos) -CH ₃ Arg (Tos) -D-Leu-NHC ₂ H ₅ in the presence of anisole
Synthesized by treatment with CF ₃ COOH] 4.986 g and 0.726 ml of N-methylmorpholine in dimethylformamide (12 ml) are added, and the mixture is stirred at about -5 ° C for 2 hours. After concentration, the residue is dissolved in ethyl acetate and washed successively with aqueous sodium hydrogen carbonate and water. After concentration and solidification with methanol-ether, Boc-Leu-Arg (Tos) -CH ₃ Arg (Tos) -D-Leu-NHC ₂ H ₅ 5.28
3 g are obtained.

Melting point: 120-125 ° C. (decomposition) TLC: Rf value 0.66 (methanol: chloroform,
1: 7) Optical rotation: [α] _D = -25.8 ° (C = 1, methanol) Elemental analysis value: C ₄₆ H ₇₅ N ₁₁ O ₁₀ S ₂ · CH ₃ OH CHN theoretical value (%) 54.36 7.67 14.84 Actual value (%) 54.49 7.63 14.62

5) Boc-Phe-Leu-Arg (Tos) -CH ₃ Arg (Tos) -D
-Synthesis of Leu-NHC ₂ H ₅ 1.465 g of Boc-Phe-OH was dissolved in 12 ml of dimethylformamide, cooled to -30 ° C, and 0.608 ml of N-methylmorpholine and 0.528 ml of ethyl chlorocarbonate were added. 5 minutes later, CF ₃ COOH
H-Leu-Arg (Tos) -CH ₃ Arg (Tos) -D-Leu-NHC ₂ H ₅ [Boc-Leu
-Arg (Tos) -CH ₃ Arg (Tos) -D-Leu-NHC ₂ H ₅ treated with CF ₃ COOH in the presence of anisole] 4.691 g and N-methylmorpholine 0.608 ml dimethylformamide (12 ml )
Add the solution and stir at about -5 ° C for 2 hours. After concentration, the residue is dissolved in ethyl acetate and washed successively with aqueous sodium hydrogen carbonate and water. After concentration methanol - when solidified with ether Boc-Phe-Leu-Arg ( Tos) -CH 3 Arg (Tos) -D-Leu-NHC 2 H 5 5.
072 g are obtained.

Melting point: 127-132 ° C. (decomposition) TLC: Rf value 0.66 (methanol: chloroform,
1: 7) Optical rotation: [α] _D = -25.4 ° (C = 1, methanol) Elemental analysis value: C ₅₅ H ₈₄ N ₁₂ O ₁₁ S ₂・ CH ₃ OH CH N theoretical value (%) 56.74 7.48 14.18 Measured value (%) 56.64 7.33 13.86

6) Synthesis of Boc-CH ₃ Tyr (Cl ₂ Bzl) -Gly-Gly-OH BT Cheung et al. [Can. J. Chem., Vol. 55, 906 (1977)
] Boc-CH ₃ Tyr (chlorine ₂ Bzl) OH [[α]
_D = -49 ° C (C = 1, ethanol)] 9.09 g and N-hydroxysuccinimide 2.53 g are dissolved in tetrahydrofuran 150 ml. After cooling with ice, 4.12 g of dicyclohexylcarbodiimide
And stir overnight in the refrigerator. H-Gly-G after filtering white sediment
An aqueous solution of 2.91 g of ly-OH and 1.848 g of sodium hydrogen carbonate 3
Add 8 ml. After stirring for 2 days at room temperature, concentrate, add dilute aqueous citric acid solution and ethyl acetate, and separate the ethyl acetate layer. After washing with water and concentration, silica gel column chromatography (M
eOH: CH chlorine ₃ = 1:30 eluted) and purified with ether-n-
When solidified with hexane, Boc-CH ₃ Tyr (chlorine ₂ Bzl) -Gly-Gly-
9.23 g of OH are obtained.

Melting point: 70-80 ° C. (decomposition) TLC: Rf value 0.79 (methanol: acetic acid: chloroform, 4: 1: 12) Optical rotation: [α] _D = -47 ° (C = 1, methanol) Elemental analysis _{value: C 26 H 31 N 3 O} 7 Cl 2 · 1/2 C 2 H 5 OC 2 H 5 as C H N theoretical value (%) 55.54 5.99 6.94 Found (%) 55.45 5.81 6.89

7) Boc-CH ₃ Tyr (Cl ₂ Bzl) -Gly-Gly-Phe-Leu
-Arg (Tos) -CH ₃ Arg (Tos) -D-Leu-NHC ₂ H ₅ Synthesis Boc-CH ₃ Tyr (Cl ₂ Bzl) -Gly-Gly-OH 682 mg and N-hydroxybenzotriazole 195 mg in dimethylformamide 4 ml
Dissolve in dicyclohexylcarbodiimide under ice cooling 272
Add mg. After stirring for 2 hours CF ₃ COOH ・ H-Phe-Leu-Arg (T
os) -CH ₃ Arg (Tos) -D-Leu-NHC ₂ H ₅ [Boc-Phe-Leu-Arg (To
s) -CH ₃ Arg (Tos) -D-Leu-NHC ₂ H ₅ in the presence of anisole CF ₃ C
Synthesized by treatment with OOH] 1.167 g and 0.132 ml of N-methylmorpholine in dimethylformamide (8 ml) are added, and the mixture is stirred overnight in a refrigerator. The precipitate was filtered off, concentrated, and subjected to silica gel column chromatography (MeOH: CH ₃
= 1: 20)) and solidified with methanol-ether, Boc-CH ₃ Tyr (Cl ₂ Bzl) -Gly-Gly-Phe-Leu-Arg.
(Tos) -CH ₃ Arg (Tos) -D-Leu-NHC ₂ H ₅ 1.391 g is obtained.

Melting point: 130-135 ° C. (decomposition) TLC: Rf value 0.64 (methanol: chloroform,
1: 7) Optical rotation: [α] _D = -35.3 ° (C = 1, methanol) Elemental analysis value: C ₇₆ H ₁₀₅ N ₁₅ O ₁₅ S ₂ Chlorine ₂・ CH ₃ OH ・ H ₂ O CHN Theoretical value (%) 55.92 6.77 12.70 Actual value (%) 56.06 6.49 12.52

8) CH ₃ Tyr-Gly-Gly-Phe-Leu-Arg-CH ₃ Arg-
Synthesis of D-Leu-NHC ₂ H ₅ Boc-CH ₃ Tyr (Cl ₂ Bzl) -Gly-Gly-Phe-Leu-Arg (Tos) -CH ₃ Arg
220 mg of (Tos) -D-Leu-NHC ₂ H ₅ was added to 0.2 ml of anisole in a closed hydrogen fluoride (HF) reactor at -5 ° C to produce HF 10
Dissolve in ml and stir for 1 hour, then distill off HF from the reaction system.
The residue is washed with ether, dissolved in water, treated with Amberlite IRA-93 (acetic acid type) and freeze-dried. 120 mg of the freeze-dried crude peptide was analyzed by high performance liquid chromatography [Nucleosil ₅ C ₁₈ , 2 Ф × 25 cm, 0.1% HCl (H ₂ O-CH ₃ CN,
81:19)] and lyophilized to give CH ₃ Tyr-Gly.
-Gly-Phe-Leu-Arg- CH 3 Arg-D-Leu-NHC 2 H 5 70mg is obtained.

TLC: Rf value 0.70 (butanol: acetic acid: pyridine: water = 15: 5: 5: 8) Optical rotation: [α] _D = -21.8 ° (C = 0.4, 0.01N-HCl) mass spectrometry (FAB ): 1036 ([M + H] ⁺ ) Amino acid analysis: Gly 1.87 (2), Leu 1.96 (2), Phe 1.00
(1), Arg 0.95 (1) (CH ₃ Tyr and CH ₃ Arg peaks are not calculated)

Next, in order to show the effect of the present invention, a clinical test example will be given as an example.

【Example】

(Method) 6 healthy adult boys were blinded to 4 and 2
Divided into 2 groups, 4 of which are compounds of the present invention N-methyl-L-tyrosyl glycyl glycyl-L-phenylalanyl-L-leucyl-L-alkynyl-N ² -methyl-L-alkynyl-N
-Ethyl-D-leucinamide 3 hydrochloride injectable formulation, while two other healthy adult males received a placebo formulation with the same appearance at a scheduled (9:00) single intramuscular dose. A phase I test was performed. From the day before administration, keep the water intake constant,
Urine volume, urinary electrolyte concentration, and creatinine clearance of all subjects were measured at a fixed time period (9: 00-13: 00) the day before administration and at the same time period (9: 00-13: 00) on the administration day. Then, a significant difference test (paired t-test) was performed between the compound administration group of the present invention and the placebo administration group. N-methyl-L-tyrosyl glycyl glycyl-L-phenylalanyl-L-leucyl-L-alkynyl-N ² -methyl-L-alkynyl-N-ethyl-D-leucinamide 3 hydrochloric acid used in this test Injectable formulations containing salt are listed in Table-
It is shown in 3.

(Results) The results are shown in Table 1. The upper row in the table shows the results on the day before administration, and the lower row shows the results on the administration day.

[0039]

[Table 1]

From the above-mentioned table, the compounds of the present invention can be treated without changing the renal filtration amount and the excretion amount of electrolytes into urine.
It is clear that it has a water diuretic effect that promotes excretion of only water.

Next, the results of the acute toxicity test of the compound of the present invention will be shown.

[Acute toxicity test] 8-week-old Slc: SD rats and Slc: IC
A single-dose toxicity study by intramuscular, intravenous and oral administration was carried out using 5 male and 5 female R mice in each group. (Medium;
Saline) The LD ₅₀ values are summarized in the table below.

[0042]

[Table 2]

In many cases of death, the intramuscular and intravenous administrations occurred in both rats and mice within 2 days immediately after the administration, and in the oral administration in rats within 24 hours. These L
The D ₅₀ value is about 100 times higher than the clinical dose, and the safety is extremely high.

From the above experimental examples, the compound of the present invention has an excellent aquatic diuretic action, and is therefore useful as an agent for improving and treating edema. Specifically, unlike conventional diuretics, without causing hyponatremia / dehydration, hypokalemia / potassium deficiency, cardiac edema (congestive heart failure), renal edema, hepatic edema, pregnancy It can be administered for a long period of time as a highly safe diuretic agent capable of improving and treating various edemas such as toxicosis / pregnancy edema and edema due to peripheral vascular disease.

The administration route and dose for administering the compound of the present invention to a patient as a diuretic vary greatly depending on the patient's symptoms, the type / degree of edema, age, heart / liver / renal function, etc., but are not particularly limited. , Usually in adults, 0.01 to 100 per day
mg, preferably 0.1 to 20 mg, more preferably 0.5
~ 10 mg, more preferably 1-5 mg, is administered intramuscularly, orally, rectally, or intranasally.

The dosage form includes, for example, powders, fine granules,
Granules, tablets, capsules, suppositories, injections and the like can be mentioned. When formulating, a usual pharmaceutical carrier is used and it is manufactured by a conventional method. That is, when preparing a solid preparation for oral use, an excipient, and if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc. are added to the main drug, and then a tablet is prepared by a conventional method, Coated tablets, granules, powders, capsules, etc. As the excipient, for example, lactose, corn starch,
Sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, etc., as the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin,
Shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc., as disintegrants, for example, starch, agar, powdered gelatin, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, etc. Examples of the agent include magnesium stearate, talc,
Polyethylene glycol, silica, hydrogenated vegetable oil, etc. are permitted to be added to pharmaceuticals as colorants, but as flavoring agents, cocoa powder, peppermint brain, aromatic acids, peppermint oil, dragon brain, cinnamon powder, etc. Is used. Of course, these tablets and granules may be sugar-coated, gelatin-coated, or any other suitable coating, if necessary. When preparing an injectable preparation, a pH adjusting agent, a buffering agent, a stabilizing agent, a solubilizing agent and the like are added to the main drug as necessary, and an intravenous injection is prepared by a conventional method. Next, the compound of the present invention, N-methyl-L
-Tyrosyl glycyl glycyl-L-phenylalanyl-L-leucyl-L-alkenyl-N ² -methyl-
Formulation examples of injections, oral preparations, and nasal drops containing L-alkynyl-N-ethyl-D-leucinamide trihydrochloride (main drug) as an active ingredient are shown below. Each formulation is prepared by a conventional method according to the following formulation examples, but it goes without saying that the formulation examples of the present invention are not limited thereto. (Injection)

[0047]

[Table 3]

(Oral agent)

[0049]

[Table 4]

(Suppository)

[0051]

[Table 5]

(Nasal drops)

[0053]

[Table 6]

Claims (4)

[Claims] 1. N-methyl-L-tyrosyl glycyl glycyl-L-phenylalanyl-L-leucyl-L-alkynyl-N ² -methyl-L-alkynyl-N-ethyl-D-leucinamide or pharmacology. Edema-improving / therapeutic agent containing a pharmaceutically acceptable salt as an active ingredient 2. N-Methyl-L-tyrosyl glycyl glycyl-L-phenylalanyl-L-leucyl-L-alkynyl-N ² -methyl-L-alkynyl-N-ethyl-D-leucinamide 3 hydrochloride An edema-improving / therapeutic agent according to claim 1, which comprises: 3. N-Methyl-L-tyrosyl glycyl glycyl-L-phenylalanyl-L-leucyl-L-alkynyl-N ² -methyl-L-alkynyl-N-ethyl-D-leucinamide or pharmacology. Diuretic with a pharmaceutically acceptable salt as the active ingredient 4. N-methyl-L-tyrosyl glycyl glycyl-L-phenylalanyl-L-leucyl-L-alkynyl-N ² -methyl-L-alkynyl-N-ethyl-D-leucinamide 3 hydrochloride The diuretic according to claim 3, wherein the active ingredient is