WO1999005146A1 - Hyponatremia remedies - Google Patents

Abstract

Hyponatremia remedies containing as the active ingredient opioid λ receptor agonists represented by general formula (I) or the like; and a method of treatment therewith. The agonists exhibit both the property as a hydragogue diuretic of specifically excreting water and the effect of keeping blood sodium level, which is not linked up with the diuretic action, and cause only negligible adverse effects, thus being ideal hyponatremia remedies useful for the drug therapy of hyponatremia.

Description

 Description Low Nat '] Pememia Treatment Technical Field

 TECHNICAL FIELD The present invention relates to a drug useful for treating hyponatremia and a method of treatment using the same. Background art

 In normal individuals, the blood sodium concentration is adjusted to a relatively narrow range of 135-145 mE QZL. In general, when the blood sodium concentration falls below 135 mEqZL, the potential clinical problem of hyponatremia is often 130 mE QZL or less. Clinical symptoms such as general malaise, weakness, headache, anorexia, nausea, vomiting, impaired consciousness, and convulsions are seen. In acute onset, 125 mEqZL can cause severe symptoms, but in chronic cases, 115 mE QZL can be asymptomatic (Toyama Prefectural Central Hospital Medical Journal 17: 1-5, 1994).

 Hyponatremia is roughly classified into three types according to changes in extracellular fluid volume. (1) Extracellular fluid volume represented by renal sodium loss (diuretic administration, Addison's disease, sodium loss nephritis, etc.) and extrarenal sodium loss (severe burns, loss from the digestive tract, etc.) If decreased, (2) acute water poisoning, antidiuretic hormone secretion syndrome (SI ADH), polydipsia, myxedema, dalcocorticoid deficiency (pituitary dysfunction), drug that enhances antidiuretic hormone secretion or action (3) When extracellular fluid volume including acute renal failure, chronic renal failure, heart failure, cirrhosis, and nephrotic syndrome increases, You.

 Depending on the condition, the treatment of hyponatremia is mainly supplementation with isotonic sodium and water restriction. In severe cases, 3% hypertonic saline may be used. In addition, a loop diuretic may be used in combination.

In any case, sudden correction of blood sodium concentration and onset of hypotension rheumatism Care needed to be taken (Toyama Prefectural Central Hospital Medical Journal 17: 1-5, 1994, Kidney and Dialysis Extra Issue: 29-31, 352-354, 1996). In addition, loop diuretics have the effect of simultaneously promoting sodium and water excretion, and thus inherently have the potential to cause electrolyte problems.

 In other words, a safer and more effective drug for the treatment of hyponatriumemia has been desired.

On the other hand, it has been known that some agonists having affinity for opioid κ receptor have an effect of reducing sodium excretion in urine (C 1 in. Pharmsiol. 22: 891-902, 1995). For example, U50, 488H has been reported to exhibit an anti-sodium excretion effect in rats (Ashtonn. N. eta 1. Br. J. Pharmacoco 1.99: 18 1— 185, 199 0). However, this compound has an affinity not only for the / ί receptor but also for the σ receptor, and has not been put to practical use because of the mental action expressed via this receptor.

 The objectives of the present invention are to achieve renal sodium loss (administration of diuretics, Addison's disease, sodium-losing nephritis, etc.) and extrarenal sodium loss (severe burns, loss from the digestive tract, etc.), acute water poisoning, Antidiuretic hormone secretion syndrome (SI ADH), polydipsia, myxedema, dalcocorticoid deficiency (pituitary dysfunction), antidiuretic hormone secretion or pathology associated with drugs that enhance the action, acute renal failure, chronic renal failure, An object of the present invention is to provide a safe hyponatremia drug and a method for treating hyponatremia associated with diseases such as heart failure, cirrhosis, and nephrotic syndrome. Disclosure of the invention

 The present inventors have conducted intensive studies to solve the above-described problems, and as a result, have found that a morphinan derivative represented by the general formula (I) and having a / c receptor agonist action has a property of a diuretic that specifically excretes water. The present inventors have found that they have a blood sodium storage effect that is not linked to a diuretic effect, and have completed the present invention.

That is, the present invention provides a compound represented by the general formula (I):

 (I)

[Wherein, 2 represents a double bond or a single bond, R ¹ is alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkenylalkyl having 5 to 7 carbons, 6 carbons Represents aralkyl with 7 to 13 carbon atoms, aralkyl with 7 to 13 carbon atoms, alkenyl with 4 to 7 carbon atoms, aryl, furan-12-alkyl with 1 to 5 carbon atoms, or thiophen-2-ylalkyl with 1 to 5 carbon atoms. , R ² is hydrogen, hydrate port alkoxy, nitro, alkanoyloxy Noi Ruo alkoxy having 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, alkyl of 1 to 5 carbon atoms, one NR9R ^1. R ⁹ represents hydrogen, alkyl having 1 to 5 carbons, R ¹⁰ represents hydrogen, alkyl having 1 to 5 carbons, one C (= 〇) R ¹¹ , and R ¹¹ represents hydrogen, phenyl, carbon R ³ represents hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms, and A represents one XC (= Y)-, one XC (= Υ) Ζ— — X— or one XS〇 ₂ — (where X, Υ, and Ζ each independently represent NR ⁴ , S, or 、, where R ⁴ is hydrogen, and has 1 to 5 carbon atoms. Represents a straight-chain or branched alkyl, or aryl having 6 to 12 carbon atoms, wherein R ⁴ may be the same or different), and B represents a valence bond, a straight-chain or branched alkylene having 1 to 14 carbon atoms. (However, alkoxy having 1 to 5 carbons, alkanoyloxy having 1 to 5 carbons, hydroxy, fluorine, chlorine, bromine, It may be substituted with at least one or more substituents selected from the group consisting of iodine, amino, nitro, cyano, trifluoromethyl and phenoxy, and one to three methylene groups are replaced by carbonyl groups. ), A straight-chain or branched non-cyclic unsaturated hydrocarbon having 2 to 14 carbon atoms and containing 1 to 3 double bonds and Z or triple bonds (however, alkoxy having 1 to 5 carbon atoms, 1 carbon atom) Or 5 is substituted with at least one substituent selected from the group consisting of alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl and phenoxy. Or 1 to 3 methylene groups may be replaced by carbonyl groups), or a straight chain of 1 to 14 carbon atoms containing 1 to 5 thioether, ether and / or amino bonds. Or a branched saturated or unsaturated hydrocarbon (note that a hetero atom is not directly bonded to A, and that 1 to 3 methylene groups may be replaced by carbonyl groups), and R ⁵ is Hydrogen or the following basic skeleton:

An organic group having an organic group represented by R ⁵ (however, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoyloxy having 1 to 5 carbons, hydroxy, fluorine, chlorine, bromine, iodine, Amino, nitro, Shiano, isothiocyanato, triflumizole Ruo Russia methyl, triflumizole Ruorometokishi represents may also be) optionally substituted by at least one or more substituents selected from the group consisting of Mechirenjiokishi, R ^e is hydrogen, R ⁷ is hydrogen , Hydroxy, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, or R 6 and R ⁷ together form one O—, one CH ₂ —, one S— And R ⁸ represents hydrogen, alkyl having 1 to 5 carbons, or alkanol having 1 to 5 carbons. Ma The general formula (I) includes (+)-, (1-)-, and (sat) -forms), or a pharmacologically acceptable acid addition salt thereof. Hyponatremia as an active ingredient and a drug containing the above-mentioned opioid / c receptor agonist compound or a pharmacologically acceptable acid addition salt as an active ingredient for hyponatrememic patients BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to a method for treating hyponatremia characterized by administering

The compound represented by the general formula (I) is a compound that exhibits selectivity for the opioid κ receptor and does not exhibit drug dependence and aversion. The / c receptor agonist shown in the general formula (I) is defined as a K e value ([antagonist] Z (1) using GPI or MVD (evaluation of contraction inhibition of electrical stimulation of guinea pig ileum or mouse vas deferens) _5. Compounds with Ke ()> Ke (κ) and Ke (δ)> Ke (κ) when the ratio — 1)) is determined, ie, κ receptors rather than ά receptors Represents compounds that are selective for the body.

Among the compounds represented by the general formula (I) of the present κ receptor agonist, R ¹ is alkyl having 1 to 5 carbons, cycloalkylmethyl having 4 to 7 carbons, cycloalkenylmethyl having 5 to 7 carbons Phenylalkyl having 7 to 13 carbon atoms, alkenyl and aryl having 4 to 7 carbon atoms, furan-2-ylalkyl having 1 to 5 carbon atoms, and thiophene1-2-ylalkyl having 1 to 5 carbon atoms are preferred. Particularly, methyl, ethyl, propyl, butyl, isoptyl, cyclopropylmethyl, aryl, benzyl, phenethyl, furan-2-methyl, and thiophen-2-methyl are preferred.

R ² is preferably hydrogen, hydroxy, nitro, acetoxy, methoxy, methyl, ethyl, propyl, amino, dimethylamino, acetylamino, benzoylamino, particularly preferably hydrogen, hydroxy, nitro, acetoxy, methoxy, dimethylamino.

R ³ is preferably hydrogen, hydroxy, acetoxy or methoxy, and particularly preferably hydroxy, acetoxy or methoxy.

As A, one NR ⁴ C (= 0)-,-NR ⁴ C (= S)-,-NR ^ C (= 0) O-,-NR ⁴ C (= 0) NR ⁴ -,-NR C (= S) NR —, — NR C (= 0 ) S—, — OC (= 0) One, One OC (= 0) O—, — SC (= 0) —, — R ^ —, One O—, One NR4S O2—, One OS Os— one particularly NR4C (= 〇) - one ^{NR 4 C (= S) -} , - RC (= 0) O-, - R 4 C (= 0) NR 4 -, - NR 4 C (= S) NR 4 —, NR ⁴ S〇 ₂ — is preferred.

R ⁴ is preferably hydrogen, straight-chain or branched alkyl having 1 to 5 carbon atoms, and particularly preferably straight-chain or branched alkyl having 1 to 5 carbon atoms, particularly, methyl, ethyl, propyl, butyl, and isobutyl.

As B, one (CH ₂ ) n— (n = 0 to 10), — (CH ₂ ) _n — C (= 0) one (n = l to 4), — CH = CH— (CH ₂ ) n— (n = 0 to 4), one C≡C one (CH ₂ ) n— (n = 0 to 4), one CH ₂ — O—, one CH ₂ — S—, one (CH ₂ ) “0 — CH ₂ —, — CH = CH— CH = CH— (CH ₂ ) _n — (n = 0 to 4), especially 1 (CH ₂ ) π — (n = 1 to 3), — CH = CH — (CH ₂ ) _n — (n = 0-4), —C≡C— (CH ₂ ) n— (n = 0-4), one CH ₂ —one, one CH ₂ —S— is preferred.

R ^s is hydrogen or the following basic skeleton: S, S, O

An organic group having an organic group represented by R ⁵ (however, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoyloxy having 1 to 5 carbons, hydroxy, fluorine, chlorine, bromine, iodine, Amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy, and may be substituted with at least one substituent selected from the group consisting of hydrogen, phenyl, and 4-methyl. Tylphenyl, 3-methylphenyl, 2-methylphenyl, 3,4-dimethylphenyl Phenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 4-hydroxyphenyl, -3-hydroxyphenyl, 3,4 —Dihydroxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 3,4-difluorophenyl, perfluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl , 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4-bromophenyl 2-Trophenyl, 3-Nitrophenyl, 2-Nitrophenyl, 4-Aminophenyl, 3-Aminophenyl, 2-Aminophenyl, 4-Trif O-methylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 3, 4-Methylenedioxyphenyl, 3-furel, 2-furanyl, 3-thenyl, 2-thenyl, cyclopentyl, and cyclohexyl are preferred, but of course are not limited thereto. These kappa receptor agonists represented by the general formula (I) can be produced, for example, according to the method described in Japanese Patent No. 25255552.

 The pharmacologically preferable acid addition salts for the κ receptor agonist include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate, acetate, and the like. Lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate, etc. Organic sulfonates such as sulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate and the like, among which hydrochloride, hydrobromide, phosphate, Tartrate, maleate, methanesulfonate and the like are preferred, but of course are not limited thereto. The above-mentioned κ receptor agonist and its pharmacologically acceptable acid addition salt have the property of a water diuretic which specifically excretes water, and have a blood sodium retention action which is not linked to a diuretic action. It is useful as a drug for treating hyponatremia.

These A / C receptor agonists have been purified for pharmaceutical use and After passing, it can be administered orally or parenterally as it is or as a pharmaceutical composition mixed with known pharmacologically acceptable acids, carriers, excipients and the like. Examples of the dosage form include injections, tablets, capsules, granules, powders, syrups, suppositories and the like. The amount to be used is appropriately selected according to the symptoms, age, body weight, administration method, etc., but for an adult, the amount of the active ingredient is 0.001 mg to 1 g per day in the case of an injection. In the case of an oral preparation, the dose is 0.005 mg to 10 g, which can be administered once or in several divided doses.

 The above pharmaceutical compositions may be used for renal sodium loss (administration of diuretics, Addison's disease, sodium loss nephritis, etc.) and extrarenal sodium loss (severe burns, loss from the digestive tract, etc.), acute water poisoning, Antidiuretic hormone secretion syndrome (SIADH), polydipsia, myxedema, darcocorticoid deficiency (pituitary dysfunction), conditions associated with antidiuretic hormone secretion or administration of drugs that enhance its effects, acute renal failure, chronic renal failure It can be used for the treatment of hyponatremia associated with diseases such as heart failure, cirrhosis, and nephrotic syndrome. It can also be used in combination with other diuretics, such as loop diuretics and thiazide diuretics, for the treatment of hyponatremia.

【Example】

 Hereinafter, the present invention will be described more specifically based on examples. However, the following examples are described only for illustrative purposes, and are not limited to these in any case.

 [Example 1]

A Wistar male rat (Japanese SLC) was used at about 11 weeks of age. One hour before drug administration, the rats were removed from the water supply and water was removed. The drug or solvent was administered via the tail vein, and at the same time, 20 ml / kg body weight saline for injection was orally administered using an oral probe. (I) 17-cyclopropylmethyl-3,144-dihydroxy-4,5 α-epoxy-16 / 3- [N-methyl-1-trans-3- (3-furyl) acrylamide] morphinan hydrochloride Salt (hereinafter abbreviated as Compound 1)

Was used by dissolving it in a 5% (w / v) mannitol solution. Immediately after administration, animals were housed in metabolic cages (one cage per animal). During the experiment, animals were not given water or food.

 Five hours after drug administration, the amount of accumulated urine and urine osmolality were measured. For animals, serum was collected from the blood collected from the jugular vein under light ether anesthesia, and the serum sodium concentration and serum osmotic pressure were measured. Electrolyte concentration and osmotic pressure were measured using STAX-1 (Techno Medic Co., Ltd.) and Advanced Osmometer 3D3 (Advanced Instrumentts, Inc.), respectively. Free water clearance, one of the indicators of water excretion in urine, was calculated by the following formula.

Free water clearance-(1 urine osmotic pressure / serum osmotic pressure) X excreted urine volume rate

The results are shown in Tables 1 and 2.

Compound 丄 increases serum sodium concentration and serum osmotic pressure

Significant at 1% risk compared to 0 rag / kg group (Dunne's test) CT / JP98 / 00800 Table 2

 Compound 1 increases urine output and increases free water clearance

 * Significant at a 5% risk rate compared to the 0 mg / kg group (Dunne U's test)

 ** Significant at 1% risk compared to the 0 mg / kg dose group (Dunnet's s test) Dose-dependent increase in serum sodium concentration was observed by intravenous administration of Compound II. Increased serum osmotic pressure was observed. A dose-dependent increase in urine excretion was observed. The change in the free water clearance from a negative value to a positive value in a dose-dependent manner indicates that the compound-induced increase in urine output has a diuretic effect.

 [Example 2]

 A Wistar male rat (Japan SLC) was used at about 11 weeks of age. Hypophysectomy and sham surgery were outsourced to Japan SLC. The pituitary gland was removed by an external auditory canal method (using a hypophysectomy needle) under pentobarbital anesthesia using a 9-week-old male Wistar rat for surgery. One hour before drug administration, the rats were disconnected from the water supply and drained. The drug or solvent was administered via the tail vein, and at the same time, physiological saline for injection having a weight of 2 Om 1 Zkg was orally administered using an oral probe. Compound I was used after being dissolved in a 5% (w / v) mannitol solution. Animals were housed in metabolic cages immediately after administration (one cage per animal). No water or food was given to the animals during the experiment.

Five hours after drug administration, the amount of accumulated urine was measured. In addition, serum sodium concentration and serum osmotic pressure were measured 5 hours after drug administration under light ether anesthesia by sampling serum from blood collected from intravenous veins. Electrolyte concentration and osmotic pressure were measured using STAX-1 (Techno Medic Co., Ltd.) and Advanced Osmometer 3D3 (Advanced Intensuments, Inc.), respectively. Table 3 shows the results Show. Table 3

 -Compound II increases serum sodium levels in hypophysectomized animals

 * * Significant at 1% risk compared to 0 mg / kg group (Dunne's test)

Intravenous administration of Compound I also showed a dose-dependent increase in serum sodium concentration in hypophysectomized animals. On the other hand, no significant increase in urine volume was observed. From the above results, it was clarified that Compound I had an effect of increasing serum sodium concentration, which was separate from the diuretic effect.

 [Example 3]

Fluctuations in serum sodium concentration due to repeated intramuscular administration of the compound were examined in healthy adult males aged 20 to 45 years. Compound 丄 was dissolved in 5% mannitol and administered at a dose of 10 g Z 60 Kg, adjusted to a volume of 1 ml per 60 kg body weight. The administration timing is 9:00 on the first day (when fasting in the morning), 9:00 on the second to fourth days (when fasting on the morning) and 19:00:00 (before dinner), and 9:00 on the fifth day. 0 (morning fasting). Blood was collected 24 hours before, before administration on the first day, and before morning administration from the next day, and the sodium concentration in the serum was measured. Table 4 shows the results.

Table 4

 Elevating effect of serum sodium concentration on compounds in humans

 The test was conducted between the placebo group and the Compound II group at each time.

 A non paired t test was performed. *, **, *** are each 5%,

 1%, 0.1 Significance is shown at a risk rate of less than 1%. From 24 hours after the initial administration to 24 hours after the end of the administration, a significant increase in serum sodium concentration was observed as compared with the placebo group. In this test, the increase in urine volume after administration of Compound II from day 2 onward was not clear compared to placebo, but an increase in serum sodium concentration was observed. Industrial applicability

 The medicament of the present invention is characterized by containing a morphinan derivative represented by the general formula (I) having an opioid / c receptor agonist activity as an active ingredient, and is useful for pharmacotherapy of hyponatremia.

Claims

Claims i. —- General formula (I)

 (D [Wherein, 2 represents a double bond or a single bond, R ¹ is alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkenylalkyl having 5 to 7 carbons, 6 carbons Aralkyl with 7 to 13 carbon atoms, aralkyl with 7 to 13 carbon atoms, alkenyl and aryl with 4 to 7 carbon atoms, furanyl peralkyl with 1 to 5 carbon atoms, or thioalkyl with 1 to 5 carbon atoms. R ² represents hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms or NR9R ¹ . The stands, R ⁹ represents an alkyl of 5 hydrogen or carbon number 1, R ^1. Represents hydrogen, alkyl having 1 to 5 carbons or — C (== 〇) R ¹¹ , Ri ¹ represents hydrogen, phenyl or alkyl having 1 to 5 carbons, and R ³ represents hydrogen, hydroxy, carbon number Represents an alkanoyloxy having 1 to 5 or an alkoxy having 1 to 5 carbon atoms, wherein A is one XC (= Y) —, — XC (= Υ) Ζ—, one X— or one XS〇 ₂ — (where X, Y, and 各 々 each independently represent NR ⁴ , S, or 0; R ⁴ represents hydrogen, linear or branched alkyl having 1 to 5 carbons, or aryl having 6 to 12 carbons; ⁴ represents the same or different, and B represents a valence bond, a linear or branched alkylene having 1 to 14 carbon atoms (however, an alkoxy having 1 to 5 carbons, an alkanoyl having 1 to 5 carbons) Xy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoro It may be replaced by at least one substituent selected from the group consisting of methyl and phenoxy, and one to three methylene groups are replaced by carbonyl groups. ), A straight-chain or branched non-cyclic unsaturated hydrocarbon having 2 to 14 carbon atoms containing 1 to 3 double bonds and / or triple bonds (however, an alkoxy having 1 to 5 carbon atoms, and having 1 carbon atom) To alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl and phenoxy, and is substituted by at least one substituent selected from the group consisting of Or 1 to 3 methylene groups may be replaced by a carbonyl group), or a straight chain of 1 to 14 carbon atoms containing 1 to 5 carbon atoms, ether bonds and amino or amino bonds. Or a branched saturated or unsaturated hydrocarbon (however, a heteroatom is not directly bonded to A, and may have 1 to 3 methylene groups replaced by carbonyl groups) R ⁵ is hydrogen or the following basic skeleton:

Organic group represented by R ⁵ Organic group having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, triflumizole Ruo Russia methyl, triflumizole Ruorometokishi and may be substituted by at least one or more substituents selected from the group consisting of Mechirenjiokishi) represents, R ^e is hydrogen, R ⁷ is hydrogen, heat Represents droxy, alkoxy having 1 to 5 carbons or alkanoyloxy having 1 to 5 carbons, or R ⁶ and R ^{7 taken} together represent 1-, 1-CH'- or 1-S-; ⁸ represents hydrogen, alkyl having 1 to 5 carbons or alkanol having 1 to 5 carbons. In addition, the general formula (I) includes (+)-, (-)-, and (sat) -forms), or a pharmacologically acceptable acid addition salt thereof. A therapeutic agent for hyponatremia as an active ingredient. 2. R ¹ is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, aryl, benzyl or phenethyl, R ² and R ³ are each independently hydrogen, hydroxy, acetyl or methoxy; gar XC (= Y) - (in here, X represents a NR ^4, S or O, Y represents 〇, R ⁴ represents an alkyl having 1 to 5 hydrogen or carbon) or single XC (= Y) Z-, one X- or single XS0 ₂ i (where X represents NR ^4, Y represents S or O, Z represents NR ⁴ or 〇 R ⁴ represents hydrogen or alkyl having 1 to 5 carbons), B is linear alkylene having 1 to 3 carbons, R ⁶ and R ⁷ are taken together to form 1 O—, R 2. The therapeutic agent for hyponatremia according to claim 1, wherein ⁸ is hydrogen. 3. A is one XC (= Y) — or one XC (= Y) Ζ— (where X represents NR ⁴ , Y represents 〇, Z represents 、, and R ⁴ represents 1 carbon atoms. 3. The therapeutic drug for hyponatremia according to claim 2, wherein the alkyl represents 5 alkyl. 4. R ¹ is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, aryl, benzyl or phenethyl, R ² and R ³ are each independently hydrogen, hydroxy, acetyl or methoxy; X X (= Y)-(where X represents NR ⁴ , S or O, Y represents 、, R ⁴ represents hydrogen or alkyl having 1 to 5 carbon atoms) or one XC (= Y) Ζ—, one X— or one X SO 2— (where X represents NR ⁴ , Y represents S or 〇, Z represents NR ⁴ or 0, R ⁴ represents hydrogen or C 1 B represents linear alkylene having 1 to 3 carbon atoms, and R ⁵ represents hydrogen or the following basic skeleton: Q: O, S

An organic group having an organic group represented by R ⁵ (however, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoyloxy having 1 to 5 carbons, hydroxy, fluorine, chlorine, bromine, iodine, Amino, nitro, Shiano, isothiocyanato, triflumizole Ruo Russia methyl, optionally substituted by at least one or more substituents selected from the group consisting of triflumizole Ruorometokishi and Mechirenjiokishi is also be), the R ⁶ and R ⁷ gar緖2. The therapeutic agent for hyponatremia according to claim 1, wherein R ⁸ is hydrogen. 5. A is one XC (= Y) — or one XC (= Υ) Ζ— (where X represents NR ⁴ , Υ represents 、, Ζ represents 、, and R ⁴ represents 1 carbon atoms. 5. The therapeutic agent for hyponatremia according to claim 4, which represents alkyl of 5). 6. R ¹ is methyl, ethyl, propyl, butyl, isobutyl, cyclopropyltyl, aryl, benzyl or phenethyl; R ² and R ³ are each independently hydrogen, hydroxy, acetoxy or methoxy; but one XC (= Y) - in (here, X represents a NR ^4, Upsilon represents 〇, R ⁴ represents an alkyl having 1 to 5 carbon atoms ), Β is one CH = CH—, one Cmi C—, one CH ₂ 〇one or one CH ₂ S—, R ^e and R ⁷ together are one O—, R ⁸ 2. The remedy for hyponatremia according to claim 1, wherein is hydrogen. 7. R ¹ is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, aryl, benzyl or phenethyl; R ² and R ³ are each independently hydrogen, hydroxy, acetoxy or methoxy; Is XC (= Y)-(where X represents NR ", 表 し represents 、, and represents alkyl having 1 to 5 carbon atoms. ) Where Β is one CH = CH—, — C≡C—. — CH2〇 one or one CH ₂ S— R ⁵ is hydrogen or the following basic skeleton: Q,  Q: O, S

Organic group represented by R ⁵ Organic group having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, (It may be substituted by at least one substituent selected from the group consisting of isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy), and R ⁶ and R ⁷ together form 1 O— 2. The method of claim 1, wherein R ⁸ is hydrogen. 8. The therapeutic agent for hyposodiumemia according to claim 6, wherein B is -CH = CH- or 1C≡C-. 9. The therapeutic agent for hyponatremia according to any one of claims 1 to 8, which has an action of specifically excreting water. 10. The therapeutic agent for hyponatremia according to any one of claims 1 to 8, which has a blood sodium retention activity. 1 1. Hyponatremia, renal sodium loss, extrarenal sodium loss, acute water poisoning, antidiuretic hormone secretion syndrome (SIADH), polydipsia, myxedema, glucocorticoid deficiency (pituitary dysfunction) The method according to any one of claims 1 to 10, wherein the disease is associated with administration of a drug that enhances antidiuretic hormone secretion or action, acute renal failure, chronic renal failure, heart failure, cirrhosis, or nephrotic syndrome. Drug for the treatment of hyponatremia. 12. —General formula (I)

 (D [Wherein, 2 represents a double bond or a single bond, R ¹ is alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkenylalkyl having 5 to 7 carbons, 6 carbons From 12 to aralkyl, 7 to 13 carbon atoms, aralkyl with 4 to 7 carbon atoms, aryl, 1 to 5 carbon atoms of furan-12-alkyl, or 1 to 5 carbon atoms of thiophene1-2- ^ alkyl R ² is hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms or one NR9R ¹ . R ⁹ represents hydrogen or alkyl having 1 to 5 carbons, R ¹⁰ represents hydrogen, alkyl having 1 to 5 carbons or 1 C (= 0) R ¹¹ , and R ¹¹ represents hydrogen, phenyl or carbon R ³ represents hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms or alkoxy having 1 to 5 carbon atoms, A represents one XC (= Y)-, one XC (= Υ) Ζ -, one X- or a XS0 ₂ - (wherein ^{X, Y, Ζ NR 4,} S or each independently is represents 0, R ⁴ is hydrogen, a carbon number of 1 to 5 Represents a straight-chain or branched alkyl or aryl having 6 to 12 carbon atoms, wherein R ⁴ may be the same or different), and B represents a valence bond, a straight-chain or branched chain having 1 to 14 carbon atoms. Alkylene (however, alkoxy having 1 to 5 carbons, alkanoyloxy having 1 to 5 carbons, hydroxy, fluorine, chlorine, It may be replaced by at least one substituent selected from the group consisting of bromine, iodine, amino, nitro, cyano, trifluoromethyl, and phenoxy, and one to three methylene groups are carbonyl groups. May be substituted), straight-chain or branched non-cyclic unsaturated hydrocarbon having 2 to 14 carbon atoms containing 1 to 3 double bonds and 1 or 3 triple bonds (however, alkoxy having 1 to 5 carbon atoms) At least one substitution selected from the group consisting of alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl and phenoxy Or 1 to 3 methylene groups may be replaced by carbonyl groups), or 1 to 5 carbon atoms containing 1 to 5 thioether, ether and / or amino bonds. From 1 to 14 linear or branched saturated or unsaturated hydrocarbons (however, heteroatoms are not directly bonded to A, and 1 to 3 methylene groups may be replaced by carbonyl groups) In the table, R ⁵ is hydrogen or the following basic skeleton:

Organic group represented by R ⁵ Organic group having 1 to 5 carbon atoms (alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, May be substituted by at least one substituent selected from the group consisting of cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy), R ^e is hydrogen, R ⁷ is hydrogen, hydroxy, Alkoxy having 1 to 5 carbons or alkanoyl having 1 to 5 carbons Represents oxy, or R 6 together represents 1 O—, 1 CH ₂ — or 1 S—, and R ⁸ is hydrogen, alkyl having 1 to 5 carbons, or alkanoic having 1 to 5 carbons. Represents In addition, the general formula (I) includes (+)-, (-)-, and (sat) -forms] of an obioid / <receptor agonist compound or a pharmacologically acceptable acid addition salt thereof. A method for treating hyponatremia, comprising administering an effective amount. 1 3. R ¹ is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, aryl, benzyl or phenethyl, R ² and R ³ are each independently hydrogen, hydroxy, acetoxy or methoxy; A XC (= Y)-(where X represents NR ⁴ , S or 、, Y represents O, R ⁴ represents hydrogen or alkyl having 1 to 5 carbon atoms) or one XC (= Y ) Ζ—, one X— or one XS 〇 ₂ — (where X represents NR ⁴ , Υ represents S or 、, Ζ represents NR ⁴ or 〇, and R ⁴ represents hydrogen or C 1 13. represents an alkyl of 5), Β is a straight-chain alkylene having 1 to 3 carbon atoms, R ⁶ and R ⁷ are combined to be 1 and R ⁸ is hydrogen. To treat hyponatremia. 14. Α is one XC (= Y) —or one XC (= Y) Ζ— (where X represents NR ⁴ , Y represents O, Z represents 〇, and R ⁴ has 1 carbon atom. 14. The method for treating hyponatremia according to claim 13, which represents alkyl of 1 to 5). 1 5. R ¹ is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, aryl, benzyl or phenethyl, R ² and R ³ are each independently hydrogen, hydroxy, acetoxy or methoxy; A Where X represents NR ⁴ , S or 、, Y represents 、, R ⁴ represents hydrogen or alkyl having 1 to 5 carbon atoms, or XC (=- Y) Ζ—, one X— or one XS 〇 ₂ — (where X represents NR ⁴ , Y represents S or O, Z represents NR ⁴ or 、, and R ⁴ represents hydrogen or carbon 1 B represents a straight-chain alkylene having 1 to 3 carbon atoms, and R ⁵ represents hydrogen or the following basic skeleton: , Q,  Q: O, S

An organic group having an organic group represented by R ⁵ (however, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoloxy having 1 to 5 carbons, hydroxy, fluorine, chlorine, bromine, iodine , Amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy, which may be substituted with at least one substituent selected from the group consisting of R ⁸ and R ⁷ together a connexion one O-, and a method of treating low Natoriumu hyperlipidemia of claim 12, wherein R ⁸ is hydrogen. 16. A is one XC (= Y) — or one XC (= Υ) Ζ — (where X represents NR ⁴ , Υ represents 、, Ζ represents 、, and R ⁴ has 1 carbon atom. 16. The method for treating hyponatremia according to claim 15, wherein 17. R ¹ is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, aryl, benzyl or phenethyl, R ² and R ³ are each independently hydrogen, hydroxy, acetyl or methoxy, and 、 is chromatography XC (= Y) - (wherein, X represents a NR ^4, Upsilon represents 0, R ⁴ is table to an alkyl of 1 to 5 carbon atoms) is, beta is one CH-CH-, one 13. The low sodium stream according to claim 12, wherein C≡C—, one CH ₂ single or one CH ₂ S—, R ^e and R ⁷ together are one O—, and R ⁸ is hydrogen. How to treat blood. 18. R ¹ is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, aryl, benzyl or phenethyl, R ² and R ³ are each independently hydrogen, hydroxy, acetoxy or methoxy, and A is Table chromatography XC (= Y) i (where, X represents a NR ^4, Upsilon represents 〇, the alkyl of R or 1 to 5 carbon atoms Is to), B gar CH = CH-, one C Mi C-, a S- one CH ₂ 〇 one or a CH _2, basic R ⁵ is hydrogen or the following skeleton: Q: Ο, S

An organic group having an organic group represented by R ³ (however, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoloxy having 1 to 5 carbons, hydroxy, fluorine, chlorine, bromine, iodine, Amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy, and may be substituted with at least one substituent selected from the group consisting of R ^e and R ⁷ together. 13. The method for treating hyponatremia according to claim 12, wherein R ⁸ is hydrogen. 19. The method for treating hyponatremia according to claim 17, wherein B is one CH-CH— or one C—C—. 20. The method for treating hyponatremia according to any one of claims 12 to 19, wherein water is specifically excreted. 2 1. The therapeutic agent for hyponatremia according to any one of claims 12 to 19, which retains blood sodium. 22. Hyponatremia, renal sodium loss, extrarenal sodium loss, acute water poisoning, antidiuretic hormone secretion syndrome (SI ADH), polydipsia, myxedema, glucocorticoid deficiency (pituitary dysfunction) The method according to any one of claims 12 to 21, wherein the disease is associated with administration of a drug that enhances antidiuretic hormone secretion or action, acute renal failure, chronic renal failure, heart failure, cirrhosis, or nephrotic syndrome. How to treat hyposodiumemia.