WO1999051242A1 - Medicinal compositions for treating edema - Google Patents

Abstract

Medicinal compositions for treating edema selected from among hepatic edema, cardiac edema and renal edema which contain as the active ingredient nitrogen-containing aromatic 5-membered fused ring benzazepine derivatives represented by general formula (I) or pharmaceutically acceptable salts thereof, wherein each symbol has the following meaning: B: an optionally substituted nitrogen-containing aromatic 5-membered ring having at least one nitrogen atom optionally together with an oxygen or sulfur atom; R?1 and R2¿: being the same or different, hydrogen, halogeno, lower alkyl, lower alkyl-O-, or amino optionally substituted by lower alkyl; A: a single bond or -(CR3R4)n-CONH-; n: 0 or an integer of 1 to 3; R?3 and R4¿: being the same or different, hydrogen or lower alkyl (or R?3 and R4¿ may form together lower C¿2-7? alkylene); and C: an optionally substituted benzene ring.

Description

 Pharmaceutical composition for the treatment of edema

 The present invention relates to a medicament, especially a pharmaceutical composition for treating edema selected from hepatic edema, cardiac edema and renal edema.

Background art

 Edema is a condition in which interstitial fluid is excessively stored in the interstitial space, and its cause is not unique. Edema includes systemic edema and local edema.Systemic edema is further attributed to cardiac edema, renal edema, hepatic edema, endocrine edema, orthostatic edema, dystrophic edema, iatrogenic It is classified into edema, idiopathic edema, etc., and the treatment method differs for each.

 Hepatic edema is edema or ascites that occurs in severe liver injury such as cirrhosis. Treatment of hepatic edema or ascites is basically a diet that aims at rest, restriction of Na, and improvement of hypoalbuminemia, but if it is still ineffective, diuretics are used. The most widely used diuretics at present are anti-aldosterone drugs, loop diuretics, thiazide diuretics, etc. (Latest Internal Medicine, Vol. 49, Cirrhosis, 231-14-241, 19) 9 Published in 1 year, Nakayama Shoten).

 Anti-aldosterone drugs are the first-line drug in cirrhosis, which causes secondary aldosteronism and increases the tendency for Na retention and K loss. Spironolactone and its derivatives such as potassium canrenoate, which antagonize aldosterone in the distal renal tubule and cortical collecting duct of the kidney to increase Na excretion and reduce K excretion, have been used.

Loop diuretics act on the ascending limb of the Henle snare and suppress the reabsorption of water and Na. Furosemide is a typical example, and the onset of diuretic action is generally fast and powerful. A thiazide diuretic is a drug that acts on the origin of the distal tubule, suppresses Na reabsorption and promotes K reabsorption, and its diuretic effect, such as hydrocloth thiazide, is slow and lasting. Yes, often with long-term use in combination with anti-aldosterone drugs. Patients with advanced cirrhosis or peritonitis or malignancy may not respond to these diuretics at all. For these so-called intractable or diuretic-resistant edema, administration of an albumin preparation is inevitable. If the effect is still not recognized, ascites puncture, ascites reconcentration, and surgical treatment ( Abdominal single vena cava shunting) has also been attempted.

 However, albumin preparations are expensive and may be infected by human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). In addition, large amounts of albumin supplementation can increase circulating plasma volume and cause esophageal varices rupture and pulmonary edema.

 On the other hand, the effect of ascites removal by peritoneal puncture is usually transient, and long-term effects cannot be expected. Rather, they can cause infection, protein loss, electrolyte imbalance, shock due to a sudden decrease in circulating plasma volume, hepatic encephalopathy, and gastrointestinal bleeding. In addition, ascites reconcentration has many problems with side effects such as fever, transient tachycardia, flatulence, abnormal electrolyte balance, and decreased platelets.

 Cardiac edema is edema that occurs in congestive heart failure. Administration of loop diuretics 併 用 If concomitant use with thiazide diuretics is not successful, use of digitalis, increased renal blood flow by dopamine administration, and reduction of preload and afterload by nitrite and ACE inhibitor are tried.

 Renal edema is edema associated with acute glomerulonephritis, nephrotic syndrome, and renal failure. Edema in nephrotic syndrome is mainly caused by hypoalbuminemia, and it is often difficult to treat edema with diuretics alone, and it is often necessary to use albumin concomitantly. Syzaid diuretics are ineffective for edema of renal failure with glomerular filtration below 20 ml / min and loop diuretics are used. In addition, it usually takes a considerable amount (1,000-2, OOOmg per day in the case of furosemide), but in renal failure, the blood half-life of diuretics decreases from 1 hour to 4-20 hours from normal. It is prolonged and frequent administration of large doses is dangerous.

Thus, current treatments for hepatic edema, cardiac edema, and renal edema are problematic. Therefore, powerful treatments for hepatic edema, cardiac edema, renal edema, There is a need for the development of orally available therapies with new mechanisms of action to treat intractable (or diuretic-resistant) edema where conventional diuretics do not work.

Disclosure of the invention

 Under such circumstances, the present inventor has suggested that a compound represented by the following general formula (I) or a salt thereof can be used for treatment of hepatic edema, especially for patients with hepatic edema in which conventional diuretics are ineffective or insufficiently effective. Was found to be effective. Furthermore, the present inventors have found that the compound represented by the following general formula (I) or a salt thereof is also effective for treating cardiac edema and renal edema.

 That is, the present invention provides a hepatic edema, a cardiac edema and a hepatic edema containing, as an active ingredient, a nitrogen-containing aromatic 5-membered fused benzazepine derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof. The present invention relates to a pharmaceutical composition for the treatment of edema selected from renal edema, particularly to a therapeutic agent for hepatic edema resistant to diuretics.

(The symbols in the formula have the following meanings.

 Ring B: a nitrogen-containing aromatic 5-membered ring which may have a substituent, has at least one nitrogen atom, and may further have one oxygen or sulfur atom

R ¹ and R ^{2 are the} same or different and may be substituted with a hydrogen atom, a halogen atom, a lower alkyl, a lower alkyl—O—, or an amino group optionally substituted with a lower alkyl group;

A: A single bond or a group represented by the formula — (CR ³ R ⁴ ) _n — CONH—

 n: 0 or an integer from 1 to 3

R ³ , R ⁴ : same or different, hydrogen atom, lower alkyl group (however, R ³ and R ⁴

Even if R ⁴ together form a lower alkylene group having 2 to 7 carbon atoms, Good)

 Ring c: a benzene ring which may have a substituent)

 Further, the present invention provides a nitrogen-containing aromatic 5-membered fused benzazepine derivative represented by the general formula (I) for the manufacture of a medicament for treating edema selected from hepatic edema, cardiac edema and renal edema. Or the use of a pharmaceutically acceptable salt thereof. Also, the present invention provides a method for administering a therapeutically effective amount of a nitrogen-containing aromatic 5-membered fused benzazepine derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof, The present invention relates to a method for treating edema selected from cardiac edema and renal edema.

 It is known that the nitrogen-containing aromatic 5-membered fused benzazepine derivative represented by the general formula (I) or a salt thereof has an arginine vasopressin receptor antagonistic activity (WO 95/033). 3 0 5). In addition, it has been shown that oral administration increases the urine output in normal rats, and these findings suggest that it may be useful as a diuretic.

 Aquaretic ic is defined as a drug that produces hypotonic urine and positive free water clearance (1st International Diuretic Congress; 1998), ie, excretes mainly water It is a diuretic. However, it has not yet been put to practical use and it has not been determined what therapeutic effects it has in human clinical practice.

 The present inventors have found that a nitrogen-containing aromatic 5-membered fused benzazepine derivative represented by the general formula (I) or a salt thereof is effective for treating three types of edema, hepatic edema, cardiac edema and renal edema This was clinically confirmed for the first time, and based on this, the present invention was completed. In addition, surprisingly, hepatic edema is surprisingly effective in patients with diuretic-resistant or refractory edema, where conventional diuretics are ineffective or ineffective. It was done. In this respect, the medicament of the present invention is a remarkably superior edema therapeutic agent as compared with conventional diuretics.

 Hereinafter, the present invention will be described in more detail.

The active ingredient of the medicament of the present invention includes all of the compounds embraced by the general formula described in the aforementioned International Publication No. The definition of the option can be used as it is as a general concept of the present invention or the definition of the option You. That is, to put it simply, "lower" means a linear or branched carbon chain having 1 to 6 carbon atoms. Therefore, a lower alkyl group is a methyl, ethyl group or the like. And a lower alkenyl group is a linear or branched C 2-6 alkenyl group such as ethenyl or aryl group, and a lower alkylene group is methylene. , An ethylene group or other linear or branched C 1-6 alkylene group, and a lower alkenylene group is a linear or branched C 2-6 alkenylene group such as vinylene or probenylene. It is.

 Nitrogen-containing nitrogen-containing aromatic 5-membered ring which may have a substituent, has at least one nitrogen atom, and may further have one oxygen or sulfur atom, represented by ring B Examples of the aromatic 5-membered ring moiety include a pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, isothiazole, thiazol, oxaziazole, and thiadiazole ring. These rings may have a substituent and are fused to a benzazepine ring at two adjacent ring-forming atoms.

The substituent may be a substituent that is generally used as a substituent on a 5-membered nitrogen-containing aromatic ring of Ring B or on a benzene ring of Ring C. The 5-membered nitrogen-containing aromatic ring in ring B can have 1-2 substituents, and the benzene ring in ring C can have 1-5 (preferably 1-3) substituents. The substituent on the benzene ring of ring C is preferably at the o (ortho) position. Examples of such a substituent include a substituted or unsubstituted alkyl, alkenyl or alkynyl group; a substituted or unsubstituted cycloalkyl or cycloalkenyl group; a substituted or unsubstituted aryl group; a substituted or unsubstituted saturated or unsubstituted group. Saturated heterocyclic group; further halogen atom; hydroxyl group; substituted or unsubstituted lower alkyl—0—, lower alkenyl—O—, lower alkynyl—0—, cycloalkyl—o_, cycloalkenyl, —aryl — O—, aryl-lower alkyl-O—, aryl lower alkenyl—O— or aryl lower alkynyl—0—group; mercapto, lower alkyl—S—, lower alkenyl S—, lower alkynyl —S—, cycloalkyl—S—, cycloalkenyl—S—, aryl Lower alkyl - S-, § Li one Roux lower alkenyl -S- Or aryl-lower alkynyl-S— group; lower alkyl—O—CO—, lower alkenyl-0—CO—, lower alkynyl_0—CO—, cycloalkyl-1-o—CO— group, cycloalkenyl—O—CO—, a Reducing 0—CO—, aryl—lower alkyl—O—CO—, aryl—lower alkenyl O—CO— or aryl—lower alkynyl—O—CO—group; lower alkyl—NH—CO—; lower alkyl—CO —, Lower alkenyl—CO—, lower alkynyl—CO—, aryl—CO—, lower alkyl—CO—O—, lower alkenyl CO—o—, lower alkynyl—CO—O— or aryl-CO—o— Groups; rubamoyl, carboxyl, sulfone, oxo, thioxo, cyano, nitro, amino, mono- or di-substituted amino, guanidino, amidino, Or unsubstituted imino group can be exemplified. Examples of the substituent on the benzene ring include a divalent group which is further substituted or unsubstituted and optionally contains a hetero atom, and which is bonded to two adjacent carbon atoms of the benzene ring to form a condensed ring with the benzene ring. Examples thereof include lower alkylene, lower alkenylene, lower alkynylene and —o-lower alkylene-o— group.

Examples of the substituent of the “substituted alkyl, alkenyl or alkynyl group” which is a substituent on the nitrogen-containing aromatic 5-membered ring or benzene ring include, for example, a cycloalkyl or cycloalkenyl group; a substituted or unsubstituted aryl. A substituted or unsubstituted saturated or unsaturated heterocyclic group; a halogen atom; a hydroxyl group; an alkyl—o—, a lower alkenyl—o—, a lower alkynyl—o—, a cycloalkyl—o—, a cycloalkenyl— o-, aryl-o-, aryl-lower alkyl-o-, aryl-lower alkenyl-o- or aryl-lower alkynyl-o-group; mercapto, lower alkyl-S-, lower alkenyl-S-, lower alkynyl- S-, cycloalkyl-S-, cycloalkenyl-S-, aryl-S-, aryl-lower alkyl S-, aryl-lower alkenyl-S- or aryl-lower alkynyl-S-group; lower alkyl-O-CO-, lower alkenyl-O-CO-, lower alkynyl-〇—C〇-1, cycloalkyl—〇— CO—group, cycloalkenyl—〇—C〇, aryl—O—CO—, aryl—lower alkyl—O—CO—, Aryl lower alkenyl— o— C〇— or aryl lower alkynyl o

—CO—group; lower alkyl—NH—CO—; lower alkyl—CO—, lower alkenyl—CO—, aryl—CO—, lower alkyl—CO—O—, lower alkenyl—CO—O— or aryl—CO — O— groups; examples include carbamoyl, carboxyl, sulfone, oxo, thioxo, cyano, nitro, amino, mono- or disubstituted amino, guanidino, amidino, substituted or unsubstituted imino groups.

 Examples of the substituent of the "substituted alkyl-o-group" include a halogen atom, cyano, a hydroxyl group, carboxyl, lower alkyl-CO-, lower alkyl-CO-, lower alkyl-CO-0, , Lower alkyl—NH—CO—, imide group and the like.

 Examples of the substituent of the “mono- or di-substituted amino group” include lower alkyl, lower alkenyl, lower alkynyl, and lower alkyl-CO— group.

 Examples of the substituent of the "substituted aryl group" include a halogen atom, lower alkyl, lower alkenyl, lower alkynyl, lower alkyl mono-, amino, mono- or di-lower alkylamino, hydroxyl group, carboxyl group and the like.

 Preferred examples of the "aryl group" include phenyl, biphenyl, naphthyl, anthryl, and phenanthryl groups.

 Specific examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. The active ingredient of the present invention may form a salt with an inorganic acid such as hydrochloric acid, an organic acid such as fumaric acid, an inorganic base such as sodium, or an organic base such as diethanolamine. Include pharmaceutically acceptable salts of the above compounds. Further, the active ingredient of the present invention includes a mixture of various isomers and all of its isolated, hydrated, and solvated forms. In addition, some of the active ingredients of the present invention have a compound having a polymorphism, and include all the crystal forms.

Particularly preferred is 4, -C (2-methyl-1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine-6- described in WO 94Z03305. Le) carbonyl] — 2-phenylpenzanilide Or a pharmaceutically acceptable salt thereof.

 These compounds can be easily obtained by the production method described in the above-mentioned International Publication No. 95/03330, or according to the production method.

 In the present invention, diuretic resistant edema (or intractable edema) refers to edema in which anti-aldosterone drugs, loop diuretics, and thiazide diuretics conventionally prescribed for the treatment of edema are ineffective or insufficiently effective. Examples of anti-aldosterone drugs include spironolactone (trade name: aldactone A), potassium canrenoate (trade name: sulductone), and triamtellene (trade name: triteren). Yunide (brand name Lunetron), ethacrynic acid (brand name Edecryl), and azosemide (brand name Dyad) are listed. Flutran), metrazone (trade name Normeran), tripamide (trade name normonal), and mefluside (trade name baicalone).

 The drug of the present invention is prepared as an oral solid preparation, an oral liquid preparation or an injection using an organic or inorganic carrier, excipient, or other additive suitable for oral or parenteral administration according to a conventional method. be able to. Most preferred are oral solid dosage forms that can be easily taken by patients and that are easy to store and carry.

As oral solid preparations, tablets, powders, fine granules, granules, capsules, pills, sustained-release preparations and the like are used. In such solid dosage forms, the one or more active substances may include at least one inert diluent, such as lactose, mannitol, glucose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate. Mixed with. The composition may be prepared according to conventional methods, with additives other than inert diluents, such as hydroxypropylcellulose, binders such as hydroxypropylmethylcellulose (HPMC), magnesium stearate, polyethylene glycol, starch, talc. Lubricants, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, solubilizing agents such as glutamic acid or aspartic acid, and coloring agents such as titanium oxide. . Tablets If necessary, pills may be coated with a sugar coating such as sucrose, gelatin, agar, pectin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or a film of a gastric or enteric substance.

 Oral liquid preparations include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents, for example, purified water, ethanol including. The composition may contain, in addition to the inert diluent, auxiliaries such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

 Injections for intravenous injection, intramuscular injection, subcutaneous injection and the like include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Diluents for aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of diluents for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria storage filter, blending of a bactericide or irradiation. They can also be used in the manufacture of a sterile solid composition which is dissolved in sterile water or a sterile solvent for injection before use. The dose of the active ingredient compound (I) of the present invention is appropriately determined depending on the individual case in consideration of the administration route, the symptoms of the disease, the age and gender of the administration target, and the like. The active ingredient per adult is about 0.1 to 200 mg Z days, preferably 0.5 to 100 mg Z days, most preferably 1 to 8 O mg / day, once or It is orally administered in 2 to 4 divided doses.

 The drug of the present invention can be used simultaneously with the other diuretics described above or at a later time.

Furthermore, the drug of the present invention includes an antiviral drug, an inhalation feron, a hepatoprotective drug, a liver function improving drug, a liver protein metabolism improving drug, a liver preparation, a liver immunostimulant, a choleretic drug, a steroid, an anticancer drug, It can be used with or at the same time as a liver disease drug such as herbal medicine, immunoglobulin, or hepatitis vaccine. For example, it can be used in combination with the drug of the present invention. Acyclovir (trade name Zovirax), Lamivudine (trade name epipivir) as an antiviral agent, INF-α (trade name Sumiferon) as an interferon, INF-a2a (trade name Kyaferon A, mouth) Feron A), I NF-α2b (trade name: Intron A), I NF-i3 (trade name: Feron), I NF—acon (YM643), 'Glycyrrhizin combination as liver protectant (trade name: strong neomy Nophagen C), liver-improving agents such as Dalc-Noractone (brand name Glonsan), glucuronamide (brand name glonamine), aminoethylsulfonic acid (brand name taurine) diisopropylamine dichloroacetate (brand name Livaol) ) Chop Mouth Nin (trade name: Thiola), Dal-Yu Thion (trade name: Tathion), Polyenphosphatidylcholine (trade name: EPL), Liver protein Improving agent is malotilate (trade name: Kantec), liver preparation: liver hydrolyzate (trade name: Prohepar), liver immunostimulant: propagermanium (trade name: Serosion), bile agent: ursodeoxy Cholic acid (trade name urso), steroid as prednisolone, anticancer drug dinostin chinstimarama (trade name Smanx), fluorouracil (trade name five eff), tegafur (trade name futrafl), camofur (trade name) Yamafur), Tegafur 'ゥ uracil (trade name u-efty), and herbal medicines include Sho-saiko-to.

Industrial applicability

 According to the present invention, an excellent therapeutic agent for hepatic edema, cardiac edema and renal edema, particularly a therapeutic agent effective for diuretic-resistant hepatic edema can be provided.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail based on examples and test examples, but the present invention is not limited to these examples and the like. The compound 1 used in the following examples and the like has a 4 '-[(2-methyl-1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine-6-yl) Luponyl] —means 2-phenylpenzanilide hydrochloride. Example 1 Tablet Compound 1 1 part by weight, HPMC 2910 3 parts by weight, polysorbate 800.5 parts by weight were dissolved in 45.5 parts by weight of a mixed solution of methanol and water (9: 1), and then a solid dispersion was prepared by a spray drying method. .

 45 mg of the above solid dispersion, 75 mg of lactose, and 30 mg of sodium bicarbonate are uniformly mixed, and the mixture is compressed using an oil press at a tableting pressure of 500 kg / punch and 150 mg per tablet (10 mg of compound 1). 5 mm tablets were produced. Example 2 tablets

 45 mg of the solid dispersion obtained in Example 1, 90 mg of lactose, and 15 mg of sodium hydrogen carbonate were uniformly mixed, and the mixture was compressed using an oil press at a tableting pressure of 500 kPunch with 15 Omg / tablet (compound). 1 10 mg) Tablets with a diameter of 7.5 mm were produced. Example 3 Tablet

 45 mg of the solid dispersion obtained in Example 1, 75 mg of lactose, and 3 Omg of sodium bicarbonate were uniformly mixed, and the mixture was compressed with an oil press at a tableting pressure of 500 kg g. (Compound 1 10 mg) A tablet having a diameter of 7.5 mm was produced. Example 4 Tablet

Compound 1 100 g, HPMC2910 300 g, and polysorbate 80550 g were dissolved in methanol / water mixed solution (9: 1) 4550 g. Next, 442 g of lactose and 150 g of sodium hydrogen carbonate were fluidized using a fluid bed granulator (UNIGRAT, manufactured by Okawara Seisakusho KK), and the solution was sprayed to obtain a granulated powder. 834 g of the obtained granules, 240 g of crystalline cellulose (trade name Avicel PH 102, manufactured by Asahi Kasei Corporation), 120 g of croscarmellose sodium (trade name: Ac—Di—Soshi, manufactured by Asahi Kasei Corporation), stearic acid 6 g of magnesium were mixed uniformly, and the mixture was compressed using a rotary tableting machine (manufactured by Hata Seisakusho) with a tableting pressure of 700 kgZ punch. 150 mg (Compound Omg) Tablets with a diameter of 7.5 mm were manufactured <Example 5 Capsules

 Compound 1 100 g, HPMC 2910 300 g, polyethylene-hardened castor oil (60) (trade name Nikkor 60, Nikko Chemicals Co., Ltd.) 50 g were dissolved in methanol / water mixed solution (9: 1) 4550 g. Next, 435 g of lactose and 150 g of sodium bicarbonate were fluidized using a fluid bed granulator (manufactured by UNIGRAT Okawara Seisakusho), and the solution was sprayed to obtain a granulated powder. 1572 g of lactose was uniformly mixed with 828 g of the obtained granules, and 0.3 g (compound 11 Omg) was filled per capsule (capsule size No. 1) to produce a capsule. Example 6 Injection

 Test Example 1 Clinical test for patients with hepatic edema

 A clinical study was performed on patients with edema (femoral edema, ascites, etc.) due to liver disease under the following conditions.

Subjects: 7 patients with hepatic edema or hepatic ascites

Study drug and administration method: Compound 1 tablets were orally administered once daily after breakfast.

Dosage: Start with lmg after 2 days of observation period, and administer the same dose for 3 days if urine volume increases more than 20 Oml from the observation period until 4 hours after administration. . If the increase in urine volume is less than 20 Om 1, increase the dose to 5 mg, 1 Omg, 2 Omg, 3 Omg and up to 3 Omg every day.

Evaluation method: The degree of increase in urine volume was used as the primary endpoint, and at any dose The case where the urine volume from the start of administration to 4 hours after administration increased by 20 Oml or more from the observation period was regarded as “effective”, and the case where no increase of 200 ml or more was observed was regarded as “ineffective”. The evaluation of edema and ascites was secondary due to lack of objectivity.

Results: As shown in Table 2, the test drug showed effective results for patients with hepatic edema. In particular, it was also effective in patients who had ineffective or inadequate effects of administering diuretics, which are currently used as treatments for hepatic edema or ascites, prior to administration of the study drug. Based on the above results, administration of albumin or peritoneal administration to hepatic edema or ascites, which is insufficiently effective for treatment with conventional diuretics, when used alone or in combination with other diuretics. It was suggested that the treatment could be performed without puncture.

 Table 2

 L a: Lasix, S o: solderductone, A 1: aldactone A Test Example 2 Clinical study on patients with cardiac edema

 A clinical study was conducted on patients with edema (lower leg edema, pulmonary depressed blood, etc.) due to heart disease under the following conditions.

Target: 6 patients with cardiac edema

Study drug and administration method: Compound 1 tablets were orally administered once daily after breakfast.

Dosage: Start with lmg after 2 days of observation period, and administer the same dose for 3 days if urine volume increases more than 20 Oml from the observation period until 4 hours after administration. . If the increase in urine volume is less than 20 Om 1, increase the dose to 5 mg, 1 Omg, 2 Omg, 3 Omg and up to 3 Omg every day.

Evaluation method: The degree of increase in urine volume was used as the primary endpoint, and at any dose The case where the urine volume from the start of administration to 4 hours after administration increased by 20 Oml or more from the observation period was regarded as “effective”, and the case where no increase of 200 ml or more was observed was regarded as “ineffective”. The evaluation of edema and pulmonary depressed blood was secondary, due to lack of objectivity.

Results: As shown in Table 3, the test drug showed effective results for patients with cardiac edema. In addition, although the effect of Caseix 4 was not sufficient even when Lasix was administered, effective results were obtained by administration of this drug. Based on the above results, it can be expected that this drug alone or in combination with other diuretics will have an effect on cardiac edema, as with the conventional loop diuretics.

 Table 3

 *: No leg edema was observed before administration. Test Example 3 Clinical study for patients with renal edema

 A clinical study was performed on patients with edema (eg, leg edema) due to renal disease under the following conditions.

Subjects: 3 patients with renal edema

Study drug and administration method: Compound 1 tablets were orally administered once daily after breakfast.

Dosage: After 2 days in the observation period, start with lmg. If the urine volume from the start of administration to 4 hours after administration increases by 200 ml or more from the observation period, administer the same dose for another 3 days. If the increase in urine output is less than 20 Om1, increase the dose to 5 mg, 1 Omg, 2 Omg, 3 Omg and a maximum of 3 Omg every day.

Evaluation method: The degree of increase in urine volume was used as the main evaluation item, and “effective” was defined as the case where the urine volume at any dose from the start of administration to 4 hours after administration increased by 20 Oml or more from the observation period ^ A case where no increase of 20 Om 1 or more was observed was regarded as “invalid”. The evaluation of edema was secondary because it lacked objectivity.

Results: As shown in Table 4, the test drug showed effective results for patients with renal edema. Based on the above results, it can be expected that this drug alone or in combination with other diuretics will have an effect on renal edema, as with the conventionally used loop diuretics.

 Table 4

 Case Final administration Effect on test drug

 Number Volume Increased urine output Lower leg edema

 1 1 mg valid unchanged

 2 5 mg valid valid

 3 1 O m g Valid Valid

Claims

Scope of Claim Hepatic edema, cardiac edema and kidney containing a nitrogen-containing aromatic 5-membered fused benzazepine derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition for the treatment of edema, selected from edema.

 (The symbols in the formula represent the following meanings. Ring B: a nitrogen-containing aromatic 5-membered ring R ¹ , R ² which may have a substituent, has at least one nitrogen atom, and may further have one oxygen or sulfur atom : The same or different, a hydrogen atom, a halogen atom, a lower alkyl, a lower alkyl-〇- or a lower amino group which may be substituted with a lower alkyl group, A: A single bond or a group represented by the formula — (CR ³ R ⁴ ) _n — CONH—  n: 0 or an integer from 1 to 3 R ³ , R ⁴ : same or different, hydrogen atom, lower alkyl group (however, R ³ and R ⁴ R ⁴ is taken together to form a lower alkylene group having 2 to 7 carbon atoms, and fc is good)  Ring C: benzene ring optionally having substituent (s)  2. The pharmaceutical composition according to claim 1, which is a therapeutic agent for hepatic edema.  3. The pharmaceutical composition according to claim 1, which is a therapeutic agent for cardiac edema.  4. The pharmaceutical composition according to claim 1, which is a therapeutic agent for renal edema.  5. The pharmaceutical composition according to claim 2, wherein the hepatic edema is diuretic resistant edema. 6. The active ingredient is 4 '_ [(2-methyl-1,4,5,6-tetrahydroimida Zo [4, 5-d] [1] benzazepine-6-yl) carbonyl] — one phenylbenzanilide or a salt thereof according to any one of claims 1 to 5 The pharmaceutical composition according to any one of the preceding claims.