JP2003342175A - Therapeutic agent for meniere disease comprising new benzazepine derivative or its salt as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an excellent therapeutic agent against Meniere disease, Meniere syndrome, dizziness, hearing disability or ringing in the ears. <P>SOLUTION: The medicine comprises a new 1,4,5,6-tetrahydroimidazo[4,5- d]benzazepine derivative represented by general formula (ring D is a phenylene or pyridinediyl; X and Y are the same or different and are each CH or N; R<SP>1</SP>, R<SP>2</SP>and R<SP>3</SP>are the same as or different from each other and are each a hydrogen atom, a hydroxy group, a halogen or a lower alkyl) or its pharmaceutically permissible salt as active ingredient. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 1,4
Use of 5,6-tetrahydroimidazo [4,5-d] benzazepine derivative or a salt thereof, that is, novel 1,4
The present invention relates to a therapeutic agent for Meniere's disease or Meniere's syndrome, which comprises a 5,6-tetrahydroimidazo [4,5-d] benzazepine derivative or a salt thereof as an active ingredient.

[0002]

2. Description of the Related Art Meniere's disease or Meniere's syndrome is a disease in which recurrent dizziness attacks are accompanied by cochlear symptoms such as hearing loss and tinnitus. There is no special incentive and intense dizziness occurs, which lasts tens of minutes at the shortest and lasts several hours or more at the longest. At the time of an attack, nausea and vomiting are often involved, and stiff shoulders and mild headaches may be added, but they are not accompanied by central nervous system symptoms such as consciousness disorder, retrospective vision, sensory disturbance, and movement disorder (new Illustrated Otolaryngology / Head and Neck Surgery, Vol. 1, Inner Ear, 178-181 pages, Medical View Co., Tokyo, 2000). The cause of Meniere's disease or Meniere's syndrome is unknown, but the main pathological condition is considered to be endolymphatic hydrops characterized by protrusion of Reissner's membrane from the temporal bone pathological findings of patients with Meniere's disease or Meniere's syndrome. Endolymphatic hydrops is caused by the impaired absorption of endolymphatic fluid in the endolymphatic sac according to the obstruction experiment of the endolymphatic vasculature and endolymphatic sac. There are various theories such as hypoplasia of the endolymphatic sac, and no definitive opinion has been obtained at this time.

[0003] Conventionally, therapeutic agents for Meniere's disease or Meniere's syndrome are divided into treatments for the acute phase of vertigo vertigo accompanied by nausea and vomiting and the intermittent phase of dizziness subsided. In the acute phase, in addition to maintaining physical and physical rest, diphenhydramine diprophylline, perphenazine,
Intravenous drip infusion of chlorpromazine hydrochloride, Ringer's lactate solution (Dextran 40 added), sodium hydrogen carbonate solution, etc. is performed. During the intermittent period, isosorbide is used as a treatment for the cause of dizziness, betahistine mesylate for the purpose of improving inner ear function, adenosine triphosphate disodium, mecobalamin, antihistamines for indefinite complaints and its analogues betahistine mesylate, dimen Oral administration of hydrinate, meclizine hydrochloride, diphenidol hydrochloride, anxiolytics, etc. is performed (Today's Treatment 2002 version 919-920 pages, Nankodo, Tokyo, 2002). The current drug treatment has not gone beyond the control of treatment, and endolymphatic sac surgery, which is a typical surgical operation for Meniere's disease or Meniere's syndrome, is also difficult to determine because of its indication, recurrence and sequelae. Not popular. Isosorbide, which is an osmotic diuretic, is widely used to reduce endolymphatic hydrops, which is the essential form of Meniere's disease or Meniere's syndrome, and is one of the few therapeutic agents based on histological evidence. However, since commercially available isosorbide preparations are drenches, there are problems that they are difficult to carry and inconvenient, and because they have a unique taste, they are difficult to drink, and new drugs that replace the isosorbide preparations are desired in the future.

A novel 1,4,5,6-tetrahydroimidazo [4,5-d] which is an active ingredient of the medicine of the present invention.
As a compound related to a benzazepine derivative or a salt thereof, a fused benzazepine derivative having the following general formula, which is useful as an arginine vasopressin receptor antagonist, or a salt thereof is described in WO 95/03305. .

[Chemical 2] (For the symbols in the formula, refer to this publication) That is, although some of the fused benzazepine derivatives or salts thereof are disclosed in this publication, they are compounds which are active ingredients of the medicament of the present invention,
Ring B is 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, and R ¹ is hydrogen. in atom, a is _{^{-NHCO- (CR 3 R 4) n}} - is, in n is 0,
There is no specific disclosure of a compound in which the C ring is a benzene ring which may have a substituent. In addition, although the compound of the publication describes the V ₁ and / or V ₂ receptor antagonism of AVP, it does not disclose or suggest the relationship with Meniere's disease or Meniere's syndrome, dizziness, deafness or tinnitus.

Further, carbostyryl derivatives and benzohetero compounds are disclosed in JP-A-10-120592, and benzamide derivatives are disclosed in JP-A-11-503721.
Each of them is disclosed as a drug useful for Meniere's disease, but it is 1, 4, 5, 6- which is the active ingredient of the drug of the present invention.
There is no description or suggestion of a tetrahydroimidazo [4,5-d] benzazepine derivative or a salt thereof. further,
The above-mentioned JP-A-10-12059 discloses that "a compound having a vasopressin antagonistic action can be suitably used as a therapeutic agent for Meniere's disease or Meniere's syndrome." The present invention is limited to only two compounds, a benzazepine derivative and a carbostyril derivative, which have different structures from the compound which is the active ingredient of the drug of the present invention. From the pharmacological test results of these two cases, all compounds having vasopressin antagonism However, it cannot be said that it can be suitably used as a therapeutic agent for Meniere's disease or Meniere's syndrome. Further, no mention is made of the CYP3A4 inhibitory action of these two compounds.

[0006]

Under such circumstances, excellent Meniere's disease or Meniere's syndrome, dizziness,
There is a great need for the development of a treatment for hearing loss or tinnitus.

[0007]

SUMMARY OF THE INVENTION The present inventors have developed a novel 1,4,5,6-tetrahydroimidazo [4,5-d]
As a result of intensive studies on the therapeutic potential of benzazepine derivatives for specific diseases, the compound as an active ingredient of the pharmaceutical agent of the present invention is effective against Meniere's disease or Meniere's syndrome, dizziness, deafness or tinnitus. The present invention has been completed by finding the above.

Therefore, the present invention provides a novel 1,4,5,6-tetrahydroimidazo [4,5-d] benzazepine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. To an agent for treating Meniere's disease or Meniere's syndrome, which comprises

[Chemical 3] (The symbols in the formulas have the following meanings: Ring D: phenylene or pyridinediyl. X and Y: same or different CH or N. R ¹ , R ² and R ³ : same or different hydrogen atom, hydroxyl group, Halogen or lower alkyl.

Preferably, in the above general formula (I),
A compound wherein Ring D is 1,4-phenylene or pyridine-2,5-diyl or pyridine-3,6-diyl or a pharmaceutically acceptable salt thereof; more preferably in the above general formula (I) , Ring D is 1,4-phenylene or pyridine-2,5-diyl or pyridine-3,6-
A compound or a pharmaceutically acceptable salt thereof, which is diyl, X and Y are CH, and R ¹ is a hydrogen atom; more preferably, in the above general formula (I), ring D is 1,
4-phenylene, X and Y are CH, R ¹ is a hydrogen atom, and R ² and R ³ are both hydrogen atoms, or a pharmaceutically acceptable salt thereof. Diseases or Meniere syndrome therapeutic agent.

Particularly preferably, N- {4- [2- (2-pyridyl)-
1,4,5,6-Tetrahydroimidazo [4,5-d] [1] benzazepine-6-carbonyl] phenyl} biphenyl-2-carboxamide, N- {3-fluoro-4- [2- (2- Pyridyl) -1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine-6-carbonyl] phenyl} biphenyl-2-carboxamide, 2'-fluoro-N- {4- [2 -(2-Pyridyl) -1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine-6-carbonyl] phenyl}
Biphenyl-2-carboxamide, N- {5- [2- (2-pyridyl)-
1,4,5,6-Tetrahydroimidazo [4,5-d] [1] benzazepine-6-carbonyl] -2-pyridyl} biphenyl-2-carboxamide, N- {6- [2- (2-pyridyl ) -1,4,5,6-Tetrahydroimidazo [4,5-d] [1] benzazepine-6-carbonyl] -3-
Pyridyl} biphenyl-2-carboxamide, N- {2-hydroxy-4- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine-6 -Carbonyl] phenyl}
The present invention relates to a therapeutic agent for Meniere's disease or Meniere's syndrome, which comprises biphenyl-2-carboxamide or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the novel 1,4,5,6-tetrahydroimidazo [4,5-5- (III) represented by the above general formula (I) is used.
d] Benzazepine derivative; preferably a compound in which ring D in the above general formula (I) is 1,4-phenylene or pyridine-2,5-diyl or pyridine-3,6-diyl; more preferably, In the general formula (I), ring D is 1,4-phenylene or pyridine-2,5
-Diyl or pyridine-3,6-diyl, X
And Y is CH, and R ¹ is a hydrogen atom; more preferably, in the general formula (I), ring D is 1,4-phenylene, X and Y are CH, and R is R.
^A compound in which ¹ is a hydrogen atom and R ² and R ³ are both hydrogen atoms; particularly preferably N- {4- [2- (2-pyridyl) -1,4,
5,6-Tetrahydroimidazo [4,5-d] [1] benzazepine-6
-Carbonyl] phenyl} biphenyl-2-carboxamide,
N- {3-fluoro-4- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine-6-carbonyl] phenyl} biphenyl-2 -Carboxamide, 2'-fluoro-N-
{4- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo [4,
5-d] [1] benzazepine-6-carbonyl] phenyl} biphenyl-2-carboxamide, N- {5- [2- (2-pyridyl) -1,4,5,
6-Tetrahydroimidazo [4,5-d] [1] benzazepine-6-
Carbonyl] -2-pyridyl} biphenyl-2-carboxamide, N- {6- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine- 6-Carbonyl] -3-pyridyl} biphenyl-2-carboxamide, N- {2-hydroxy-
4- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo [4,5
-d] [1] benzazepine-6-carbonyl] phenyl} biphenyl-2-carboxamide; or a therapeutic agent for dizziness, deafness, or tinnitus containing a pharmaceutically acceptable salt thereof as an active ingredient .

A novel 1,4,5,6-tetrahydroimidazo [4,5-d] which is an active ingredient of the medicine of the present invention.
The benzazepine derivative has a structural feature in that a 6-membered aromatic ring having a nitrogen atom at the 2-position is substituted at the 2-position of the imidazobenzazepine ring, and has a arginine vasopressin receptor antagonistic action pharmacologically. It has the characteristics of.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The compound which is an active ingredient of the medicine of the present invention will be further described as follows. In the present specification, the term “lower alkyl” means a straight or branched carbon chain (C _1-6 ) having 1 to 6 carbon atoms, and specifically, for example, methyl, ethyl, propyl, isopropyl. ,
Butyl, tert-butyl, pentyl, neopentyl,
Hexyl and the like can be mentioned, with preference given to C _1-3 alkyl methyl, ethyl and isopropyl, with methyl and ethyl being particularly preferred. "Halogen" includes fluorine, chlorine, bromine and iodine atoms. The above substituents R ¹ , R ² and R ³ may be bonded to any position of each ring, but R ³ is preferably bonded to the ortho position or the para position.

The compound represented by the general formula (I) may contain an asymmetric carbon atom depending on the kind of the substituent.
Optical isomers based on this may exist. The present invention includes all mixtures and isolated ones of these optical isomers. Further, the compound represented by the general formula (I) is considered to be a positional isomer based on imidazole fused to the benzodiazepine ring. The present invention includes all pharmaceuticals containing a mixture of these positional isomers or an isolated one as an active ingredient.

Further, the compound represented by the general formula (I) is
It may form an acid addition salt and is included in the present invention as long as such a salt is a pharmaceutically acceptable salt. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, and maleic acid. Acid addition salts with organic acids such as lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamic acid. Furthermore, the present invention also includes a drug containing various hydrates or solvates of the compound which is an active ingredient of the pharmaceutical agent of the present invention and a pharmaceutically acceptable salt thereof and a substance having a crystalline polymorph as an active ingredient. . Incidentally, in the present invention,
It also includes all compounds which are metabolized in vivo and converted into the compound having the general formula (I) or a salt thereof, that is, a drug containing a so-called prodrug as an active ingredient. Examples of groups forming a prodrug of a compound which is an active ingredient of the medicine of the present invention include groups described in Prog. Med. 5: 2157-2161 (1985) and Hirokawa Shoten 1990 "Development of Pharmaceuticals". 7
The groups described in Volume Molecular Design 163-198 can be mentioned.

(Manufacturing Method) The compound which is an active ingredient of the medicine of the present invention and its pharmaceutically acceptable salt utilize various characteristics of known basic syntheses by utilizing the characteristics based on the basic skeleton or the kind of the substituent. Can be applied to manufacture. A typical production method is illustrated below. Depending on the type of functional group, it may be effective in terms of manufacturing technology to replace the functional group with an appropriate protecting group at the stage of the raw material or intermediate, that is, a group that can be easily converted into the functional group. is there. After that, the protecting group can be removed if necessary to obtain the desired compound. Examples of such a functional group include a hydroxyl group and a carboxyl group, and examples of the protective group thereof include Greene and Wuts, "Protective Groups in Organic Synthes".
The protecting groups described in “is (third edition)” can be mentioned, and these may be appropriately used depending on the reaction conditions. Further, as another method, for example, a method of deprotecting a protected benzyl ether of a hydroxyl group by allowing pentamethylbenzene to act in a strongly acidic solution such as trifluoroacetic acid can be mentioned.

(First manufacturing method)

[Chemical 4] This production method comprises the process of reacting an optionally protected substituted aromatic carboxylic acid of formula (II) or a reactive derivative thereof with formula (I
The optionally protected benzazepine derivative represented by II) or a salt thereof is amidated by a conventional method, and the protecting group is removed if necessary to give a compound (I) which is an active ingredient of the medicament of the present invention. It is a manufacturing method.

As the reactive derivative of the compound (II),
Ordinary esters such as methyl ester, ethyl ester, tert-butyl ester; acid halides such as acid chloride and acid bromide; acid azides; active esters with N-hydroxybenzotriazole, p-nitrophenol, N-hydroxysuccinimide and the like; Symmetrical acid anhydrides; examples include mixed acid anhydrides with alkyl carbonic acid, p-toluenesulfonic acid, and the like. When the compound (II) is reacted with a free acid, or when the active ester is reacted without isolation, dicyclohexylcarbodiimide,
Carbonyldiimidazole, diphenylphosphoryl azide, diethylphosphoryl cyanide and 1-ethyl-3-
It is preferred to use a condensing agent such as (3-dimethylaminopropyl) carbodiimide hydrochloride.

The reaction varies depending on the reactive derivative or condensing agent used, but is usually a halogenated hydrocarbon such as dichloromethane, dichloroethane or chloroform, an aromatic hydrocarbon such as benzene, toluene or xylene, an ether or a tetrahydrofuran. The reaction is carried out in an organic solvent inert to the reaction such as ethers, esters such as ethyl acetate, acetonitrile, N, N-dimethylformamide and dimethylsulfoxide under cooling, cooling to room temperature or room temperature to heating.

In the reaction, compound (II) is used in excess, N-methylmorpholine, trimethylamine, triethylamine, N, N-dimethylaniline, pyridine, 4- (N, N-dimethylamino) pyridine, picoline, It may be advantageous to react in the presence of a base such as lutidine in order for the reaction to proceed smoothly. Alternatively, a salt of a weak base and a strong acid such as pyridine hydrochloride, pyridine p-toluenesulfonate, and N, N-dimethylaniline hydrochloride may be used. In this case, the imidazole ring fused to benzazepine and the strong acid form a salt, and the free weak base serves as a catalyst. Pyridine can also be the solvent. In particular, the reaction is preferably performed in a solvent such as acetonitrile or N, N-dimethylformamide in the presence of a base such as pyridine or N, N-dimethylaniline or a salt such as pyridine hydrochloride.

(Second manufacturing method)

[Chemical 5] (In the formula, ^one of Y ¹ and Y ² , and Y ³ and Y ⁴ is an oxo group (=
O), Means ) In this production method, an optionally protected haloketone represented by the formula (IV) and an optionally protected amidine represented by the formula (V) or a salt thereof are cyclized by a conventional method, and if necessary, It is a method for producing a compound (I) which is an active ingredient of the medicament of the present invention by removing a protecting group.

In this reaction, the corresponding amidine may form a salt with the acid. Further, in order to promote the reaction, a salt of an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or potassium hydrogen carbonate or a weak base with a strong acid,
Or pyridine, diisopropylethylamine, 1,5-
It may be carried out in the presence of an organic base such as diazabicyclo [4,3,0] non-5-ene. As the solvent used in the reaction, methanol, ethanol, alcohol solvents such as 2-propanol, ether, tetrahydrofuran,
Ether solvents such as dioxane, halogenated hydrocarbon solvents such as dichloromethane, chloroform and carbon tetrachloride, solvents inert to the reaction such as acetonitrile, dimethylformamide and dimethyl sulfoxide are preferable, and the reaction temperature is from room temperature to reflux of the solvent. It is preferably carried out at temperature. Also, the reaction is optionally carried out under pressure.

Oxazoles may be formed in this reaction. In this case, the imidazoles can be provided as a main product by carrying out the reaction under conditions such as addition of ammonium carbonate, ammonium acetate, formamides in an ammonia stream.

Starting compound (IV) used in this reaction
Is an optionally protected aromatic carboxylic acid (VI) or a reactive derivative thereof, as shown in the following reaction formula:
Benzazepine derivative (VII) which may be protected
Alternatively, it can be prepared by amidation with a salt thereof in the same manner as in the first production method, and then by reacting this with a halogenating agent (if necessary, the protecting group is removed at any stage). The aromatic carboxylic acid (VI) is a corresponding optionally protected 2-phenylbenzoic acid (IX) or a reactive derivative thereof and an optionally protected aminoaromatic carboxylic acid (X) or It can be produced by amidating the salt with the salt as in the first production method.

[0025]

[Chemical 6] (In the formula, one of Y ⁵ and Y ⁶ , and Y ⁷ and Y ^{8 represents} an oxo group (=
O), Means ) Regarding the amidation in the first step, the type of reactive derivative, reaction conditions, etc. are the same as in the first production method.

The halogenating agent used in the halogenation process may be any halogenating agent commonly used for halogenating saturated cyclic ketones, such as copper (II) bromide and copper (II) chloride. Copper (II) halide
Metal reagents such as dioxane dibromide, phenyltrimethylammonium tribromide, pyridinium hydrobromide perbromide, pyridine such as pyrrolidone hydrotribromide, α-pyrrolidone, quaternary ammonium, perbromide such as dioxane are preferably used. chlorine,
It is also possible to use simple halogen such as bromine or hydrohalic acid such as hydrogen chloride or hydrogen bromide. In the reaction using a metal reagent or a perbromide, a compound (VIII) and this halogenating agent are usually a halogenated hydrocarbon solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether solvent such as ether, tetrahydrofuran or dioxane. ,
Methanol, ethanol, alcohol solvent such as 2-propanol, benzene, toluene, aromatic hydrocarbon solvent such as xylene, acetic acid, organic solvent inert to the reaction such as ethyl acetate or water or a mixed solvent thereof, necessary It is advantageous to carry out the reaction at room temperature or under heating in the presence of a small amount of a catalyst such as hydrogen halide.

Further, a halogen simple substance is used as a halogenating agent, and the compound (VIII) is allowed to act on a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride or the like, or in a solvent inert to the reaction such as ethylene glycol or acetic acid. Alternatively, hydrogen halide is used as the halogenating agent, and the compound (V is used in an acidic solution or a basic solution such as an aqueous solution of sodium hydroxide).
It can also be obtained by acting on III). The reaction temperature at this time is preferably from -30 ° C to the reflux temperature of the solvent used.

The thus-produced compound which is an active ingredient of the medicament of the present invention is isolated or purified as a salt thereof in a free state or after a salt-forming treatment by a conventional method. Isolation / purification is carried out by applying usual chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization and various chromatographies.

Various isomers can be isolated by a conventional method by utilizing the difference in physicochemical properties between the isomers. For example, a racemic mixture can be converted into an optically pure isomer by a general racemate resolution method such as a method of converting a racemic mixture into a diastereomeric salt with a general optically active acid such as tartaric acid and performing optical resolution. . Further, the diastereomeric mixture can be separated by, for example, fractional crystallization or various chromatographies. The optically active compound can also be produced by using an appropriate optically active raw material.

The medicine of the present invention is usually used by using one or more compounds represented by the general formula (I) and a drug substance, an excipient, and other additives which are usually used for formulation. Can be prepared by any method. Administration is tablets,
Oral administration by pills, capsules, granules, powders, liquids, etc., injections such as intravenous injection, intramuscular injection, etc., or suppositories, nasal, transmucosal,
Any form of parenteral administration such as transdermal administration may be used.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances comprise at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminometasilicate. Mixed with magnesium etc. According to a conventional method, the composition has an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin glycolate, a stabilizer such as lactose, glutamic acid or asparagine. It may contain a solubilizing agent such as an acid. If necessary, the tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a gastric or enteric film. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and generally used inert diluents such as purified water. , Including ethanol. This composition may contain, in addition to an inert diluent, auxiliary agents such as a wetting agent and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent and a preservative.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 and the like. Such compositions may further comprise preservatives, wetting agents, emulsifiers, dispersants, stabilizers such as lactose, auxiliaries such as solubilizers such as glutamic acid and aspartic acid. . These are sterilized by, for example, filtration through a bacteria-retaining filter, addition of a bactericide, or irradiation. They can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

Usually, in the case of oral administration, a daily dose of about 0.001 to 50 mg / kg, preferably about 0.1 to 5 mg / kg of body weight is suitable. Administer in 4 divided doses. When intravenously administered, the daily dose is about 0.0001 to 5 mg per body weight.
/ Kg, preferably about 0.001 to 0.5 mg / kg is suitable, and the dose is administered once to several times a day. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex and the like. The drug of the present invention can be used concurrently with other drugs used for treatment of dizziness or at a time interval. Examples of such agents include diphenhydramine diprophylline, perphenazine, chlorpromazine hydrochloride, Ringer's lactate solution (dextran 40
), Anti-anxiety agents such as sodium hydrogen carbonate solution; diuretics such as isosorbide and acetazolamide; inner ear circulation improving agents such as betahistine mesylate and adenosine triphosphate disodium; vitamin agents such as mecobalamin; anxiolytics such as chlordiazepoxide and oxazolam. Agents; antiemetics; antihistamines such as dimenhydrinate; and similar drugs.

[0034]

EXAMPLES Next, the present invention will be specifically described by way of Examples, Test Examples and Production Examples, but the present invention is not limited to these Examples and the like.

Example 1 Injection 1.0 mg of the compound of Example 6, propylene glycol 3
00 mg and 100 mg of ethanol are mixed, and the total amount is 1 mL.
Water for injection may be added to prepare an injection.

Example 2 Capsule Preparation 1 part of the compound of Production Example 6, 3.5 parts of hydroxypropylmethylcellulose (trade name: TC5-E) and 0.5 part of polysorbate were mixed with methylene chloride / methanol (8 parts).
/ 2) Dissolved in 45 parts and prepared a solid dispersion by a spray drying method. To 100 mg of this solid dispersion, 160 mg of lactose and 40 mg of sodium hydrogen carbonate were added, and the mixture was filled in a gelatin capsule (size: 1) to give the compound of Production Example 6.
A capsule containing 20 mg was obtained.

The pharmacological action of the compound which is the active ingredient of the medicament of the present invention was confirmed by the following test examples.

Test Example 1 V _1A Receptor Binding Experiment (V _1A re
ceptor binding assay) Nakamura et al.'s method (Journal of Biological Chemistry,
Vol 258, No. 15, pp.9283-9289, 1983), a rat liver membrane preparation was prepared. 30 μg of rat liver membrane preparation [ ³
H] -Arg-vasopressin (hereinafter simply referred to as [ ³ H] -vasopressin) (0.5 nM, Specific activity = 75 Ci /
mmol) and test compound (10 ^-10 to 10 ^- with ⁶ M), 10
mM magnesium chloride, 0.1% bovine serum albumin (BSA)
Total volume of 50 mM Tris-HCl buffer (pH = 7.4) containing 2
Incubated in 50 μl for 60 minutes at 25 ° C. Thereafter, free using a cell harvester ^[3 H] - vasopressin the receptor bound ^[3 H] - vasopressin was separated, receptor bound to Unifilter plate GF / B glass filters ^[3 H] - vasopressin Was adsorbed. After being sufficiently dried, it was mixed with a microplate scintillation cocktail, the amount of receptor-bound [ ³ H] -vasopressin was measured using a top count, and the inhibition rate was calculated by the following formula. Inhibition rate (%) = 100− (C ₁ −B ₁ ) / (C ₀ −B ₁ ) ×
100 C ₁ : The amount of [ ³ H] -vasopressin bound to the membrane preparation when a known concentration of the test compound and [ ³ H] -vasopressin coexist and are treated with the receptor membrane preparation C ₀ : no test compound present When [ ³ H] -vasopressin and the receptor membrane preparation are treated below, the amount of [ ³ H] -vasopressin bound to the membrane preparation B ₁ : an excess amount of vasopressin (10 ⁻⁶ M) and [ ³ H] ] -When co-existing with vasopressin and treating with a receptor membrane preparation,
Amount of [ ³ H] -vasopressin bound to the membrane preparation The concentration of the test compound (IC ₅₀
Value) was calculated, and the affinity of the test compound for the receptor, that is, the dissociation constant (Ki) was calculated from the following formula. Ki = IC ₅₀ / (1+ [L] / Kd) [L]: [ ³ H] -Vasopressin concentration Kd: Dissociation constant of [ ³ H] -Vasopressin for a receptor determined by a saturation binding experiment. The negative value was taken as the pKi value by taking the logarithm of the obtained Ki value. The results are shown in Table 1.

Test Example 2 V ₂ Receptor Binding Experiment (V ₂ rece
ptor binding assay) Campbell's method (Journal of Biological Chemistr
y, Vol 247, No. 19, pp. 6167-6175, 1972). Rat kidney meningeal membrane specimen
200 μg of [ ³ H] -vasopressin (0.5 nM, Specific a
ctivity = 75 Ci / mmol) and test compound (10 ^-10 to 10 ^-6)
In the same manner as in the above-mentioned V _1A receptor binding experiment with M), the same measurement was carried out to determine the pKi value. The results are shown in Table 1.

[0040]

[Table 1]

As shown in Table 1, the effective composition of the medicine of the present invention is shown.
Compounds that are minutes are V_1AReceptor and V ₂Excellent for receptors
It has been revealed that the
It was

Test Example 3 Cytochrome P450 (3A
4) Enzyme inhibition experiment (Cytochrome P450 3A4 inhibition a
ssay) Method of Crespi et al. (Analytical Biochemistry, 248, 188-
190, 1997). Using a 96-well plate, BFC (5 × 10 ⁻⁵ M), test compound (9.1 × 10 ⁻⁸ to 2 × 10 ⁻⁵ M) and enzyme (10 ⁻⁸ M) were used as substrates.
3 mM NADP +, 3.3 mM glucose-6-pharpahte, 3.3 mM magnesium chloride and 0.4 Units / ml glucose-6-phosphate
Incubation was carried out at 37 ° C. for 30 minutes in a total volume of 100 μl of 20 mM phosphate buffer (pH = 7.4) containing dehydrogenase. Then, 100 mM Tris buffer containing 80% acetonitrile was added to stop the reaction, and the fluorescence intensity (excitation wavelength; 409 nm, fluorescence wavelength; 530 nm) was measured with a fluorescence plate reader. The inhibition rate was calculated from the following formula, and the test compound concentration (IC ₅₀ ) at which the inhibition rate was 50% was determined. Inhibition rate (%) = 100− (C ₁ −B ₁ ) / (C ₀ −B ₁ ) ×
100 C ₁ : Fluorescence intensity in the presence of a known concentration of the test compound, enzyme and substrate C ₀ : Fluorescence intensity in the absence of the test compound, in the presence of enzyme and substrate B ₁ : Fluorescence intensity of blank well

As a result, for example, International Publication No. 95/03
The N- [4- (2-
Benzyl-1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine-6-carbonyl) phenyl] biphenyl-2-carboxamide The inhibitory activity of hydrochloride is IC ₅₀ = 0.21μ
While the inhibitory activity of the compound of Production Example 6 was I,
C ₅₀ = 7.82 μM. That is, the compound, which is the active ingredient of the drug of the present invention, has an extremely small inhibitory effect on the drug-metabolizing enzyme CYP3A4, as compared with the known 1,4,5,6-tetrahydroimidazo [4,5-d] benzazepine derivative. Therefore, it became clear that the concern of drug interaction with other drugs metabolized via CYP3A4 is extremely small.

Test Example 4 Hearing-improving effect of a single administration in endolymphatic hydrops model (method) Female white guinea pig (23 cases, 332 to 420)
g, Japan SLC, Inc.) were used for the experiment. Nembutal was intraperitoneally administered, and strained otoacoustic emission (hereinafter abbreviated as "DPOAEs") before the preparation of endolymphatic hydrops was measured in both ears under spontaneous breathing (preoperative value). Next, the method of Kimura et al. (Practica Oto-Rhino-Laryngologica, Vol27,
pp 343-354, 1965.), the guinea pig skull was excised and the cerebellum was excreted inward with the dura of the brain to reach the left endolymphatic sac. After opening the endolymphatic sac, the soft tissue was removed up to the endolymphatic vessel with a hand drill, and the portion was occluded with bone meal and bone wax. Two weeks after the endolymphatic sac obstruction, DPOAEs were measured under Nembutal anesthesia (postoperative value). Three weeks after the endolymphatic sac occlusion, the test animals were divided into three groups, and (1) Production Example 13
For the administration group (7 cases), the compound of Production Example 13 was dissolved in an aqueous solution containing propylene glycol-200 (30%), 5 mM aqueous phosphoric acid solution (10%) and 1 M aqueous hydrochloric acid solution (2%) to produce For the (2) isosorbide group (8 cases), the dose of the compound of Example 13 corresponding to 3 mg per 1 kg of body weight was diluted with 3 ml of 0.5% methylcellulose aqueous solution per 1 kg of body weight. )) "Isobide" 2 ml (total 5 ml), (3) solvent group (8
For example, 0.5% methylcellulose aqueous solution was orally administered once. DPOAEs were measured again 3 hours after drug or solvent administration (post-dose value). The results are shown as the average value ± error. To compare the preoperative value with the postoperative value, a paired t-test was performed, and a case where the risk rate was less than 5% was regarded as a significant difference. In addition, in order to compare the post-dose values of the Production Example 13 group or the isosorbide group and the solvent group, multiple comparisons (Dunnett's test) that do not correspond to each other after the one-way analysis of variance were performed, and when the risk rate was less than 5%, it was regarded as a significant difference. Regarded (Results) As shown in Tables 2 and 3, compared with DPOAEs before the preparation of endolymphatic hydrops, DPOA of the left ear after preparation of endolymphatic hydrops
Es was significantly decreased at 2 and 4 kHz. No changes were seen in DPOAEs at 6 and 8 kHz. Production example 1 of 3 mg / kg was added to this left ear lymphedema guinea pig.
Single oral administration of 3 compounds decreased 2 and 4k
Hz DPOAEs were improved, and the effect was higher than that of the existing drug, isosorbide. DPOAEs in the right ear, which served as a control, showed no significant changes in preoperative, postoperative, and post-administration values.

[0045]

[Table 2]

[0046]

[Table 3]

Test Example 5 Hearing improving effect by repeated administration in endolymphatic hydrops model (method) Female white guinea pig (30 cases, 340 to 500)
g, Japan SLC, Inc.) were used for the experiment. Nembutal was intraperitoneally administered, and DPOAEs before the production of endolymphatic hydrops were measured in both ears under spontaneous breathing (preoperative value). Next, a left in-ear lymphedema model was prepared in the same manner as in Test Example 4. Two weeks after the endolymphatic sac obstruction, DPOAEs were measured under Nembutal anesthesia (postoperative value). Then, Production Example 13
Or the solvent (the dosage form is the same as in Test Example 4. Production Example 13 group: 10 cases, Isosorbide group: 10 cases, Solvent group: 10 cases) for 1 day daily for 2 weeks.
Oral administration was repeated multiple times. The day after the final administration of the drug or solvent,
The DPOAEs were measured again (value after administration). The results are shown as the average value ± error. To compare the preoperative value with the postoperative value, a paired t-test was performed, and a case where the risk rate was less than 5% was regarded as a significant difference. In addition, in order to compare the post-dose values of the Production Example 13 group or the isosorbide group and the solvent group, multiple comparisons (Dunnett's test) that do not correspond to each other after the one-way analysis of variance were performed, and when the risk rate was less than 5%, it was regarded as a significant difference. Regarded (Results) As shown in Tables 4 and 5, compared with DPOAEs before the preparation of endolymphatic hydrops, DPOA of the left ear after preparation of endolymphatic hydrops
Es was significantly decreased at 2 and 4 kHz. No changes were seen in DPOAEs at 6 and 8 kHz. Production example 1 of 3 mg / kg was added to this left ear lymphedema guinea pig.
Repeated oral administration of the compound No. 3 once daily for 2 weeks improved the lowered DPOAEs at 2 and 4 kHz, and the effect was more than that of the existing drug, isosorbide. DPOAEs of the right ear as a control were compared by preoperative value, postoperative value, post-administration value,
No significant change was observed.

[0048]

[Table 4]

[0049]

[Table 5]

Test Example 6 Histological improvement effect by repeated administration in endolymphatic hydrops model (method) Female white guinea pig (30 cases, 340-500)
g, Japan SLC, Inc.) were used for the experiment. Nembutal was intraperitoneally administered, and DPOAEs before the production of endolymphatic hydrops were measured in both ears under spontaneous breathing (preoperative value). Next, a left in-ear lymphedema model was prepared in the same manner as in Test Example 4. Two weeks after the endolymphatic sac obstruction, DPOAEs were measured under Nembutal anesthesia (postoperative value). Then, Production Example 13
Or the solvent (the dosage form is the same as in Test Example 4. Production Example 13 group: 10 cases, Isosorbide group: 10 cases, Solvent group: 10 cases) for 1 day daily for 2 weeks.
Oral administration was repeated multiple times. The day after the final administration of the drug or solvent,
After lethal exsanguination by saline perfusion under ether anesthesia,
Perfusion fixation was carried out with a phosphate buffered fixative containing 2.5% glutaraldehyde and 5% formalin. The cochlea was removed with the left and right temporal bones connected, and fixed with the same fixative solution for 24 hours. Then deash with ethylenediaminetetraacetic acid aqueous solution,
Trimming was done. Then, it was washed with water, dehydrated with alcohol, embedded in paraffin, and sliced. After slicing, hematoxylin and eosin staining is performed to prepare a tissue sample,
It was observed under an optical microscope. The cross-sectional area of endolymphatic hydrops was measured using an apparatus equipped with a television camera and a computer in addition to the optical microscope. To measure the cross-sectional area of endolymphatic hydrops, a section cut at the center of the cochlea axis was used. A schematic diagram of the measurement of endolymphatic hydrops cross-sectional area is shown in FIG. According to the method of Takeda et al. (Hearing Research Vol 140, pp 1-6, 2000.), the area of the endolymphatic vessel surrounded by the solid line xy where the Reissner membrane was originally located was defined as S, and this was used as a reference value. . Further, the area surrounded by the solid line Reissner film and the solid line xy was measured as S ′. Calculation formula: S '/ S x 1
The rate of change of edema (%) was determined by measuring 00. In addition, the cross-sectional area of the endolymphatic vessel of the right ear, which is a non-operative ear as a control ear, was also measured. In addition, in order to compare the production example 13 group or the isosorbide group with the solvent group, unpaired multiple comparisons (Dunnett's test) were performed after one-way analysis of variance, and a case where the risk rate was less than 5% was regarded as a significant difference. (Results) As shown in FIG.
The protrusion of the Reissner membrane was confirmed. That is, it was also histologically observed that endolymphatic hydrops was caused by endolymphatic sac obstruction. In addition, as shown in Table 6, when 3 mg / kg of the compound of Production Example 13 was repeatedly orally administered once a day for 2 weeks to this left ear lymphedema guinea pig, the endolymphatic edema was reduced and the edema change rate was increased. It was significantly improved, and its effect was superior to that of the existing drug, isosorbide. In the right ear as a control, no significant change was observed in any of Production Example 13, the isosorbide group, and the solvent group.

[0051]

[Table 6]

The compound which is the active ingredient of the medicine of the present invention is
It was manufactured according to the following manufacturing method. In addition, the manufacturing method of the raw material compound used in a manufacturing example is demonstrated as a reference manufacturing example.

Production Example 1 1.0 g of N- [4- (5-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-carbonyl) phenyl] biphenyl-2-carboxamide was dissolved in 30 ml of tetrahydrofuran. And phenyltrimethylammonium tribromide 0.902 g
Was added and stirred at room temperature for 150 minutes. The insoluble matter in the reaction solution was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 30 ml of chloroform, to which 1.70 g of 2-amidinopyridinium hydrochloride hydrate and 2.1 g of potassium carbonate were added, and the mixture was heated under reflux for 9 hours. The reaction solution was cooled and washed with water, and the chloroform layer was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the obtained residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (70: 1). To the eluate, 0.9 ml of 4M hydrochloric acid-ethyl acetate solution in chloroform was added, and the residue obtained after evaporation of the solvent was recrystallized from acetonitrile to give 0.830 g of N- {4- [2-
(2-pyridyl) -1,4,5,6-tetrahydroimidazo [4,5-d]
[1] Benzazepine-6-carbonyl] phenyl} biphenyl
-2-carboxamide hydrochloride was obtained.

Then, the compounds of Production Examples 2 to 4 shown in Table 7 were produced in the same manner as in the above Production Example 1 using the corresponding starting materials. The following abbreviations are used in the table (same below). Pn: Production example number, Rpn: Reference production example number, salt: salt (not shown: free form; HCl: hydrochloride; H ₂ O: hydrate), Data:
Physicochemical data, MS: FAB-MS (M + H) ⁺ , MS-: FAB-MS (M-
H) ⁻ , NMR: ¹ H-NMR δ (ppm), mp: melting point (° C.).

[0055]

[Table 7]

Reference Production Example 1 2.0 g of 1,2,3,4-tetrahydro-1- (4-methylbenzenesulfonyl) -1-benzazepin-5-one was dissolved in 30 ml of chloroform and bromine was added at room temperature. 0.33 ml of chloroform 10
The solution dissolved in ml was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction solution was washed with saturated sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in 30 ml of chloroform, 5.0 g of 2-amidinopyridinium hydrochloride hydrate and 5.3 g of potassium carbonate were added, and the mixture was heated under reflux for 10 hours. After cooling the reaction solution, the solvent was distilled off. To the obtained residue, 30 ml of 1M hydrochloric acid aqueous solution was added, and the precipitated solid was collected by filtration. The obtained solid was suspended in chloroform, washed with 1M aqueous sodium hydroxide solution, and the chloroform layer was dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent was recrystallized from ethanol to give 1.70 g of 2-
(2-Pyridyl) -1,4,5,6-tetrahydro-6- (4-methylbenzenesulfonyl) imidazo [4,5-d] [1] benzazepine was obtained. ¹ H-NMR (DMSO-d ₆ ); δ2.12 (3H, s), 3.00-3.33 (4H, br), 7.13
(2H, d, J = 8.1Hz), 7.21 (1H, dt, J = 1.4Hz, 8.1Hz), 7.29-7.43
(5H, m), 7.89 (1H, dt, J = 1.4Hz, 8.1Hz), 8.07 (1H, d, J = 8.1H
z), 8.17 (1H, d, J = 7.3Hz), 8.60 (1H, d, J = 4.4Hz).

Reference Production Example 2 2.93 g of the compound of Reference Production Example 1 was added to 9 ml of sulfuric acid and 4.3 ml of acetic acid.
After being dissolved in, the mixture was heated and stirred in a hot water bath at 70 ° C for 90 minutes. The reaction solution was poured into 100 ml of ice water, basified by adding 10 M sodium hydroxide aqueous solution, and 200 ml of methyl ethyl ketone was added for liquid separation operation. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was crystallized from ethyl acetate, and the precipitated crystals were collected by filtration and dried to obtain 1.038 g of 2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo. [4,5-d] [1] benzazepine was obtained. ¹ H-NMR (DMSO-d ₆ ); δ2.97 (2H, t, J = 5.1Hz), 3.20-3.26 (2H,
m), 5.95 (1H, t, J = 3.7Hz), 6.73-6.82 (2H, m), 6.93 (1H, dt, J
= 1.5Hz, 7.3Hz), 7.34 (1H, dd, J = 4.4Hz, 8.1Hz), 7.86 (1H, d
t, J = 1.5Hz, 8.1Hz), 8.11 (1H, d, J = 8.1Hz), 8.24 (1H, dd, J =
1.5Hz, 8.1Hz), 8.59 (1H, d, J = 4.4Hz), 12.67 (1H, s).

Reference Production Example 3 2-phenylbenzoic acid 0.66 g, tetrahydrofuran 7 ml,
0.29 ml of thionyl chloride was added to a solution of 1 drop of N, N-dimethylformamide under ice cooling, and the reaction solution was stirred at room temperature for 2 hours.
The reaction mixture was concentrated under reduced pressure, 3 ml of toluene was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained residue was dissolved in 3 ml of chloroform, 0.56 g of methyl 4-amino-2-fluorobenzoate,
Dichloroaniline 0.63 ml chloroform solution (6 ml)
Was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with 1M aqueous hydrochloric acid solution and 1M aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (3: 1) to give 1.00 g of 4 Methyl [-((biphenyl-2-carbonyl) amino] -2-fluorobenzoate was obtained.

Hereinafter, the compounds of Reference Production Examples 4 to 7 shown in Table 8 were produced in the same manner as in the above Reference Production Example 3 using the corresponding starting materials.

[0060]

[Table 8]

Reference Production Example 8 The compound of Reference Production Example 3 (1.00 g) was dissolved in ethanol (10 ml), and 1M aqueous sodium hydroxide solution (4.35 ml) was added. The reaction solution was stirred at room temperature for 2 days. The reaction mixture was adjusted to pH 6 with a 1 M aqueous hydrochloric acid solution, and the precipitated solid was collected by filtration. The obtained solid was recrystallized from ethyl acetate to give 0.77.
g of 4-[(biphenyl-2-carbonyl) amino] -2-fluorobenzoic acid was obtained.

Hereinafter, the compounds of Reference Production Examples 9 to 12 shown in Table 9 were produced in the same manner as in the above Reference Production Example 8 using the corresponding starting materials.

[0063]

[Table 9]

Production Example 5 4-[(biphenyl-2-carbonyl) amino] benzoic acid 3.60
1.21 ml of thionyl chloride was added to a suspension of g, 100 ml of tetrahydrofuran and 1 drop of N, N-dimethylformamide under ice cooling, and the reaction solution was stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, 5 ml of toluene was added to the residue, and the mixture was concentrated again under reduced pressure. An acetonitrile solution (90 ml) of 2.84 g of the compound of Reference Production Example 2 was added to the obtained residue, and the mixture was heated and stirred in a hot water bath at 80 ° C. for 17 hours and 30 minutes. After cooling the reaction solution at room temperature, the deposited precipitate was collected by filtration and washed with acetonitrile.
The obtained solid was suspended in a 1 M aqueous sodium hydroxide solution,
It was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate to obtain 4.921 g of N- {4- [2- (2-
Pyridyl) -1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine-6-carbonyl] phenyl} biphenyl-2-carboxamide monohydrate was obtained. ¹ H-NMR (DMSO-d ₆ ); δ2.61-3.30 (3H, m), 4.93-5.40 (1H, m),
6.72 (1H, d, J = 7.3Hz), 6.88 (2H, d, J = 7.8Hz), 6.96 (1H, t, J =
7.8Hz), 7.24-7.56 (13H, m), 7.94 (1H, dt, J = 2.0Hz, 7.8Hz),
8.19 (1H, d, J = 7.8Hz), 8.29 (1H, d, J = 7.3Hz), 8.65 (1H, d, J =
4.4Hz), 10.28 (1H, s), 13.05 (1H, s) FAB-MS (M + H) ⁺ ; 562. Elemental analysis; C ₃₆ H ₂₇ N ₅ O ₂ .H ₂ O (calculated value) C: 74.59%; H: 5.04%; N: 12.08%; O: 8.28
(Actual value) C: 74.89%; H: 5.01%; N: 12.15%.

Production Example 6 To 1.0 g of the compound of Production Example 5 was added 20 ml of acetonitrile,
The mixture was heated and stirred in an oil bath at 95 ° C for 35 minutes. After cooling the suspension at room temperature, the precipitate was collected by filtration, washed with 6 ml of acetonitrile and 0.85 g of N- {4- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo [ 4,5-d] [1] Benzazepine-6-carbonyl]
Phenyl} biphenyl-2-carboxamide was obtained. ¹ H-NMR (DMSO-d ₆ ); δ2.97-3.26 (3H, m), 4.97-5.00 (1H, m),
6.71 (1H, d, J = 7.6Hz), 6.88 (2H, d, J = 8.4Hz), 6.95 (1H, t, J =
7.6Hz), 7.24-7.57 (13H, m), 7.94 (1H, dt, J = 1.6Hz, 7.6Hz),
8.18 (1H, d, J = 7.6Hz), 8.30 (1H, d, J = 8.0Hz), 8.63 (1H, d, J =
4.8Hz), 10.27 (1H, s ), 13.03 (1H, s) FAB-MS (M + H) +;. 562 mp;. 240-242 ° C. Elemental analysis: as _{C 36 H 27 N 5 O 2} , ( Calculated) C: 76.99%; H: 4.85%; N: 12.47%; O: 5.70
(Actual value) C: 77.08%; H: 4.93%; N: 12.39%.

Production Example 7 4-[(biphenyl-2-carbonyl) amino] benzoic acid 0.605
0.167 ml of ice-cooled thionyl chloride was added to a suspension of g, 10 ml of tetrahydrofuran, and 1 drop of N, N-dimethylformamide, and the reaction solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, 5 ml of toluene was added to the residue, and the mixture was concentrated again under reduced pressure. An acetonitrile solution (25 ml) containing 0.385 g of the compound of Reference Production Example 2 was added to the obtained residue, and the mixture was placed in a water bath at 80 ° C for 4 hours.
The mixture was heated and stirred for an hour. After cooling the reaction solution at room temperature, the deposited precipitate was collected by filtration and washed with acetonitrile. The obtained solid was suspended in a 1 M sodium hydroxide aqueous solution and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (49: 1). The eluate was concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate to give 0.56
6 g of N- {4- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine-6-carbonyl] phenyl} biphenyl-2- A carboxamide was obtained. The obtained crystals were suspended in a mixed solution of ethyl acetate-methanol, 477M hydrochloric acid-ethyl acetate solution (0.277 ml) was added, and the solvent was evaporated under reduced pressure.
The obtained residue was suspended in 20 ml of ethanol and heated and stirred in a hot water bath at 80 ° C for 10 minutes. After cooling the suspension at room temperature, the precipitate is collected by filtration, washed with ethanol, and 0.350 g of N-
{4- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo [4,
5-d] [1] benzazepine-6-carbonyl] phenyl} biphenyl-2-carboxamide hydrochloride was obtained. The physicochemical data of Production Example 7 was the same as that of Production Example 1.

Thereafter, the compounds of Production Examples 8 to 11 shown in Tables 10 and 11 and the compound of Reference Production Example 13 were produced in the same manner as in the above Production Example 7 using the corresponding starting materials.

Production Example 12 0.525 g of the compound of Reference Production Example 13 was added to 6 m of trifluoroacetic acid.
It was dissolved in 1, and 0.466 g of pentamethylbenzene was added thereto. The reaction solution was stirred at room temperature for 3 hours, 0.233 g of pentamethylbenzene was added to the reaction solution again, and the reaction solution was further stirred at room temperature for 2 hours.
Stir for 1 hour. The reaction solution was concentrated under reduced pressure, 3 ml of toluene was added to the residue, and the mixture was concentrated again under reduced pressure. Dissolve the obtained residue in 10 ml of chloroform,
ml was added, and the precipitated solid was collected by filtration. To the obtained solid was added 4M hydrochloric acid-ethyl acetate solution 0.20 ml in ethyl acetate,
The residue obtained after distilling off the solvent was recrystallized from ethanol to give 0.300 g of N- {2-hydroxy-4- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo [4 , 5-d] [1] Benzazepine-6-carbonyl] phenyl} biphenyl-2-carboxamide hydrochloride was obtained.

[0069]

[Table 10]

[0070]

[Table 11]

Production Example 13 To 1.0 g of the compound of Production Example 5 was added 40 ml of 70% acetone water, and the mixture was added to 60 g.
The mixture was heated and stirred at ℃. To this, add 826 mg of maleic acid to 30
Heated to reflux for minutes. The reaction solution was cooled at room temperature and then stirred for 24 hours. The obtained precipitate was collected by filtration and 1.107 g of N- {4- [2-
(2-pyridyl) -1,4,5,6-tetrahydroimidazo [4,5-
d] [1] Benzazepine-6-carbonyl] phenyl} biphenyl-2-carboxamide monomaleate monohydrate was obtained. ¹ H-NMR (DMSO-d ₆ ); δ2.96-3.30 (3H, m), 4.92-5.05 (1H,
m), 6.25 (2H, s), 6.73 (1H, d, J = 7.4Hz), 6.90 (2H, d, J = 7.8H
z), 6.98 (1H, t, J = 7.3Hz), 7.24-7.57 (13H, m), 7.97 (1H, dt,
J = 1.5Hz, 7.8Hz), 8.19 (1H, d, J = 7.8Hz), 8.27 (1H, d, J = 7.8H
z), 8.66 (1H, d, J = 4.8Hz), 10.27 (1H, s). FAB-MS (M + H) ⁺ ; 562. Elemental analysis; C ₃₆ H ₂₇ N ₅ O ₂ .C ₄ H ₄ As O ₄ .H ₂ O (calculated value) C: 69.05%; H: 4.78%; N: 10.07%; O: 16.10
% (Actual value) C: 68.91%; H: 4.67%; N: 9.90%

Tables 12 to 14 below show the structures of other compounds as active ingredients of the medicament of the present invention. These can be easily produced by using the above-mentioned production method, the method described in the production examples, the method obvious to those skilled in the art, or these modified methods. In the table, No indicates the compound number.

[0073]

[Table 12]

[0074]

[Table 13]

[0075]

[Table 14]

[0076]

From the above results, it became clear that the medicament of the present invention is effective as a therapeutic agent for Meniere's disease or Meniere's syndrome, dizziness, deafness or tinnitus.

Further, since the compound or its salt, which is the active ingredient of the medicament of the present invention, has a very small inhibitory effect on the drug-metabolizing enzyme CYP3A4, it is known that the drug may interact with other drugs metabolized via CYP3A4. 1,
Compared to the 4,5,6-tetrahydroimidazo [4,5-d] benzazepine derivative, it is less and is superior in that it can be safely used in combination therapy with other agents. Examples of the drug metabolized by CYP3A4 include simvastatin, lovastatin, fluvastatin, atorvastatin, midazolam, nifedipine, amlodipine, nicardipine and the like (general clinical practice, 48 (6), 1427-1431, 1999).

[0078]

[Brief description of drawings]

FIG. 1 is a diagram schematically showing a method for measuring a cross-sectional area of endolymphatic hydrops.

FIG. 2 is a diagram showing the states of the intra-cochlear Reissner membrane of the surgical ear (left ear) and the control ear (right ear), showing that the Reissner membrane is located at the tip of the wedge.

Continued front page    (72) Inventor Yukinori Arai             21 Miyukigaoka, Tsukuba City, Ibaraki Prefecture Yamanouchi Pharmaceutical             Within the corporation (72) Inventor Katsumi Sudo             21 Miyukigaoka, Tsukuba City, Ibaraki Prefecture Yamanouchi Pharmaceutical             Within the corporation F-term (reference) 4C050 AA01 AA07 BB05 CC10 EE03                       FF05 GG01 HH04                 4C086 AA01 AA02 CB11 MA01 MA02                       MA17 MA37 MA66 NA14 ZA32                       ZA34

Claims (8)

[Claims] 1. A compound represented by the general formula (I): 1,4,5,6-
A therapeutic agent for Meniere's disease or Meniere's syndrome, comprising a tetrahydroimidazo [4,5-d] benzazepine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. [Chemical 1] (The symbols in the formulas have the following meanings: Ring D: phenylene or pyridinediyl. X and Y: same or different CH or N. R ¹ , R ² and R ³ : same or different hydrogen atom, hydroxyl group, Halogen or lower alkyl.) 2. Ring D is 1,4-phenylene or pyridine-
The therapeutic agent for Meniere's disease or Meniere's syndrome according to claim 1, which is 2,5-diyl or pyridine-3,6-diyl. 3. The therapeutic agent for Meniere's disease or Meniere's syndrome according to claim 2, wherein X and Y are CH and R ¹ is a hydrogen atom. 4. The therapeutic agent for Meniere's disease or Meniere's syndrome according to claim 3, wherein ring D is 1,4-phenylene, and R ² and R ³ are both hydrogen atoms. 5. N- {4- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine-6-carbonyl]
Phenyl} biphenyl-2-carboxamide, N- {3-fluoro-4- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine-6 -Carbonyl] phenyl} biphenyl-2-carboxamide, 2'-fluoro-N- {4- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo [4,5-d] [1] Benzazepine-6-carbonyl]
Phenyl} biphenyl-2-carboxamide, N- {5- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo
[4,5-d] [1] benzazepine-6-carbonyl] -2-pyridyl}
Biphenyl-2-carboxamide, N- {6- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo
[4,5-d] [1] benzazepine-6-carbonyl] -3-pyridyl}
Biphenyl-2-carboxamide, N- {2-hydroxy-4- [2- (2-pyridyl) -1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine-6-carbonyl ]
The therapeutic agent for Meniere's disease or Meniere's syndrome according to claim 1, which comprises phenyl} biphenyl-2-carboxamide or a pharmaceutically acceptable salt thereof as an active ingredient. 6. A therapeutic agent for dizziness comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient. 7. A therapeutic agent for hearing loss comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient. 8. A tinnitus therapeutic agent comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.