WO1994014796A1

WO1994014796A1 - Novel n-(pyridylcarbonyl)benzazepine derivative and intermediate therefor

Info

Publication number: WO1994014796A1
Application number: PCT/JP1993/001838
Authority: WO
Inventors: Yuzo Matsumoto; Akihiro Tanaka; Akira Matsuhisa; Kazumi Kikuchi; Ken-Ichiro Sakamoto; Takeyuki Yatsu; Isao Yanagisawa
Original assignee: Yamanouchi Pharmaceutical Co., Ltd.
Priority date: 1992-12-21
Filing date: 1993-12-17
Publication date: 1994-07-07
Also published as: AU5692094A

Abstract

An N-(pyridylcarbonyl)benzazepine derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof, useful for preventing and treating cardiac failure, hyponatremia, syndrome of inappropriate secretion of vasopressin (SIADH), hypertension, renal failure, edema, water metabolism disorder, and the like on the basis of arginine vasopressin receptor antagonism; and a benzazepinylcarbonylpyridine derivative represented by general formula (II) or a salt thereof, useful as an intermediate for the production of the compound (I) and so forth, wherein R represents hydrogen, lower alkyl, lower alkoxy, halogen, or phenyl which may be substituted by lower alkyl; X represents -NHCO- or -CON(R1)-; n represents 0 or 1; and R1 represents hydrogen or (a) wherein R is as defined above, wherein n is as defined above; and Y represents COOH, activated carboxy, protected carboxy, or optionally protected HN(R1)-.

Description

Description Novel N- (pyridylcarbonyl) benzazepine derivatives and their intermediates

The present invention relates to an N- (pyridylcarbonyl) benzazepine derivative, a pharmaceutically acceptable salt thereof, and an intermediate thereof, which are useful as a medicine, especially an arginine vasopressin receptor antagonist.

Background art

Arginine vasopressin (AVP) is a nine amino acid peptide that is biosynthesized and secreted by the hypothalamus-pituitary system. Conventionally, as this arginine vasopressin receptor antagonist, a peptide vasopressin receptor antagonist (see, for example, JP-A-2-32098) and a non-peptide vasopressin receptor antagonist (for example, 3-1 7370, No. 9 / 055,549 pamphlet (see 1991) has been synthesized, but the compound of the present invention is different from these compounds. It is a novel compound with a different structure. Disclosure of the invention

The present inventors have conducted intensive studies on compounds having an arginine vasopressin antagonistic activity. As a result, an N- (pyridylcarbonyl) benzazepine derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof are: Arginine vasopressin has excellent activity on both V i and V ₂ receptors, and has been found to have particularly potent V 2 receptor antagonistic activity. In addition, the compound represented by the following general formula (Π) or a salt thereof is The inventors have found that they are useful as intermediates, and have completed the present invention.

(0) n

[The symbols in the formula have the following meanings.

R: a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, or a phenyl group which may be substituted with a lower alkyl group,

X: a group represented by the formula -NHCO- or -CON-

R ¹ n: 0 or 1,

R ¹ : a hydrogen atom or a group represented by the formula: CO (wherein R has the above-mentioned meaning)].

(O) n

[Wherein, n has the meaning described above. Y has the following meaning.

Y: carboxy group, activated carboxy group, protected carboxy group,

HN-HN- group represented by the formula or protected formula

R R

1,

(Wherein R ¹ has the meaning described above)].

That is, the compound (I) of the present invention or a pharmaceutically acceptable salt thereof includes a benzazepinylcarbonyl group and a substituted or unsubstituted phenylamino group. A carbonyl group or a mono- or di- (substituted or unsubstituted phenyl) carbamoyl group having a chemical structural characteristic in that it is bonded to the pyridine ring, and has arginine vasopressin V 1 and v ₂ receptors. Although it has excellent antagonistic activity to both, it is a compound that has pharmacological characteristics, in particular in that it has a strong antagonistic effect on the V2 receptor.

In addition, the intermediate (塩) or a salt thereof of the present invention is characterized in that the benzazepinylcarbonyl group is bonded to the pyridine ring of pyridinecarboxylic acid or a substitutable aminopyridin or a derivative thereof. Is characterized by its chemical structure.

Hereinafter, the compound of the present invention will be described in detail.

In the definition of the general formula herein, unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms.

Accordingly, as the "lower alkyl group", specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl (amyl) group, isopentyl group, Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3- Methylpentyl group, 1,1-dimethylbutyl group,

1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2 Trimethylpropyl group. 1,2,2—Trimethylpropyl group, 1-Ethyl-1 monomethylpropyl group, 1-Ethyl-2-methylpropyl group, and the like. of preferably a methyl group, Echiru group, an isopropyl groups, C and butyl group, an c ₄ alkyl group, more preferred properly methyl group, an Echiru group, especially a methyl group good preferable. The “lower alkoxy group” includes a methoxy group, an ethoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butyne group, a pentyloxy (amyloxy) group, an isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group, etc., among which methoxy, ethoxyquin, propoxy, A C 1 -C 4 alkoxy group such as a butoxy group, particularly a methoxy group, is preferred.

Examples of the “halogen atom” include an iodine atom, a fluorine atom, a chlorine atom, a bromine atom and the like, and an iodine atom is particularly preferable.

The “activated carboxy group” represented by Y includes acid halides such as acid chloride and acid bromide: acid azide; phenolic compounds such as p-ditrophenol, and 1-hydroxysuccinimide; (I) Active esters obtained by reacting with N-hydroxylamine compounds such as hydroxybenzotriazole; symmetrical acid anhydrides; alkyl esters of halocarboxylic acids such as alkyl carbonate halides and pivaloyl halides Mixed acid anhydrides such as organic acid-based mixed acid anhydrides obtained by reacting with diphenylphosphoryl chloride and N-methylmorpholine, etc. Activating power Lupoxy group.

“Protected carboxy group” means a carboxy group protected by a carboxy group protecting group usually used in the art, and examples of the carboxy group protecting group include a benzyl group, a p-nitrobenzyl group, and a p-nitrobenzene group. Methoxybenzyl, 2,4,6—trimethylbenzyl, pentamethylbenzyl, methyl, ethyl, tert-butyl, benzhydryl, trityl, phthalimidmethyl, cyclopentyl, Examples include ester residues such as 2-methylthioethyl, phenacyl, and 4-picolyl. HN one

In addition, “protected groups of formula I” are also usually

R ¹ means those protected with an amino protecting group. The protecting groups for the amino group include benzyloxycarbonyl, P-methoxybenzyloxycarbonyl, p — Methylbenzyloxycarbonyl group, p-chlorobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-phenylazobenzylquinoxycarbonyl group, p-methoxyphenoxycarbonyl group Nilazobenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, 3,4,5-trimethoxybenzoyloxycarbonyl group, tert-butoxycarbonyl group, tert-amyloxyquin Urethane-type protecting groups such as carbonyl group, p-biphenyloxypropyloxycarbonyl group, diisopropylmethyloxycarbonyl group, formyl group, acetyl group, Acetyl protecting groups such as fluoroacetyl group, phthalyl group, tosyl group, o-ditrophenylsulfonyl group, p-methoxy 0-2-nitrophenylsulfenyl group, benzoyl group, chloroacetyl group, trityl group, Alkyl-type protecting groups such as benzyl group, 2-benzoyl-1-methylvinyl group and trimethylsilyl group; arylidene-type protecting groups such as benzylidene group and 2-hydroxyarylidene group; and toluenesulfonylo for tertiary suppression. Protecting groups such as xyl group, phenacylsulfonyl group, trifluorene sulfonyl group and bisbenzenesulfonyl group, and phthalimid group formed integrally with the nitrogen atom of amino group.

The compound represented by the general formula (I) may form an acid addition salt. Compound (また) also forms a salt. The present invention also includes pharmaceutically acceptable salts of compound (I), such as mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, formic acid, acetic acid and propionic acid. , Butyric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, lingoic acid, tartaric acid, carbonic acid. Organic such as glutamate, aspartic acid And salts with acids such as acids.

The intermediates of the present invention also include salts of the compound (II). Such salts include, in addition to the above-mentioned acid addition salts, metals such as sodium, potassium, magnesium, calcium, and aluminum. And salts with organic bases such as dimethylamino, dimethylamine, getylamine, trimethylamine, and triethylamine, and ammonium salts.

The compound of the present invention may contain an asymmetric carbon atom depending on the kind of the substituent, and such a compound has an optical isomer. The present invention includes isolated isomers of various isomers and mixtures thereof. Further, the compound of the present invention may be isolated as hydrates, various solvates and polymorphic substances, and the present invention includes these substances.

Among the compounds of the present invention, particularly preferred compounds are those in which X in the above formula (I) is a group represented by the formula C 0 NH—, ie, the following formula (一般)

• (O) n

(Wherein, R and n have the above meanings)

Or a pharmaceutically acceptable salt thereof. Particularly preferred compounds include the following.

(1) 2-Methyl-N— [5 — [(2,3,4,5-Tetrahydro-1H-1-benzazepine-1-yl) carbonyl] 1-2-1-pyridyl] benzamide or a pharmaceutical thereof A biologically acceptable salt.

(2) 2-(4-Methylphenyl) i N— [5— [(2, 3, 4,

5—Tetrahydr Draw 1 H—1—Benzezepine [Carbonyl] -12-pyridyl] benzamide or a pharmaceutically acceptable salt thereof.

(3) 2-phenyl-1-N— [5 -— ((2,3,4,5-tetrahydro 1H—1-benzazepine-1-yl) carbonyl] -12-pyridyl] benzamide or its Pharmaceutically acceptable

(4) 2-Feline N— [2-[(2,3,4,5-tetrahydro 1H—1 benzazepine-1 1-yl) carbonyl] -1-5-pyridyl] benzamide or Pharmaceutically acceptable compounds Preferred compounds as intermediates include compounds wherein Y is an amino group or salts thereof.

(1) 1-[(2-amino-5-pyridyl) caprolponyl] —2,3,4,5-tetrahydro—1H—1 benzazepine or its

(2) 1 [(5-Amino-2-pyridyl) caprolponyl] —2,3,4,5-tetrahydro 1H-1 —benzazepine or its preferred.

(Manufacturing method)

The compound of the present invention can be synthesized by various methods. The typical production method is illustrated below.

First manufacturing method

(IV) (O) n

Or its salt or its activated derivative

(Ila)

(Wherein, R and n have the above meanings.)

In this production method, the carboxylic acid represented by the general formula (Ila) or an activation derivative thereof and the displaceable aniline represented by the general formula (IV) or a salt thereof are amidated by a conventional method. The activated derivative of the compound (I la) may be a normal ester such as methyl ester, ethyl ester, isobutyl ester or tert-butyl ester, or the intermediate (II). )), A compound having an activated carboxy group as Y.

In addition, when reacting the compound (Ila) with a free acid or reacting with an active ester, dicyclohexylcarpoimide, carbonyldiimidazole, diphenylphosphorylazide, getylphosphorylcyanide, or 1- (3-dimethylaminopropyl) It is preferable to use a condensing agent such as 3-ethylcarbodimid hydrochloride. O

Particularly, in the present invention, an acid chloride method, a method of reacting in the presence of an active esterifying agent and a condensing agent, and a method of treating an ordinary ester with an amide can be easily and easily used as the compound of the present invention, which is advantageous. It is.

The reaction varies depending on the activated derivative used, the condensing agent, etc., but is usually halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers. Ethers, such as tetrahydrofuran, tetrahydrofuran, etc., esters, such as ethyl acetate, N, N-dimethylformamide アミ dimethylsulfoxide, etc. In an organic solvent inert to the reaction, depending on the activated derivative, it may be cooled or cooled. The reaction is carried out at room temperature or at room temperature or under heating. In the reaction, the compound (IV) may be used in excess, or N-methylmorpholine, trimethylamine, triethylamine, N, N-dimethylaniline, pyridine, 4- (N, N-dimethylamine) may be used. Mino) In some cases, it is advantageous to carry out the reaction in the presence of a base such as pyridine, picoline, lutidine, etc., in order for the reaction to proceed smoothly. Pyridines can also be used as solvents.

As shown in the following reaction formula, the intermediate (I la) of the present invention is obtained by converting pyridin carboxylic acid having a protected carboxy group or its N-oxo derivative or its activated derivative (V) into The compound can be produced by reacting with benzazepine (VI) or a salt thereof to remove the protecting group, if necessary, or activating the carboxine group, if desired.

(O) n

(VI)

Or its activated derivative or its salt

(O) n

Or its activated derivative

(Ha)

(Wherein, n has the above-mentioned meaning and Yl means a protected carboxy group) The amidation reaction is the same as the amidation for producing the above compound (la).

The removal of the protecting group depends on the type of the protecting group. When the protecting group is a methyl group or an ethyl group, the tert-butyl group is obtained by genation. When it is a petryl group, it can be easily removed by treating it with an acid such as trifluoroacetic acid. When it is a trimethylsilyl group, it can be easily removed by contact with water.

Activated derivatives can be produced according to conventional methods. For example, acid halides are inactive in the reaction of dimethylformamide, dimethylsulfoxide, methylene chloride, dichloromethane, chloroform, carbon tetrachloride, etc. It is advantageous to carry out the reaction with a halogenating agent such as thionyl chloride, lin trichloride, lin tribromide, lin pentachloride in a suitable solvent at room temperature to elevated temperature, preferably with heating to reflux. Second manufacturing method

(O) n

(lb)

(Wherein R, Rl and n have the meanings given above.)

In this production method, the compound (lb) of the present invention is produced by amidating a compound (VII) or an activated derivative thereof and an amine represented by the general formula (lib) or a salt thereof by a conventional method. Is the way.

This production method can be carried out in the same manner as the first production method.

The intermediate (lib) of the present invention comprises, for example, a protected aminobilidine carboxylic acid or its N-oxide or an activated derivative at their carboxy group and a compound (VI) or a salt thereof in the same manner as in the first production method. It can be produced by various methods such as amidation and removal of protecting groups. In particular, when the starting material is benzazepinylcarboryl pyridine acid (Ila-2) in the intermediate (Ila), as shown in the following reaction formula, the starting compound (Ila-2) and the tertiary amine are used. (VIII) and alcohol (IX) in the presence of an azide-based condensing agent, diphenylphosphoryl azide (DPPA; X), transforms the isocyanate formed by the Crutius rearrangement. Alcohol-added sulfamate compound (A compound protected with a urethane-type protecting group), and then applying a conventional method for removing the urethane-type protecting group, treating it with an acid such as trifluoroacetic acid, or using methyl iodide or the like. To produce the amisopyridine compound (lib-1) advantageously by decomposing the carbamic acid ester by catalytic reaction, or by catalytic reduction in the case of a substituted or unsubstituted benzyloxy carbonylamide group. Can be. In addition, the secondary amino pyridine compound (lib-2) is converted into a salt if necessary, and the amino group of the compound (lib-1) is protected with a protecting group for suppressing tertiary formation. It can be produced by amidation in the same manner as described above.

The carbamic acid ester compound can also be produced by applying a conventional method in which an acid halide of the compound (Ila) is azidated with an azidating agent, heated, and then the compound (Π) is added. It is.

H DPPA (X),

Mm

(lib-2)

[Wherein, R and n have the above-mentioned meanings, and other symbols have the following meanings.

: Lower alkyl group.

R ^J : an alkyl group having 1 to 7 carbon atoms; or benzyl which may be substituted with 1 to 3 methyl, methoxy, chloro, nitro, phenylazo or methoxyphenylazo. Or a biphenylisopropyl group. ] Third manufacturing method

(Ic) (Id)

Wherein X and R have the above-mentioned meanings.

The pyridine N-oxide compound represented by the general formula (Id) in the compound of the present invention can be produced by oxidizing the corresponding pyridine compound (Ic).

Oxidation is carried out in an organic solvent inert to the reaction, such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride, or alcohol such as methanol, with an oxidizing agent added at room temperature or at elevated temperature. Oxidizing agents include organic peracids such as m-chloroperbenzoic acid, perbenzoic acid, formic acid, pertrifluoroacetic acid, perphthalic acid, permaleic acid, peracetic acid, and hydrogen peroxide. Inorganic peracids such as acetic acid, peroxide, chromic anhydride, sulfuric acid peroxide and sulfuric acid peroxide are used.

The compound (I) of the present invention is a substituted or unsubstituted phenylaminocarbonylcarbiridine carboxylic acid or a substituted or unsubstituted phenylcarbonylaminoaminopyridin carboxylic acid corresponding to benzazepine or a salt thereof and N-oxides thereof. Alternatively, it can also be produced by amidation using an activated derivative thereof in the same manner as in the first production method. The reaction product obtained by each of the above methods is isolated and purified as a free compound, its salt, hydrate or various solvates. The salt can be produced by subjecting it to a usual salt formation reaction.

Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography. Industrial applicability

Compound (I) or a pharmaceutically acceptable salt of the present invention exhibits both excellent antagonism against V and v ₂ receptors arginine vasopressin are potent especially v ₂ receptor antagonism , A profile based on these effects, aquaretic effect, urea excretion promoting effect, coronary factor secretion inhibitory effect, vasodilatory effect, cardiac function enhancement effect, mesangial cell contraction inhibitory effect, mesangial cell proliferation inhibitory effect, hepatic glucose It has an inhibitory action on platelet aggregation, an inhibitory action on platelet aggregation, an inhibitory action on aldosterone secretion, an inhibitory action on endoselin production, a central blood pressure regulating action, a renin secretion regulating action, a memory regulating action, a body temperature regulating action, a prostaglandin production regulating action and the like. It is useful as a characteristic diuretic, urea excretion enhancer, vasodilator, antihypertensive, anti-heart failure agent, anti-renal failure agent, anticoagulant, etc. , Heart failure, hyponatremia, abnormal vasopressin secretion syndrome (SI ADH), hypertension, renal failure, edema, ascites, cirrhosis, hypokalemia, water metabolism disorder, diabetes, various ischemic diseases, circulatory failure, Effective for prevention and treatment of renal dysfunction.

In addition, the compound (II) of the present invention or a salt thereof has a benzazepinylcarborylvinylidine skeleton such as the compound (I) of the present invention or a pharmaceutically acceptable salt thereof having excellent vasopressin receptor antagonistic activity. It is useful as an excellent intermediate for the production of compounds having the same. The synthetic route from the intermediate (II) of the present invention or a salt thereof to the compound (I) or a pharmaceutically acceptable salt thereof is as described above.

The usefulness of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof was confirmed by the following test methods.

(1) ^ receptor binding assay (Vj receptor binding assay)

Using rat liver membrane preparations prepared according to the method of Nakamura et al. (J. Biol. Chem., 258, 9283 (1983)), [H] ³ — Arg—vasopressin (vasopressin) (2 nM, specific activity) = 75.8Ci / mmol)) and membrane preparation 70 ng and 5 mM magnesium chloride study medication ^{^{(1 0- 8 ~ 1 0- 4}} M), I mM ethylenediamine Mi emissions tetraacetic acid (EDTA) and 0.1% © shea serum albumin Incubation was performed at 25 ° C for 30 minutes in a total volume of 100 mM Tris-HCl buffer (pH = 8.0) containing (BSA). Thereafter, the incubation solution was aspirated using a cell harvester and passed through a glass filter (GFZB) to remove free ligand and excess buffer, and the labeled ligand bound to the receptor was trapped in the glass filter. . After removing the glass filter and drying it sufficiently, it was mixed with a liquid scintillation cocktail, and the amount of [H] ^3- Vasopressin bound to the membrane was measured with a liquid scintillation counter. Calculated. Inhibition rate (%) = 100-,. Top 100

0 ^1D i

d: Amount of [H] ³ -vasopressin bound to membrane in the presence of [H] ³ -vasopressin and a known amount of reagent

C ₀ : Amount of [H] ^3- vasopressin bound to the membrane when the reagent is removed

B _1: amount of binding excess vasopressin (1 0 one ⁶ M) [H] ³ one vasopressin membranes in the presence of

The _IC5Q value was determined from the concentration of the reagent at which the inhibition rate calculated above was ₅₀ %, and the binding affinity of the non-radioactive ligand, that is, the dissociation constant (Ki) was calculated from the following equation.

Ki =

1 + [L] / KD

[L]; concentration of radioactive ligand

KD; dissociation constant obtained from Scatchard 'plot The negative logarithm of Ki calculated above was taken as the pK i value. (2) Y 2 receptor bus Indy Nguatsusi (V ₂ receptor binding assay)

It was prepared according to the method of Campbell et al. (J. Biol. Chem., 247, 6167 (1972)). With Usagi renal medulla membrane ^{sample, [H] 3 - A rg} - vasopressin · (2nM, specific activity = 75.8Ci / mmol) and membrane preparation 1 0 0 ng and study medication (1 0 ^8-1 0 ⁴ M) was subjected to assimilation in the same manner as in the above-mentioned V i receptor binding assay, and the p K i value was determined in the same manner.

The compounds of the present invention although Rukoto to have a both excellent antagonistic activity against V ₂ receptor has been confirmed, and wherein the V 2 receptor antagonistic activity is powerful. The experimental results of V ₂ receptor antagonism in Table 1.

1 Arginine vasopressin V ₂ receptor antagonism

Pharmaceutical compositions containing one or more of the compounds represented by the general formula (I) and pharmaceutically acceptable salts thereof as an active ingredient are commonly used as carriers for pharmaceuticals and excipients. Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments, patches, etc., using the preparations and other additives. Is administered. The clinical dose of the compound of the present invention for humans is appropriately determined in consideration of the symptoms, weight, age, sex, etc. of the patient to which the compound is applied, but it is usually 0.1 to 500 mg orally per adult per day. mg, which is administered once or divided into several doses. Since the dose varies under various conditions, a smaller dose than the above-mentioned dose range ffl may be sufficient.

Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such a solid composition, the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, It is mixed with polyvinyl pyrrolidone and magnesium aluminate metasilicate. In a conventional manner, the composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, and stabilizers such as lactose. And solubilizing or solubilizing agents such as glutamate or aspartic acid. Tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, or hydroxypropylmethylcellulose phthalate, if necessary.

Liquid compositions for oral administration include pharmaceutically acceptable emulsifiers, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents, such as purified water. Contains ethanol. The composition may contain, in addition to the inert diluent, solubilizing or solubilizing agents, wetting agents, auxiliary agents such as suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Diluents for aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline. Examples of diluents for non-water-soluble solutions and suspensions include vegetable oils such as propylene glycol, polyethylene glycol and olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). ) And so on. Such compositions may further comprise additives such as isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents. . These are sterilized by, for example, filtration through a bacteria retaining finoletor, blending of a bactericide or irradiation. They can also be used in the manufacture of sterile solid compositions which are dissolved in sterile water or sterile injectable solvents before use. BEST MODE FOR CARRYING OUT THE INVENTION

The compound of the present invention and the method for producing the compound have been described above, and will be described in more detail with reference to examples. However, the present invention is not limited by these examples. The starting compounds of the present invention also include novel compounds, and their production examples are shown as intermediate production examples.

Example 1

2-Methyl-N— [5 — [(2,3,4,5-tetrahydro 1H-11-benzazepine-11-yl) carbonyl] -1-2-pyridyl] benzamide hydrochloride

In 4 ml of xylene, 0.19 g of ortho-toluic acid, 1—hydroxybenzotriazole 0.21 g, 1— (3-dimethylaminopropyl pill) 1-3-ethylcarposimid hydrochloride 0.30 g After stirring at room temperature for 4 hours, 1 [(2-amino-5-pyridyl) carbonyl] 1-2,3,4,5-tetratetradro-1H-1 1-benzazepine 0 38 g was added, and the mixture was heated under reflux at 150 ° C for 3 hours. Water after cooling The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After the desiccant was collected by filtration, the filtrate was concentrated and subjected to silica gel chromatography (eluent; chloroform: _methanol = 1100: 1) to obtain 0.45 _g of a free form of the above compound. . This was treated with hydrogen chloride (ethyl acetate solution) to obtain a hydrochloride as an amorphous powder. This compound has the following physicochemical properties.

i) Elemental analysis value (C24H24 3O2C 1)

C (%) H (%) N (%) C 1 (%) Calculated 6 8. 3 2 5. 7 3 9. 9 6 8. 4 0 Actual 6 8. 3 4 5. 8 9 9. 9 1 8.2 4 ϋ) Ή— NMR (DM S 0-άβ)

δ (ρ ρ m);

1.36 to 1.4.5 (1 Η, m),

1. 7 9 to 1.91 (2 Η, m),

2.0 1 to 2.04 (1 Η, m),

2. 3 5 (3Η, s),

2.68 to 2.74 (1 Η, m),

2.85 to 2.90 (1 Η, m),

3.00 to 3.06 (1Η, m),

4.83 to 4.86 (1 Η, m),

6. 8 3 (1Η, d),

7.00 ~ 7.62 (8 Η, m),

7.97 to 8.03 (2 Η, m)

The following compounds of Examples 2 to 5 were prepared in the same manner as in Example 1.

2- (4-Methylphenyl) 1- [5-[(2,3,4,5-tetrahydro 1H-1-benzazepine-11-yl) carbonyl] 1-2-pyridyl] benzamido hydrochloride i) Melting point 1 32 to 1 36 ° C

ii) Elemental analysis _{_{_{(C 30 H28N 3 O 2 C}}} 1)

C (° / o) H (° / o) N (° / o) C 1 (° / o) Calculated 7 2. 3 5 5. 6 7 8. 4 4 7.1 2 Actual 7 2, 4 1 5. 7 3 8. 4 6 7.1 1 iii) 'H- NMR (DM SO-άβ)

δ (p p m);

1.40 (1 H, m), 1.86 (2 H, m), 2.000 (1 H, m), 2.28 (3 H, s), 2.66 to 2 . 7 1 (1 H, m),

2.86 (1H, m), 2.96 to 2.99 (1H, m), 4.8 1 to 4.84 (1H, m), 6.80 (1H, d) , 6.99 ~ 7.94 (1 4 H, m)

Example 3

2—Phenylyl N— [5 — [(2,3,4,5—tetrahydro 1 H—1—benzazepine-111) carbonyl] -1-2-pyridyl] benzamide hydrochloride

i) Elemental analysis value (C29H26N3O2C 10 0.25 Η20)

C (%) H (%) Ν (%) C 1 (%) Calculated 7 1.3 0 5.4 7 8.60.7.26 Actual 7 1.4 1 5.8 28.2 4 7.28 ii) 'H-NMR (DM S 0-d ₆ )

δ (p p m);

1. 3 7 to 1.41 (1 H, m),

1.88 55 ~~ 11 .. 9 1 (2 H, m),

2. 0 0 (1 H, m),

2.66 to 2.71 (1H, m),

2.84 to 2.87 (1H, m),

2.96 to 3.02 (1H, m), 4.81 to 4.8.4 (1H, m),

6. 7 8 (1 H, d),

6.98 to 7.02 (1H, m),

7.12 to 7.16 (1 H, m),

7.26 to 7.5 7 (1 1 H, m),

7.77 (1H, m), 7.93 (1H, m) Example 4

2-Iodine N— [5 — [(2,3,4,5-Tetrahid 1H-1 Benzazepine-1-yl) carbonyl] —2-Pyridyl] benzamide hydrochloride

i) Mass spectrum FAB (P0s.); 498 (M + 1) ϋ) Ή-NMR (DMS0-d6)

δ (p p m);

1.3 9 to 1.42 (1H, m)

1.8 7 to 1.9 1 (2H, m)

2.02 (1 H, m),

2.69 to 2.73 (1 H, m)

2.87 to 2.89 (1 H, m)

3.00 ~ 3.05 (1H, m)

4.83 to 4.8.6 (1H, m)

6.82 (1 H, d),

7.00 to 7.03 (1H, m)

7.13 to 7.6 (6H, m)

7.88 to 8.03 (3H, m)

Example 5

2—Methoxy-1-N— [5 — [(2,3,4,5—7 ”trahydro 1 H—1—benzazepine-1—yl) carbonyl] -12-pyridyl] benzamide Hydrochloride

i) Mass spectrum FAB (P os.); 402 (M + 1) ii) Ή-NMR (DM S 0-d ₆ )

δ (p p m);

1.39 to 1.42 (1 H, m),

1.83-1.87 (2H, m),

1.99 9 to 2.02 (1H, m),

2.68 to 2.73 (1H, m),

2.86 to 2.90 (1 H, m),

3.00 to 3.06 (1H, m),

3.95 (3 H, s),

4.83 to 4.86 (1H, m),

6.80 (1 H, d),

6.98 to 7.02 (1H, m),

7.08 to 7.34 (4H, m),

7.55 to 8.07 (5H, m)

Example 6

1 [[2- [N, N-bis (2-methylbenzoyl) amino] -1-5-pyridyl] carbonyl] 1,2,3,4,5-tetrahydro 1H—1 benzazepine

1 [(2-Amino-5-pyridyl) carbonyl] 1,2,3,4,5-Tetrahydro-1H-1 Benzazepine 0.20 g is dissolved in methylene chloride (4 ml) and triethylamine is dissolved in 0.1 ml. 18 g were added. At 15 ° C, 0.26 g of o-tol oil chloride was added dropwise and stirred for 2 hours. After adding ice water to the reaction mixture, the mixture was extracted with chloroform and washed with aqueous sodium hydrogen carbonate, and the organic layer was dried over anhydrous sodium carbonate. After filtration, the filtrate was concentrated under reduced pressure. When ether was added, amorphous powder was precipitated to obtain 0.34 _g of the above compound. This compound has the following physicochemical properties. i) elemental analysis value (C ₃ 2H29N3_rei ₃ 0. 5 _Η2θ)

C (%) Η (%) Ν (%) Calculated 7 4.9 8 5.9 0 8.20 Actual 75.0 3 6. 6.8.29 i) Ή-NMR (CD ")

δ (p p m j;

1.48 to 1 52 (1 Η, m)

9 2 to 1.95 (2 Η, m)

0 6 2.09 (1 Η, m)

7 0 3.1 3 (3 Η,

9 4. 9 9 (1 Η,:

5 (1 Η, d),

9 2 to 6.96 (1 Η, m),

0 5 to 7.5 7 (1 2 Η, m),

1 2 to 8.1 3 (1 Η, m)

Example 7

Ν— (2-methylphenyl) -1-5-((2,3,4,5-tetrahydro 1 1—1—benzazepine-1 1-yl) carbonyl] pyridine-1 2-carboxamide

5 — [(2,3,4,5—tetrahydro-1H-1—benzazepine-11-yl) carbonyl] pyridine—0.2-gulfuronic acid 0.2 g and thionyl chloride 4 ml, Three drops of dimethylformamide were added, the mixture was heated under reflux for 30 minutes, and concentrated under reduced pressure to obtain an acid chloride. A solution of this acid chloride in 2 ml of methylene chloride was added dropwise to a mixture of 0.09 g of ortho-toluidine, 0.48 g of triethylamine and 2 ml of methylene chloride at 15 ° C. . After stirring for 20 minutes, ice water was added, extracted with chloroform, washed with aqueous sodium hydrogen carbonate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the residue is subjected to silica gel chromatography (eluate; black form: methanol) To 50: 1) to obtain 0.13 g of the desired compound. Crystallized from chloroform chloroform. This compound has the following physicochemical properties.

i) melting point; 130-132. C

ii) Elemental analysis _{_{_{(C 24 H23N 3 0 3 ·}}} 0. 2 5 H 2 0)

C () H (%) N (%) Calculated 7 3.92.6.0 7 1 0.7.8 Actual 7 3.72.6.0 8 1 0.74 iii) Ή-NMR (DM S 0-d6)

δ (p p m);

1.39 to 1.44 (1H, m),

1.9 1 (2 H, m),

2.03 to 2.07 (1H, m),

2.2 4 (3 H, s).

2.73 to 2.80 (1 H, m),

2.86 to 2.91 (1H, m).

3. 0 5 to 3.1 1 (1 H, m),

4.82 to 4.86 (1H, m),

6. 8 8 (1 H, d),

6.96 to 7.00 (lH, m),

7.09 to 7.3.4 (5H, m),

7.66 to 7.97 (3H, m),

8.45 to 8.46 (1H, m)

Example 8

N-(2-methylphenyl) — 1 oxydose 5 — [(2, 3,

4, 5—Tetrahi draw 1 H—1 —Benzazepine 1-yl) Power Luponyl] pyridine-1 3-Carboxamide

N-(2-Methylphenyl) 1 5 — [(2,3,4,5—Tetrahydro 1 H—1 —Benzazepine 1 1 1) 0.12 g of gin-1-carboxamide was dissolved in 2 ml of methylene chloride, 0.15 g of methachloroperbenzoic acid was added, and the mixture was stirred at room temperature for 3 days. After adding an aqueous solution of sodium hydrogencarbonate, the mixture was extracted with chloroform and the organic layer was concentrated under reduced pressure. The residue was subjected to column chromatography (eluate; black form) to obtain the desired compound. 0.08 g of crystals were obtained from a black hole formether.

This compound has the following physicochemical properties.

i) Melting point: 180-182 ° C

ϋ) Elemental analysis _{(C24H23N3O3 · 0. 2 5 H 2} 0)

C (%) H (%) N (%) Calculated 7 1. 0 1 5. 8 3 1 0. 3 5 Observed 7 1. 1 4 5. 8 7 1 0. 1 2 iii) NMR NMR ( CDC 13)

δ (p p m);

1.60 (1 H, m),

1.97 to 2.03 (2H, m),

2.1 ί to 2.14 (1 H, m),

2.83 to 3.02 (3 Η, m),

4.93 to 4.96 (1 H, m),

6. 7 3 (1 H, d),

7.01 to 7.10 (3H, m),

7.18 to 7.31 (5H, m),

8.2 2 to 8.2 29 (2 H, m)

Example 9

2—Methyl-N— [2— [(2, 3, 4, 5—Tetrahydro 1

— 1 1-benzazepine 1-yl) carbonyl] 1-5-pyridyl] benzamide hydrochloride

1 1 [(5-Amino-2-pyridyl) carbonyl] 1, 2,3,4,5—Tetrahydro 1H—1—Benzazepine 0.2 g, Trije 0.13 g of ruamine was dissolved in 8 ml of methylene chloride, and 0.19 g of ortho-toluoyl chloride was added dropwise under ice cooling. Two hours later, water was added, and the mixture was washed with sodium bicarbonate, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and ether was added to precipitate a solid. The solid was dissolved in ethanol, treated with hydrogen chloride (ethyl acetate solution), acidified the system, concentrated under reduced pressure, and added with ether to obtain 0.18 g of the desired product as an amorphous powder. This compound has the following physicochemical properties.

i) Elemental analysis _{_{_{(C24H 2 4N 3 0 2 C}}} 1 · 0. 5 H 2 0)

C (%) H (%) N (%) C 1 (° / o) Calculated 6 6. 8 9 5. 8 5 9. 7 5 8.2 3 Actual 6 7 .0 8 6.2 1 9 4 6 7.10 ii) Mass spectrum FAB (Pos.) 3 8 6 (M + 1) iii) Ή-NMR (DM S 0-d 6)

δ (p p m);

1.41 (1 H, m), 1 8 7 (2 H, m), 2.000 (1 H, m), 2 3 5 (3 H, m),

2.68 to 2.8 1 (2 H, m),

3.00 to 3.06 (1H, m),

4.77 to 4.8 1 (l H, m),

6.72 (1H, d),

6.91 to 6.95 (1H, m),

7.04 to 7.07 (1H, m),

7.23 to 7.47 (6H, m) ''

8.10 to 8.13 (1 H, m),

8.5 2 0 (1H, m) Example 10

2—Phenyl-N— [2 — [(2,3,4,5-tetrahydro—1H—1—benzazepine—1yl) Power-ponyl] -1-5-pyridyl] benzamide / hydrochloric acid salt

The compound of this example was produced in the same manner as in Example 9.

i) Amorphous powder

ii) Mass spectrum FAB (P os.); 4 4 8 (M + 1) iii) ¹ H-NR (DM S 0-d _fi )

δ (ρ ρ m);

1.38-1.4.01Hm)

(1.82 to 1.85 2 Hm)

1. 9 9 (1 Η, m)

(2.67 ~ 2.71 1 Hm)

(2.76 ~ 2.791 Hm)

2.96-6.3.0 21 H, m)

(4.75 ~ 4.78 1 H, m)

6.66 (1 H, d)

(6.90 ~ 6.92 1 H, m)

7.04 to 7.007 H, m)

(7.2 1 to 7.5 9.11 H, m)

7.86 to 7.88 1 H, m),

8. 2 5 (1 H, b] s)

Example 1 1

2— (2-Methylphenyl) —N— [5 — [(2,3,4,5-Tetrahydro—1H—1 benzazepine—111) carbonyl] —2—pyridyl ”benzami De hydrochloride

The compound of this example was prepared in the same manner as in Example 1.

i) Amorphous powder

ii) Elemental analysis value (C ₃ oH28N30 ₂ C 1) C (%) H (%) N (%) C 1 (%) Calculated 7 2. 3 5 5. 6 7 8. 4 4 7.1 2 Actual 7 2 4 5 5. 7 4 8.45 6. 8 7 i) Ή-NMR (DMS 0-άβ)

δ (p p m);

1.37 to 1.40 (1H, m)

1 7 9 ~ 1.85 (2 H, m)

1 9 9 (1 H, m), 2.0 7 (3 H, s)

2 6 4 to 2.70 (1 H, m)

2 8 4 to 2.86 (1 H, m)

2 95 to 3.01 (1H, m)

4 80 to 4.83 (1 H, m)

6 76 (1 H, d), 6.99 (1 H, t)

7 1 u 7.3 1 (7 H, m)

7 4 3 to 7.5 4 (2 H, m)

7 6 0 (1 H, d), 7.68 (1 H, d) 7 9 2 (1 H, b rs)

Intermediate production example A

Methyl 5 — [(2,3,4,5—tetrahydro-1-H 1-benzazepine—1-yl) pyruvonyl] pyridine-1—2-pyruvoxylate

2-Methoxycarboniviridine-5-capillonic acid 3.5 g, 50 ml of thionyl chloride, 5 drops of dimethylformamide A heated solution was refluxed for 15 minutes, concentrated under reduced pressure, and concentrated under reduced pressure. I got a do body. This acid chloride is dissolved in methylene chloride (30 ml) and cooled with ice to give 2,3,4,5-tetrahydro 1H-1 monobenzazepine hydrochloride (3.4 g, triethylamine). A mixture of 12.5 g and methylene chloride 140 ml was added dropwise over 15 minutes. 30 minutes later, water was added, the organic layer was separated, washed with aqueous sodium hydrogen carbonate, and the organic layer was dried over anhydrous magnesium sulfate. Dried with steam. After filtration, the filtrate was concentrated under reduced pressure, and ethanol was added to obtain 4.1 g of the target compound as a solid. This compound has the following physicochemical properties.

i) Mass spectrum (m / z); 310 (M)

ϋ) Ή-NMR (C D C 13)

δ (p p m);

1.6 (1 H, m), 2.0 (2 H, m),

2.7 to 3.1 (3H, m), 3.95 (3H, s), 4.9 to 5.1 (1H, m),

6.6 to 7.3 (4H, m), 7.7 (1H, dd),

7.95 (1 H, d), 8.45 (1 H, m) Intermediate Production Example B

5 — [(2,3,4,5—tetrahydro 1H—1 benzazepine 1-yl) pyruvonyl] pyridine-1 2-carboxylic acid

Methyl 5 — [(2,3,4,5—Tetrahydro-1H—1 Benzazepine-1—yl) Power Rponyl] Pyridine-1—Power Rboxylate 2.0 g, methanol A mixed solution of 400 ml and 2.9 g of potassium hydroxide was heated under reflux for 40 minutes and concentrated under reduced pressure. The residue was dissolved in a small amount of water, and 4.8 ml of concentrated hydrochloric acid was added to precipitate a solid. After filtration, this solid was dissolved in 400 ml of chloroform, washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and ether was added to obtain 2. O g of the target compound as an amorphous powder. This compound has the following physicochemical properties.

i) Mass spectrum (m / z); 296 (M ⁺ )

ii) Ή-NMR (C D C 13)

δ (p p m);

1.55 (1H, m), 1.9 to 2.2 (3H, m), 2.7 to 3.1 (3H, m), 5.0 (1H, m), 6. 6 3 (1 H, m), 6.85 to 7.30 (3H, m),

7.65 (1 H, d d), 8.0 (1 H, d),

8.4.6 (1 H, m)

Intermediate Production Example C

1 1 [(2—t er t—butyn power 5—pyridyl) power rubonyl] 1 2,3,4,5—tetrahydro 1 H—1—benzazepine

5-[(2,3,4,5—tetrahydro 1H—1—benzazepine—1—yl) carbonyl] pyridin-1-2-carboxylic acid 0.8 g, tert—butanol 2.9 ml A mixed solution of 0.27 g of triethylamine, 0.77 g of diphenylphosphoryl azide was heated to reflux for 13 hours. After cooling, the resulting crystals were collected by filtration to obtain 0.62 g of the desired compound. This compound has the following physicochemical properties.

i) Melting point: 2 16 to 2 18 ° C

ii) Elemental analysis (C2lH ₂ 5N _₃ 0 ₃₎

C (%) H (%) N (%) Calculated 68.6 4 6.86 6 1.1.4 4 Observed 68.6 2 6.88 1 1.45 5 iii) 'Η-NMR (CDC 13 )

δ (ppm) ';

1.49 (9 Η, s) 1.57 (1H, m) 1.85 to 2.1 (3H, m),

2, 7 to 3.1 (3 H, m), 5.5 (1 H, m), 6.68 (1 H, m), 6.9 to 5 (4 H, m), 7. 7 5 (1 H, d), 8.1 (1 H, m) Intermediate Production Example D

1-[(2-amino-5-pyridyl) carbonyl] 1,2,3,4,5-tetrahydro 1 H—1—benzazepine

1-[(2-tert-butoxycarbonylamino 5—pyridi 6) Trifluoroacetic acid (6 ml) was added to 0.79 g of 1,2,3,4,5-tetrahydro 1H-1 -benzazepine, stirred at room temperature for 1 hour, and concentrated under reduced pressure. An aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and ether was added. was gotten.

This compound has the following physicochemical properties.

i) Mass spectrum (mZz);

ii) Ή-NMR (C D C 13)

(5 (p p m);

1.5 to 2.1 (4 H, m),

2.6 to 3.1 (3 H, m),

5.0 (1 H, m), 6.3 (1 H, m),

6. 7 to 7.4 (5H, m), 7.9 (1H, m) Intermediate Production Example E

Methyl 2-[[(2,3,4,5-Tetrahi draw 1H-1—Benzezepine)] Pyridine—5-Carboxylate

Synthesized in the same manner as in Intermediate Production Example A, using 5-methoxycarbonylviridine-12-carboxylic acid as a starting material.

i) Mass spectrum (mZz); 310 (M ⁺ )

ii) Ή-NMR (C D C 13)

δ (p p m);

1 4 7 to 1.5 5 (1 H, m)

11 9 3 to 1.97 (1 H, m)

2 0 2 to 2.12 (2 H, m)

2 8 1 to 2.86 (2 H, m)

3 1 1 to 3.18 (1 H, m)

3 8 8 (3 H, s), 4.95 to 4.98 (1 H, m),

6.64 (1 H, d),

6.84 (1H, t), 7.03 (1H, t), 7.17 (1H, d), 7.39 (1H, d), 8.14 (1 H, dd), 8.89 (1 H, d) Intermediate Preparation Example F

2 — [(2,3,4,5—tetrahydro—1H—1—benzazepine—1yl) pyrudinyl] pyridin-1-5-rubric acid

The compound of this intermediate production example was synthesized in the same manner as in intermediate production example B.

i) Elemental analysis _{_{_{(C 17 H 16 N 2 0}}} 3 0. 5 H2O)

-C (%) H (%) N ()

Calculated value 6 6. 8 7 5. 6 1 9. 1 7 Actual value 6 6. 6 8 5. 3 8 9.0 6 ii) Mass spectrum (m / z); 29 6 (M ⁴ )

iii) Ή NMR (DM S 0-άβ)

<5 (ppm);

1.40 to 1.42 (1H, m),

1. 8 8 (2 H, m),

2.0 1 to 2.0.4 (1 H, m),

2.73 to 2.83 (2H, m),

3.00 to 3.06 (1H, m),

4.75 to 4.78 (1H, m),

6.74 (1 H, d), 6.88 (1 H t),

7.04 (1H, t), 7.22 (1Hd), 7.56 (1H, d), 8.16 (1Hdd), 870 (1H, d) ), 1 3.49 (1 H, brs) Intermediate Production Example G

1 [[5-tert-butoxycarbonylamino-2-pyridyl) carbonyl] 1,2,3,4,5-tetrahydro- 1 H- 1 -benzazepine

The compound of this intermediate production example was synthesized in the same manner as in intermediate production example C.

i) Mass spectacle FAB (Pos.); 368 (M + 1) ii) 'Η-NMR (C D C 13)

δ (p p m);

1.47 (9H, s), 1.54 (1H, m),

1 9 3 to 2.04 (3H, m)

2 7 5 to 2.81 (2H, m)

3 08 to 3.14 (1 H, m)

4 9 6 to 4.99 (1 H, m)

6 6 3 (1 H, d), 6.77 (1 H, m) 6 8 5 to 6.89 (1 H, m)

7 0 1 to 7.05 (1 H, m)

7 1 6 to 7.18 (1 H, m)

• 7.26 to 728 (1H, m)

7.82 to 784 (1H, m)

Intermediate Production Example H

1-[(5-Amino 2-Pyridyl) lipo: nil] 1,2,3,4,5-Tetrahydro 1 H-1 1 Benzazepine

The compound of this intermediate production example was synthesized in the same manner as in intermediate production example D.

i) Mass spectrum (m / z); 26 7 (IVT)

ii) Ή-NMR (C D C I3)

<5 (ppm);

1.47 to 1.53 (1H, m), 1.92 to 2.04 (3 H, m),

2.73 to 2.81 (2 H, m),

3.07 to 3.13 (1H, m),

4.98 to 5.01 (1H, m),

6.64 (1 H, d),

6.72 to 6.75 (1H, m),

6.88 (1H, t), 7.04 (1Ht)

7.12 to 7.27 (2H, m),

7.73 (1 H, b r s)

Table 2 below shows the chemical structural formulas of the compounds obtained in the above Examples and Intermediate Production Examples.

2 Example No.Chemical structure

Claims

The scope of the claims

1. An N- (pyridylcarbonyl) benzazepine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

(O) n

[The symbols in the formula have the following meanings.

X: a group represented by the formula -NHCO- or -CON-

I

R ¹ n: 0 or 1,

R

R ^{1 is a} hydrogen atom or a group represented by the formula: CO— / wherein R has the above-mentioned meaning]

2. The N- (pyridylcarbonyl) benzazepine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is represented by the following general formula (III).

(0) n

(Wherein, R and n have the above-mentioned meanings.)

3. The compound according to claim 1, wherein R is Ci—C4 alkyl group, Ci—C4 alkoxy group. Unsubstituted or Ci—C4 alkyl-substituted phenyl group, or iodine atom, or a pharmaceutically acceptable salt thereof.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein R is Ci-C4 alkyl group, Ci-C4 alkoxy group, unsubstituted or Ci-C4 alkyl-substituted phenyl group or iodine atom.

5. 2-Methyl-N— [5 — [(2,3,4,5-tetrahydro-1H-1-benzazepine-1-yl) carbonyl] -12-pyridyl] benzamide or its pharmaceuticals A biologically acceptable salt.

6. 2— (4-Methylphenyl) -N— [5 — [(2,3,4,

5-Hydroxy 1 H-1 1-Benzezepine 1-yl) Ruponyl] -12-pyridyl] benzamide or a pharmaceutically acceptable salt thereof.

7. 2—Feneru N— [5 — [(2,3,4,5—Tetrahydro-1H—1—Benzazepine — 1yl) carbonyl] —2-Pyridyl] benzamide or its Pharmaceutically acceptable salts.

8. 2-Feneru N— [2 — [(2,3,4,5-Tetrahydro-1H-1—Benzazepine-11-yl) carbonyl] -1-5-Pyridyl] benzamide or its Pharmaceutically acceptable salts.

9. A benzazepinylcarbonylpyridin derivative represented by the following general formula (II) or a salt thereof.

(O) n [Wherein n has the meaning described above, and Y has the following meaning.

Y: carboxy group, activated carboxy group, protected carboxy group,

HN

A group of formula I, or a protected group

R ¹

HN

A group represented by the formula I, wherein R ¹ has the aforementioned meaning

R 1 )]

10. The benzazepinylcarbonylvinylpyridine derivative or a salt thereof according to claim 9, wherein Y is a group represented by the formula H ₂ N—.

11. 1 — [(2-Amino-5-pyridyl) carbonyl] one, two, three, four, five

—Tetrahydro— 1H—1 Benzazepine or its salt.

12. 1-[(5-amino-2-pyridyl) carbonyl] — 2,3,4,5 —tetrahydro 1H-1 —benzazepine or a salt thereof.