WO2002074746A1

WO2002074746A1 - Benzazepine derivatives

Info

Publication number: WO2002074746A1
Application number: PCT/JP2002/002306
Authority: WO
Inventors: Kyoichi Maeno; Itsuro Shimada; Yutaka Kondoh; Hidetaka Kaku; Keizo Sugasawa; Fumikazu Wanibuchi
Original assignee: Yamanouchi Pharmaceutical Co., Ltd.
Priority date: 2001-03-16
Filing date: 2002-03-12
Publication date: 2002-09-26
Also published as: JPWO2002074746A1

Abstract

5-HT2C receptor agonists containing as the active ingredient benzazepine derivatives or pharmaceutically acceptable salts thereof; and novel benzazepine derivatives or pharmaceutically acceptable salts thereof which are 5-HT2C receptor agonists.

Description

Specification

Benzozepine derivatives

Technical field

The present invention relates to a 5-HT _{2 C} receptor agonist comprising a benzozepine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Furthermore, the present invention relates to a novel benzazepine derivative or a pharmaceutically acceptable salt thereof. Background art

Serotonin _{2 c (5 - HT 2 C} ) receptors are distributed predominantly central nervous system, the role of that is not well understood, sexual dysfunction, obesity, hyperphagia, anxiety, It is thought to be involved in central nervous system diseases such as depression and sleep disorders (Curr. Opin. Invest. Drugs 2 (4) 317 (1993)). Therefore, 5-HT _{2 C} receptor agonists are useful for preventing or treating the above diseases.

5-HT _{2 C} receptor agonists include tricyclic pyrrole or pyrazole derivatives (EP 657426, EP 700905, W098 / 56768, etc.), tetrahydrobirazinoquinoxaline derivative (W000 / 35922), or tetracyclic gamma-potassin (W000 / 77001 etc.) have been reported.

On the other hand, many compounds have been reported as benzozepine derivatives (NL

6802257, BE 719631, DE 2207430, EP 7070, EP 285287, W093 / 00094, W096 / 22290, etc.). According to those reports, as a benzozepine derivative having two or three substituents on the benzene ring, E or G in the following formula (A) is one S (O). ~ ₂ — (lower alkyl, trifluoromethyl, amino, mono- or dimethylamino or phenyl) or a compound of acetyl, a compound of G is amino and E and J are nitrogen or bromo, G is a hydroxyl group or methoxy And compounds in which E or / and J are the same or different and are hydroxyl groups, methoxy, bromo or nitro, and compounds in which E and G are nitrogen atoms.

Further, as a compound in which a heteroaromatic ring is fused to a benzene ring, the heteroaromatic ring is Compounds in which the substituent on the ring always has a cyclic amine have been reported.

Also report on the Benzoazepin derivatives Morufuin receptor Antagoni strike, 5-H Ding, receptor Agonisuto, been described for 5-HT _2A receptor Agonisu Bok or dopamine receptor antagonists, and as their pharmaceutical use, pain It describes the treatment of anorexia nervosa, hypertension, gastric motility disorders or schizophrenia. However, those reports 5-HT _2C receptor Agonisuto activity or sexual function no description regarding disorder improving action, 5 ^ HT _2C receptor Agonisu Bok activity or Benzoazepin derivative having sexual dysfunction improving effect is yet known Absent. Disclosure of the invention

The present inventors have diligently searched for a 5-HT _2C receptor agonist. As a result, the benzazepine derivative represented by the following formula (I) has excellent agonist activity at the 5-HT _2C receptor, and among the compounds represented by the formula (I), the following formula (II) The present inventors have found that a benzozepine derivative having two or more substituents on the benzene ring is a novel compound and has excellent agonist activity for 5-HT _2C receptor, and thus completed the present invention.

That is, the present invention relates to a 5-HT _2c receptor agonist comprising, as an active ingredient, a zenzazepine derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings

R \ R ² and R ^{3 are the} same or different and are 1 H, optionally substituted lower alkyl, optionally substituted lower alkenyl, acyl, 1 OH, 1 O—optionally substituted hydrocarbon group , One SH, one S-an optionally substituted hydrocarbon group, amino, mono Or di-lower alkylamino, an acylamino, halo, nitro or cyano in which nitrogen may be substituted by lower alkyl

Further, R ² may be combined with R ¹ or an adjacent R ³ to form a heteroaromatic ring which may be substituted.

Invention 5—HT ₂ . The receptor agonist (I) is preferably (5-HT _{2 according to the} present invention, wherein (^ ¹ and ³ are the same or different and are 1 H, lower alkyl or halo, and R ² is lower alkyl or halo). 5-HT ₂ of the present invention, wherein R ¹ is H, R ² is lower alkyl or H, and R ³ is —H. Receptor agonist (I) And particularly preferably 6,7-dichloro-1,2,3,4,5-tetrahydro-1H-3-benzozepine, 7-bromo-6-chloro-1,2,4,5, tetrahydro-1H-3. —Benzazepine or 6-chloro-7-methyl-2,3,4,5-tetrahydro- 1 H-3-benzobenzopine or a pharmaceutically acceptable salt thereof according to the present invention 5-HT _2c receptor agonist (I) It is.

The 5-HT _2c receptor agonist (I) of the present invention can be used as a therapeutic agent for various central nervous system diseases. Preferably, the 5-HT _2c receptor agonist (I) of the present invention is a therapeutic agent for sexual dysfunction, particularly preferably a therapeutic agent for erectile dysfunction. Further, the present invention relates to a benzazepine derivative represented by the following formula (II) or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings

R ¹¹ and R ³³ : one of them is 1 H, lower alkyl, amino, mono- or di-lower alkylamino, acylamino, halo, nitro or cyano which may have lower alkyl on nitrogen, and the other is lower alkyl , Amino, mono- or di-lower alkylamino, acylamino, halo, nitro or cyano which may have lower alkyl at nitrogen

R ²² : lower alkyl, 1 OH, 1 O—lower alkyl, amino, mono or di-low Lower alkylamino, which can be substituted with lower alkyl at the nitrogen, lower amino, dinitro or cyano

Further, R ²² may be combined with R ¹¹ or the adjacent R ³³ to form a heteroaromatic ring which may be substituted with lower alkyl, 1 OH or 1 O lower alkyl,

1) When R ^{11 is} H and R ²² is amino, R ³³ represents a group other than halo

2) When R ²² is 1 OH or methoxy, R ¹¹ and R ³³ are the same or different and represent a group other than 1 OH, methoxy, bromo or nitro

3) When R ¹¹ is chloro, R ²² represents a group other than chloro)

In the compound (II) of the present invention, preferably, one of R ¹¹ and R ³³ is —H, lower alkyl or halo, the other is lower alkyl or halo, and R ²² is lower alkyl or halo. A compound of the present invention (II), more preferably a compound of the present invention (II) wherein R ¹¹ is H, R ²² is lower alkyl or H, and R ³³ is 1 H, Preferably 7-bromo-6-chloro-1,2,3,4,5-tetrahydro-1H-3-benzozepine or 6-chloro-7-methyl-1,2,3,4,5-tetrahydro-1H-3-benzoazepine Or a pharmaceutically acceptable salt thereof of the present invention (II).

Hereinafter, the compound of the present invention (1, II) will be described in detail.

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

Examples of the “lower alkyl” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and isohexyl. Preferably, it is methyl, ethyl, propyl or isopropyl, more preferably methyl or ethyl, and particularly preferably methyl.

"Lower alkenyl J includes, for example, vinyl, 1-propenyl, aryl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-buten-1-yl, 2-methyl-1- Propenyl, 3-butene-2-yl, 2-methyl-1-propyl Re, 1-pentenyl, 2-pentenyl ^ / re, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl, etc. And preferably vinyl or aryl.

“ΓCycloalkyl” means a 1 to 3 ring aliphatic saturated hydrocarbon group having 3 to 14 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl, bicyclooctyl, bicyclononyl, bicyclodecanyl, tricycloundecanyl, tricyclododecanyl or tricyclotridecanyl, and the like, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. is there.

"Cycloalkenyl" means an unsaturated aliphatic hydrocarbon ring group in which one to three arbitrary single bonds of the above cycloalkyl group have become a double bond, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl And cycloheptenyl or cyclooctenyl and the like, preferably cyclopentenyl or cyclohexenyl.

"Aryl" means a 1 to 3 ring aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include phenyl, biphenyl, naphthyl, anthryl and phenanthryl. Is phenyl or naphthyl.

"Heteroaromatic ring" means a 5- or 6-membered heteroaromatic ring having one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, for example, pyrrole, imidazole, Furan, oxazole, isoxazole, thiophene, thiazole, isotiazole, pyridine, pyridazine or pyrimidine, etc., preferably furan, thiophene, imidazole or oxazole, particularly preferably furan or thiophene .

Examples of "cout" include fluoro, chloro, bromo or odo, preferably fluor, clo or bromo, and particularly preferably chloro or bromo.

The "mono- or di-lower alkylamino" means an amino in which the above lower alkyl is substituted by one or two, and is preferably methylamino or ethylamino, particularly preferably methylamino.

"Zacyl" means —H or the above lower alkyl, cycloalkyl, aryl, a Amino or mono- or di-lower alkylamino is substituted by sulfonyl, sulfinyl or sulfonyl, preferably acetyl, propionyl, methanesulfonyl, ethanesulfonyl or benzenesulfonyl, particularly preferably acetyl or methanesulfonyl It is.

"Acylamino" means an amino substituted by the above-mentioned acyl, preferably acetylamino, propionylamino, methanesulfonylamino, ethanesulfonylamino or benzenesulfonylamino, particularly preferably acetylamino or methane. Sulfonylamino.

"Hydrocarbon group" means the above lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl or aryl, or a group obtained by substituting or condensing each other, preferably lower alkyl, cycloalkyl or aryl. Preferably it is lower alkyl.

The term “optionally substituted” means that the compound may be substituted with 1 to 4 substituents of 1 to 3 types. Examples of the substituent include lower alkyl, 1 OH, and Lower alkyl, —SH, —S—lower alkyl, amino, mono or di-lower alkylamino, acyl, mono-O-acyl, acylamino, mono-COOH, —COO—lower alkyl, halo, nitro or cyano, etc., and are preferred. Is lower alkyl.

The compound (I, II) of the present invention may have optical isomers (optically active isomers, diastereomers, etc.) or geometric isomers depending on the type of the substituent. Therefore, the compound (I, II) of the present invention includes a mixture of these optical isomers or geometric isomers and an isolated one. In addition, the compound (I, II) of the present invention can form an acid addition salt or a salt with a base. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, Acid addition salts with organic acids such as malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid or glutamic acid, inorganic bases such as sodium, potassium, magnesium, calcium or aluminum, methylamine, ethylamine , Monoethanolamine, diethanolamine, triethanol And salts with organic bases such as amine, cyclohexylamine, lysine or ordinine. Further, the compound (1, II) of the present invention or a pharmaceutically acceptable salt thereof can form a hydrate, a solvate such as ethanol, or a polymorph. Further, the compound (I, II) of the present invention also includes a compound that is metabolized in vivo to be converted into the compound (I, II) of the present invention or a pharmaceutically acceptable salt thereof, so-called open drug. Included. Examples of the group forming a prodrug of the compound (I, II) of the present invention include the group described in Prog. Med. 5: 2157-2161 (1985) and the group described in Hirokawa Shoten 1990, “Development of Pharmaceuticals” No. 7 Groups described in Vol. Molecule Design 163-198. Specifically, it is a group which can be converted to the primary amine or secondary amine, 1 OH, 1 COOH or the like of the present invention by hydrolysis, solvolysis or under physiological conditions. Prodrugs include, for example, mono-OC (O) mono-substituted lower alkyl, mono-OC (O) -substituted aryl, mono-OC (O) mono-substituted lower alkylene-C ( O) OR (R represents 1 H or lower alkyl; the same shall apply hereinafter), -OC (O) —optionally substituted lower alkenylene-1 C (O) OR, 1 OC (O) 1 lower alkylene 1 O—lower Alkylene 1 C (O) OR, 1 OC (O) — C (O) OR, -OC (O) — optionally substituted lower alkenylene 1 S (O) ₂ OR, -O — phthalidyl, 5-methyl-1 1,3-dioxolen-12-one-14-ylmethyloxy.

(Manufacturing method)

The compounds (I, II) of the present invention can be produced by applying various synthetic methods utilizing characteristics based on the basic skeleton or the types of substituents. The typical manufacturing method will be described below.

First manufacturing method

(In the formula, R ¹ , R ² and R ³ have the same meanings as above. R ⁴ , R ⁵ and R ⁶ are each R ¹ , R ² and R ³ or R ¹ , R ² by a usual chemical reaction. And substituents convertible to R ³ I do. R ⁷ represents a protecting group for 1 H or nitrogen. The same applies hereinafter. )

The compound (I, II) of the present invention can be produced, if necessary, by subjecting R ⁴ , R ⁵ and R ⁶ of the compound (III) to functional group conversion to convert them to R ¹ , R ² and R ³ , respectively. For example, in the case of a nitro group, it can be easily converted to a chloro, bromo or cyano group by utilizing the Sandmaeyer reaction (Org. Syn. III. 185) after reduction and conversion back to amino. Further, in the case of an amino group, the substituent can be easily converted by acylation, alkylation or the like. When R ⁷ is a protecting group, the desired compound of the present invention (I, II) can be produced by deprotection (Protective groups in Organic Synthesis, second ed., JOHN WILEY & SONS, INC.). When R ¹ and R ² are combined to form a furan ring, the present invention can be carried out from a compound in which R ^{4 is} methoxy, according to the synthesis method described in Synth. Comm., 257 (1989). Compound (I, II) can be produced.

Raw material synthesis

The starting compound (III) of the first production method can be produced by the following method.

The starting compound (III) of the compound (I, II) of the present invention can be produced according to the synthesis method described in Med. Chem., 26, 1213 (1983). The phenylacetic acid derivative (IV) is converted into an isomer (V) by a conventional method, and further reduced to a substituted aminoethanol (VI). The resulting hydroxyl group is converted to a leaving group such as a chloro group to obtain a suitable compound. The compound (III) can be produced by performing an intramolecular Friedet Graft reaction in the presence of a suitable Lewis acid, for example, aluminum chloride, and the compound (VI) is converted to the corresponding aldehyde (VII) by reductive amination. The aldehyde form (VII) can be produced by, for example, US Pat. Can be produced by the method described in, for example.

Second manufacturing method

The compound (I, II) of the present invention can be produced by reducing the compound (VIII). The olefin moiety of the compound (VIII) is reduced by catalytic hydrogenation using acetic acid or ethanol or a mixed solvent thereof using a metal catalyst such as palladium carbon under ice-cooling to room temperature, and the amide moiety is converted to an amide moiety. For example, it can be produced by using a reducing agent such as porane or lithium aluminum hydride in a solvent such as tetrahydrofuran or dioxane as a solvent under ice-cooling or room temperature.

Raw material synthesis

The starting compound (VIII) for the second production method can be produced by the following method.

(Wherein, R ⁸ represents lower alkyl. The same applies hereinafter.)

The compound (VIII) can be produced by applying the synthesis method described in JP-A-63-255226 to the phenylacetic acid derivative (IV). The compound (VIII) can be produced by introducing the phenylacetic acid derivative (IV) into an amide (IX) by a conventional method, and reacting it under a suitable acid condition, for example, sulfuric acid or trifluoromethanesulfonic acid as a solvent. Third manufacturing method

The compound (I, II) of the present invention can be prepared by converting compound (X) under an appropriate acid condition, for example, sulfuric acid or The reaction can be carried out under ice cooling or room temperature using trifluoromethanesulfonic acid as a solvent, and the compound (XI) can be produced by reducing the olefin portion of the compound (XI) in the same manner as in the second production method. Raw material synthesis

The starting compound (X) of the third production method can be produced by the following method.

The aminoacetaldehyde dialkyl acetal derivative (X) can be produced by applying the synthesis method described in JP-A-55-108855 to the phenethylamine derivative (XII). Compound (X) can also be produced by a reductive amination reaction with the corresponding aldehyde compound (XIII).

Fourth manufacturing method

The compound (I, II) of the present invention can be produced by subjecting a jS- 亍 tralone derivative (XIV) to a Beckmann rearrangement reaction to reduce an amide (XV) obtained in the same manner as in the second production method. The Beckmann rearrangement reaction can be carried out using chloroform or methylene chloride as a solvent and in the presence of a suitable acid, for example, in the presence of sulfuric acid or trifluoromethanesulfonic acid, or the like, on ice or at room temperature. The raw material yS-tetralone derivative (XIV) is manufactured by the synthesis method described in Indian J. Chem., Sect. II: Org. Chem. Incl. Med. Chem., 37B (3), 281 (1998). it can.

Fifth manufacturing method

(In the formula, X represents tosyloxy, mesyloxy, halo, and the like. The same applies hereinafter.) The compound (1, II) of the present invention can be synthesized by the method described in J. Org. Ghem., 56, 2937 (1991). It can be manufactured according to Compound (III) is produced by reacting compound (XV II), which can be produced from 1,2-bis (hydroxyethyl) benzene derivative (XVI), with an appropriate amine, followed by the production according to the first production method. Invention compound (I, II) can be produced.

Sixth manufacturing method

The compound (1, II) of the present invention can be produced according to the synthesis method described in J. Med. Ghem., 27, 918 (1984). The compound having the desired substituent (XV III) is converted into a lysian form (XIX) by a conventional method, subjected to an intramolecular cyclization reaction in the presence of an appropriate acid, and subjected to reduction conditions via the compound (XX). It can be manufactured by Further, the compound (III) can be produced by subjecting the cyano form (XIX) to the conditions of intramolecular cyclization in a direct reduction manner, and then the compounds (I, II) of the present invention can be produced according to the first production method. . The compound of the present invention (1, II) thus produced is isolated as it is or as a salt thereof. The salt of the compound of the present invention can be produced by subjecting the compound of the present invention, which is a free base, to a usual salt-forming reaction.

The compound (I, II) or a salt thereof of the present invention is isolated and purified as a hydrate, a solvate, or a polymorphic substance thereof. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.

Various isomers can be separated by selecting an appropriate starting compound or by utilizing a difference in physical properties between the isomers. For example, the optical isomer can be identified by selecting an appropriate raw material or by a racemic resolution method of a racemic compound (for example, a method of leading to a diastereomer monosalt with a general optically active acid and performing optical resolution). It can lead to chemically pure isomers.

(Prescription)

Various commonly used formulations can be applied to the compound of the present invention (1, I I). The typical prescription will be described below.

The pharmaceutical composition containing one or more of the compound (I, I 1) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can contain a pharmaceutically acceptable carrier. Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments, patches, using carriers, excipients, and other additives that are usually used in formulation Orally (including sublingual administration) or parenterally.

The clinical dose of the compound of the present invention (I, II) or a pharmaceutically acceptable salt thereof to a human may be individually determined in consideration of the symptoms, body weight, age, sex, administration route, etc. of the patient to which the compound is applied. It is usually determined according to the dose, but usually 1 adult to 100 mg per day per adult, preferably in the range of 10 mg to 20 mg per day. Administered orally or intravenously in one to several doses daily, ranging from 1 mg to 50 Omg per adult per day, or 1 hour to 24 hours a day It is administered intravenously over a period of time. Of course, as described above, the dosage varies under various conditions, so that a smaller amount than the above dosage may be sufficient. 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 include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl. It is mixed with pyrrolidone and magnesium aluminate metasilicate. The composition may contain, in a conventional manner, additives other than an inactive diluent, for example, lubricating agents such as magnesium diphosphate, starch, disintegrating agents such as calcium cellulose glycolate, and lactose. A stabilizing agent and a solubilizing agent such as glutamic acid or aspartic acid may be contained. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like, or with a gastric or enteric film.

Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as , Including purified water and 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. Aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). Such compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents. good. These are sterilized by, for example, filtration through a pateria retaining filter, blending of a bactericide or irradiation. They can also be used to produce a sterile solid composition which is dissolved in sterile water or a sterile injection solvent before use.

For example, the following formulation examples can be given as tablets for oral administration, but the present invention is not limited to these formulation examples. (Prescription example)

Composition of 3 mg tablet-Compound of the present invention 3 mg

D-manni I ^^ 89.8mg

Corn starch 22.4mg

Hydroxypropyl cellulose 3.6mg

Magnesium stearate 1.2mg

Total 1 20 mg

Manufacturing method of 3 mg tablets

15 g of the compound of the present invention, 449 g of D-mannii I, and 112 g of corn starch are uniformly mixed using a fluidized-granulation coating apparatus. Then, 180 g of a 10% hydroxypropylcellulose solution is steamed and granulated. After drying, pass through a 20-mesh sieve, add 6 g of magnesium stearate, mix, and use a rotary tableting machine to make 3 mg tablets per tablet using a 7 mm mx 8.4 R mortar and punch. BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

(Production example)

Hereinafter, the method for producing the compound of the present invention (I, II) will be described in detail. The synthesis of the starting compounds used in the examples will be described as reference examples.

Reference example 1

Reductive amination of 2,3-dichlorobenzene benzeneacetaldehyde and 2- (methizoleamino) ethanol with sodium triacetoxypolyhydride yields 2-[[2- (2,3-dichloromouth phenyl). ) Ethyl] Methylaminoethanol was obtained.

Reference example 2

2-[[2- (2,3-Dichrophenyl) ethyl] methylamino] ethanol After converting the hydroxyl group to a chloro group using phosphorus pentachloride, an intramolecular Friede-Graft reaction is performed to give 6,7-dichloro-3-methyl-2,3,4,5-tetrahydro-1H-3- Nzozepine was obtained.

Reference example 3

2,4-Dichlorophenylacetic acid was converted to acid chloride using thionyl chloride, and reacted with 2- (methylamino) ethanol to obtain an amide. The obtained amide form was reduced using a 1 mol I ZL volantetrahydrofuran solution to obtain 2-[[2- (2,4-dichloromouth phenyl) ethyl] methylamino] ethanol.

Reference example 4

In the same manner as in Reference Example 2, 6,8-dichroic-3-methyl-1,2,3,4,5-tetrahydro-1H-3-benzobenzopine was obtained.

Reference example 5

The 6-chloro-1-7-nitro-1,2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride obtained in Example 1 was protected with a di-tert-butyl dicarbonate to protect the nitrogen atom. did. This was reduced with iron powder to obtain 3- (tert-butoxycarbonyl) -17-amino-16-chloro-1,2,4,5-tetrahydro-1H-3-benzobenzepine.

Reference example 6

The compound obtained in Reference Example 5 was acetylated using acetyl chloride to give 7-acetylamino-3- (tert-butoxycarpenyl) -16-chloro-2,3,4,5-tetrahydro-1H-3-benzoazepine. I got

Reference Example 7

2,3-Difluorophenylacetic acid and aminoacetaldehyde getyl acetate are amidated with 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -13-ethylcarbodiimide hydrochloride, and N- (jetoxeti) 1) 1,2,3-Difluorobenzeneacetamide was obtained.

Reference Example 8

N- (diethoxyshethyl) 1,2,3-difluorobenzeneacetamide, concentrated sulfuric acid And trifluoromethanesulfonic acid to give 1,3-dihydro-18,9-difluoro-2H-3-benzazepin 2-one.

Reference example 9 '

6-Methoxy-1,2,3,4,5-tetrahydro-1H-3-benzazepine is demethylated with 48% hydrobromic acid to give 6-hydroxy-1,2,3,4,5-tetrahydrido口一 1 H—3-Benazepine was obtained. This is acetylated with acetic anhydride and then alkylated with sodium hydride and bromoacetaldehyde getyl acetal to give 3-acetyl-6- (2,2-diethoxyethoxy) -1,2,3,4 , 5-Tetrahydro-1H-3-benzazepine was obtained.

Reference example 10

7,8,9,10-Tetrahydro-16H-furo [2,3-g] [3] Benzozepine is protected with N- (tert-butoxycarbonyl) 1) 7,8,9,10-tetrahydro-6H-furo [2,3-g] [3] Benzozepine was obtained. This is ethylated using n-butyllithium and iodine-treated methyl, and 2-ethyl-1-N- (tert-butoxycarbonyl) -17,8,9,10-tetrahydro-16H-flow [2,3- g] [3] Benzozepine was obtained.

Reference example 1 1

2- (2-Chloro-3-methoxyphenyl) ethylamine is alkylated with bromoacetaldehyde dimethyl acetyl acetal to give [2- (2-chloro-3-methoxyphenyl) ethyl] aminoacetaldehyde getyl Acetal was obtained. Reference example 1 2

6-Chloro-1-methyl-7-nitro-2,3,4,5-tetrahydro-1H-3 -Benzozepine is reduced with iron powder to give 7-amino-6-Chloro-1- Methyl-2 '

3, 4, 5-Tetrahydro-1H-3-benzazepine was obtained.

Reference Example 13

Using the same method as in Reference Example 12, 7-chloro-1--3-methyl-8-nitro-1,2,3,

4, 5-tetrahydro- 1 H- 3-benzoazepine to 7-amino-8-chloro-3 —Methyl-1,2,3,4,5-tetrahydro-1H-3-benzazepine was obtained.

Reference example 1 4

7-Amino-8-chloro-3,3-methyl-1,2,3,4,5-tetrahydro-1H-3 Benzozepine is nitrated with concentrated nitric acid in concentrated sulfuric acid to give 8-amino-7-chloro-3-. Methyl 1-6-two-row 2,3,4,5-tetrahydro-1-H-3-benzoazepine was obtained. This is reacted with sodium nitrite in acetic acid and concentrated sulfuric acid. Thereafter, the reaction solution is added to an aqueous solution of sodium hypophosphite and copper oxide (III) to deaminate, and the mixture is treated with 7-chloro-3-methyl-methyl. 6-Nitro-1,2,3,4,5-tetrahydro-1H-3-benzazepine was obtained.

Reference example 1 5

4-Bromo-1,2-dimethylbenzene is acylated using succinic anhydride and 7-luminum chloride to give 3- (2-bromo-4,5-dimethylbenzoyl) propionic acid and 3- (5-bromo1-2 A mixture of (3-dimethylbenzoyl) propionic acid was obtained. This mixture is reduced with hydrazine to give a mixture of 4- (2-bromo-1,4,5-dimethylphenyl) butanoic acid and 4- (5-bromo-1,2,3-dimethylphenyl) butanoic acid. Obtained. The mixture was cyclized by addition of 85% phosphoric acid in acetic anhydride to obtain 5-promo 7,8-dimethyl-3,4-dihydro-1 (2H) -naphthalenone.

Reference Example 1 6

Reductive amination of 4.61 mI of (3-chloro-2-methylphenyl) acetaldehyde and aminoacetaldehyde decyl acetal was carried out using sodium triacetoxyborohydride to give 2- (3-chloro-2 —Methylphenyl) ethyl] aminoacetaldehyde getyl acetal was obtained.

Reference Example 1 7

Using 1,3-dichloro-1-ethylbenzene in 1,2-dibromoethane and magnesium in tetrahydrofuran, a solution of (3-chloro-2-ethylphenyl) magnesium chloride in tetrahydrofuran was prepared. This is reacted with 2-chloro-1-N-methylacetoamide to give 2-chloro-1- (3-chloro-1-2-) Tylphenyl) Ethanone was obtained.

Reference Example 1 8

2-Chloro-3-methylbenzeneacetonitrile was reduced using lithium aluminum hydride to obtain 2-chloro-1-methylbenzeneethanamine.

Reference Example 1 9

4,5,6,7-Tetrahydro-14-oxobenzo [b] thiophen-15-acetic acid ethyl ester is reacted with sodium hydride and ethylphosphonoacetate to give 5-ethoxycarbonylmethyl-6,7-dihydro- 5 H-benzo [b] thiophene-4-ethylideneacetate was obtained. This is reacted with 10% palladium on carbon to obtain 4,5-bis (ethoxycarbonylmethyl) benzo [b] thiophene, which is then reduced using lithium aluminum hydride to give 4,5-bis (2— Hydroxyethyl) benzo [b] thiophene was obtained.

Reference Example 20

2-Methoxy-6,7-dihydro-5H-benzo [b] thiophen-14-one was reacted with 1.6M butyllithium hexane solution and ethyl bromoacetate to give 2-methoxy-4,5 , 6,7-Tetrahydro-4-oxobenzo [b] thiophen-15-acetic acid ethyl ester was obtained.

Reference Example 21

3,4-Dimethylphenol was reacted with sodium hydride and bromoacetaldehyde getyl acetal to obtain 3,4-dimethyl-11- (2,2-ethoxyethoxy) benzene. This was cyclized using polyphosphoric acid to obtain a mixture of 4,5-dimethylbenzofuran and 5,6-dimethylbenzofuran. The mixture was brominated with N-bromosuccinimide and then reacted with sodium cyanate to give a mixture of 4,5-biscyanmethylbenzofuran and 5,6-biscyanmethylbenzofuran. This mixture is cyclized in a solution of hydrogen bromide in acetic acid, and then reduced with 1 OM porane-methyl sulfide complex to give 6,7,8,9-tetrahydro-15H-furo [2,3-h] [3] benzozepine And 7,8,9,10- 亍 trahydro-6H-furo [3,2-g] [3] benzazepine. This mixture is JP02 / 02306

19 Di-tert-butyl is used to protect the nitrogen atom, and 7- (tert-butoxycarbonyl) -1,6,7,8,9-tetrahydro-5H-furo [2,3-h] [3] benzoazepine ( 21a) and 8— (tert-Butoxycarponyl) -17,8,9,10— 亍 trahydro-6H—furo [3,2-g] [3] benzazepine (21b) were obtained.

Reference Example 22

The compound obtained in Reference Example 15 was reacted with sodium borohydride to obtain 5-bromo-1,7,8-dimethyl-1,2,3,4-tetrahydro-11-naphthol. Subsequently, this was reacted with p-toluenesulfonic acid monohydrate to obtain 8-bromo-5,6-dimethyl-11,2-dihydronaphthalene. This was oxidized with m-chloroperoxybenzoic acid to obtain 5-bromo-17,8-dimethyl-1,2,3,4-tetrahydro-1,2-epoxynaphthalene. This was reacted with a boron trifluoride-jetyl ether complex to obtain 5-promo 7,8-dimethyl-3,4-dihydro-2 (1H) -naphthalenone.

Example 1

6-Chloro-3-methyl-7-nitro-1,2,3,4,5-tetrahydro-1H—3-benzazepine 2.04§ 1,2-dichloroethane In a mixture of 17mI, chloroformate 1-chloroethyl 1 mI was added, and the mixture was stirred overnight while heating under reflux. The solvent of the reaction solution was distilled off under reduced pressure, 15 ml of methanol was added to the residue, and the mixture was stirred under reflux with heating for 5 hours, and then the solvent was distilled off under reduced pressure. To the residue were added water and a saturated aqueous solution of sodium hydrogen carbonate, 50 ml each, and the mixture was extracted with chloroform (5 Om I x2). The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.06 g of a colorless oil. The oily substance obtained above was dissolved in ethyl acetate 2 Om I, 4 mol I ZL 1.5 ml of ethyl acetate monohydrochloride was added, and the precipitated insoluble material was collected by filtration. 1.2 g of 3,3,4,5-tetrahydro-1H-3-benzobenzopine hydrochloride was obtained as a white solid.

The compounds of Examples 2 to 4 were obtained in the same manner as in Example 1.

Example 2: 7-Chloro-8-Nitroguchi-1,3,4,5-tetrahydro-1H-3 Nzazepine hydrochloride

Example 3: 6,8-dichloro-1,2,4,5-tetrahydro-1H-3-benzo-azepine hydrochloride

Example 4: 6, FUJICHLORO-1,2,3,4,5-tetrahydro-1H-3Henzozepine hydrochloride

Example 5

3- (tert-butoxycarbonyl) -17-amino-6-chloro-1,2,3,5,5-tetrahydro-1H-3-benzazepine obtained in Reference Example 5, 9 Omg, ethyl acetate 2 ml and methanol 1 To the mixed solution of mI was added 0.5 ml of a 4 mol I L solution of ethyl acetate monohydrochloride, and the mixture was stirred at room temperature for 2 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the residue was washed with ethyl acetate, and 8 Omg of 7-amino-6-chloro-1,2,3,4,5-tetrahydro-1H-3-benzobenzozepine hydrochloride was added. Obtained as a white solid.

Example 6

In the same manner as in Example 5, 7-acetylamino-6-chloro-2,3,4,5-tetrahydro-1H-3-benzobenzopine hydrochloride was obtained.

Example 7

3- (tert-butoxycarbonyl) -17-amino-16-chloro-2,3,4,5-tetrahydro-1H-3-benzoazepine 0.18 g, triethylamine 0.09 ml and 1 To a mixed solution of 2,2-dichloroethane (2 ml) was added methanesulfonyl chloride (0.05 ml) under ice cooling, followed by stirring at room temperature overnight. To the reaction solution was added 30 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with a stomal form (50 mIX2). The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and 85 mg of 3- (tert-butoxycarbonyl) -16-chloro-7-mesylamino-2,3,4,5-tetrahydro-1H-3-benzoazepine was obtained as a colorless color And 6-chloro-17-mesylamino-2,3,4,5-tetrahydro-1H-3-benzobenzopine hydrochloride was obtained in the same manner as in Example 5.

Example 8

7-Acetylamino-3- (tert-butoxycarbonyl) 16-chloro-1,2 3,4,5-Tetrahydro- 1H-3-benzazepine 0.223 ₂ N-dimethylformamide To a mixture of 3 ml, add 30 mg of sodium hydride (60%) and iodine under ice-cooling. 0.05 ml of methyl chloride was added, and the mixture was stirred at room temperature for 5 hours. To the reaction solution was added 5 OmI of ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 3- (tert-butoxycarbonyl) -1-6-chloro-7-acetylmethylamino-1,2,3,4,5-tetrahydro-1H-3-benzoazepine. 0.21 g was obtained as a colorless amorphous powder. 7-Acetylmethylamino-6-chloro-2,3,4,5-tetrahydro- 1H-3-benzobenzozepine hydrochloride was obtained in the same manner as in Example 4. Obtained.

Example 9

After stirring a mixture of 100 mg of 7-acetylmethylamino-6-chloro-2,3,4,5-tetrahydro-1H-3-benzobenzopine and 2 ml of concentrated hydrochloric acid at 100 ° C for 2 hours, the solvent of the reaction solution was Was distilled off. After washing the residue with acetonitrile, the resulting crude crystals were dispersed in 30 ml of a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate (50 m IX 2), and the extract was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (3 ml) and ethyl acetate (3 ml), 4 ml of ZL hydrochloric acid ethyl acetate (0.4 ml) was added, the mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was washed with ethyl acetate to obtain 45-mg of 6-chloro-7-methylamino-1,2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride as a white solid.

Example 10

0.26 g of 1,3-dihydro-8,9-difluoro-2H-3-benzazepin-12-one was dissolved in 5 ml of acetic acid, 50 mg of 10% palladium on carbon was added, and the mixture was stirred for 5 hours under a hydrogen stream. After the reaction was completed, the filtrate was concentrated by removing the insoluble matter through Celite filtration. To this reduced form was added a 1 M poranetetrahydrofuran solution (3.3 ml), and the mixture was stirred at room temperature overnight. After adding 2 ml of methanol to the reaction solution, 1 ml of 1 ml of ZL hydrochloric acid aqueous solution was added, and the mixture was refluxed for 2 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure. To the resulting residue were added 15 ml of water and 5 ml of "Imo I ZL sodium hydroxide, and the mixture was extracted with chloroform. The layers are combined, dried using anhydrous sodium sulfate, and then dried under reduced pressure. The solvent was distilled off, and the residue was purified using silica gel column chromatography. The resulting purified product was dissolved and stirred in 4 ml of 0.5 ml of a ZL solution of ethyl acetate monohydrochloride. The precipitate was collected by filtration and dried under reduced pressure to obtain 0.14 g of 6,7-difluoro-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride as a white solid.

Example 1 1

In the same manner as in Example 10, 7-fluoro-6-methyl-1,2,3,4,5-tetrahydro-1H-3-benzobenzopine hydrochloride was obtained.

Example 1 2

2- (2-chloro-3-menu Tokishifue sulfonyl) Echiru] Aminoase Bok aldehyde di Echiruasetaru 1.50 ₈ was stirred for 1 hour at room temperature was added in ice-cooling concentrated sulfuric acid 1 Om I. The reaction mixture was poured into cold water, neutralized by adding a 2 mo I aqueous solution of ZL sodium hydroxide, and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 85 mg of 9-chloro-1,8-methoxy-2,3-dihydro-1H-3-benzozepine. This was dissolved in tetrahydrofuran (2 m), mixed with a 0.5 M aqueous solution of sodium dihydrogen phosphate (2 ml) in a mixed solvent, and sodium cyanoborohydride (0.25 g) was added thereto, followed by a reaction at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and then a solution was added thereto to separate an organic layer. The aqueous layer was washed using a black hole form, and the organic layers were combined and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography, and the obtained pale yellow oil was dissolved in 4 mo I ZL hydrochloric acid / monoacetic acid / ethyl acetate solution, and the precipitated crystals were collected by filtration and dried under reduced pressure. —Chloro-7-methoxy-2,3,4,5-ditrahydro-1H-3-benzazepine hydrochloride (54 mg) was obtained as a white solid.

Example 13

7-amino-6-chloro-3,3-methyl-2,3,4,5-tetrahydro-1H-3-1-benzazepine 0.40 g aqueous solution (2.5 ml) in 47% hydrogen bromide aqueous solution 1 mI Was added and the mixture was heated under reflux for 20 minutes. The reaction solution was ice-cooled, and 0.13 g of sodium nitrite was added little by little so that the temperature of the reaction solution did not exceed 10 ° C or higher, followed by stirring for 20 minutes. This anti The reaction solution was added to a solution obtained by mixing 0.33 g of an aqueous solution (2 ml) of copper bromide (1) and 0.65 ml of a 47% aqueous solution of hydrogen bromide. And stirred for 2 hours. The reaction solution was poured into ice water, 1 mol I ZL aqueous solution of sodium hydroxide was added to make the solution viscous, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography, and 7-bromo-16-chloro-3-methyl-1,2,3,4,5-tetrahydro-1H-3-benzobenzopine 0.16 g as a pale brown oil, and 47 mg of 7-bromo-16-chloro-2,3,4,5-tetrahydro-1H-3-benzobenzozepine hydrochloride as a colorless solid was obtained in the same manner as in Example 1. Obtained. ·

Example 14

Copper chloride (I) 1.19 g of an aqueous solution (5 ml) was added to 3.13 g of aqueous solution of potassium cyanide (9 m), stirred at room temperature for 30 minutes, and then added with 32 ml of benzene. A solution of copper (I) cyanide was prepared 7-amino-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3benzoate 1.20 _§ of a 2121 aqueous solution of hydrochloric acid (21m2) 0.5 g of sodium nitrite was added little by little to I) under ice-cooling so that the temperature of the reaction solution did not exceed 10 ° C., and the mixture was stirred for 30 minutes. This layer was neutralized with sodium carbonate, and the solution was added dropwise to the copper (I) cyanide solution prepared above under ice-cooling so that the temperature of the reaction solution did not exceed 10 ° C, followed by stirring for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with 10% aqueous sodium carbonate solution, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography, and 6-chloro-7-cyano-3-methyl-2,3,4,5-tetrahydro-1H-3-benzobenzopine 0.75 g was obtained as a pale brown solid, and 428 mg of 6-chloro-7-cyano-1,2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride as a colorless solid was obtained in the same manner as in Example 1. Example 15

Using the same method as in Reference Example 8, 6-amino-17-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzobenzepine was obtained, and the same method as in Example 13 was used. 6-bromo-1,2,3,4,5-tetrahydro-1H-3-benzo Azepine hydrochloride was obtained.

Example 16

7-Amino-6-chloro-1,3-dimethyl-1,2,3,4,5-tetrahydro-1H-3-benzazepine 0.58 g was dissolved in 1.26 ml of a 48% aqueous solution of tetrafluoroboric acid, and the mixture was cooled on ice. After 0.19 g of sodium nitrate was added little by little, the mixture was stirred for 1 hour. After water of the reaction solution was distilled off under reduced pressure, the mixture was stirred at 160 ° C. for 3 hours. After cooling, the reaction solution was diluted with saturated aqueous ammonia, extracted with a lip mouth form, and dried with anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography, and 0.48 g of 6-chloro-7-fluoro-3-methyl-1,2,3,4,5-tetrahydro-1H-13-benzazepine was pale brown. This was obtained as an oil, and 6-chloro-7-fluoro-2,3,4,5-ditrahydro-1H-3-benzobenzozepine hydrochloride was obtained in the same manner as in Example 1.

Example 17

Dissolve 0.79 g of 5-bromo-1,7,8-dimethyl-1,4-dihydro-2 (1H) -naphthalenone in 45 ml of chloroform and add 19 ml of concentrated sulfuric acid under ice-cooling. After stirring for 5 minutes at room temperature and adding 406 mg of sodium azide over 25 minutes, the mixture was stirred at room temperature for 7 hours. The reaction solution was poured into ice, dissolved, extracted with chloroform, and the combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. 9-Dimethyl-2-oxo-1,2,3,4,5-tetrahydro-1-H-3-benzazepine and 6-bromo-8,9-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-2 There were obtained 71 8 mg of a mixture of benzazepines. After repeating the above steps again, 816 mg of the obtained mixture was dissolved in 75 ml of tetrahydrofuran, 1N borane-tetrahydrofuran complex and 15.2 ml of tetrahydrofuran solution were added, and the mixture was added at room temperature for 1 hour. The mixture was stirred at ° C for 2.5 hours. To the reaction solution was added 1 mo IZL hydrochloric acid aqueous solution (152 ml), heated under reflux for 40 minutes, made basic with 1 mo IL aqueous sodium hydroxide solution, extracted with chloroform, and the combined organic layer was diluted with saturated saline. After washing, the extract is dried over anhydrous sodium sulfate, the solvent is distilled off, and the residue is purified by silica gel column chromatography, and the obtained product is dissolved in 4moI ZL ethyl acetate monohydrochloride. The mixture was treated with the liquid to obtain 9-promo 6,7-dimethyl-2,3,4,5-tetrahydro- 1 H-13-benzazepine hydrochloride (161 mg) as a colorless solid.

Example 18

Dissolve 128 mg of 9-bromo-6,7-dimethyl-1,2,3,4,5-tetrahydro-1H-3-benzazepine in ethanol 2 Om I, add 10% palladium carbon 2 Omg, and add 1 atmosphere hydrogen atmosphere The mixture was stirred overnight at room temperature. The reaction solution was filtered through celite, the solvent was distilled off, saturated aqueous sodium bicarbonate was added, the mixture was extracted with ethyl acetate, and the combined organic layers were washed with saturated saline, dried over anhydrous potassium carbonate, and the solvent was distilled off. . The same reaction procedure was repeated again until the disappearance of the raw materials was confirmed. After recrystallization, 5,7-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (5 Omg) was obtained as a colorless solid.

Example 19

Using a method similar to that in Example 12, 7-chloro-6-methyl-1,2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride was obtained.

Example 20

Using the same method as in Reference Example 16 and Example 12, 7-chloro-6-ethyl-1,2,3,4,5-tetrahydro-1H-3-benzobenzopine hydrochloride was obtained.

Example 21

Using the same method as in Reference Example 11 and Example 12, 6-chloro-7-methyl-2,3,4,5-tetrahydro-1H-3-benzoazepine hydrochloride was obtained.

Example 22

3-Acetyl-6- (2,2-ethoxyethoxy) -1,2,3,4,5-tetrahydro-1H-3-benzazepine obtained in Reference Example 1. 1.65 g of a benzene solution (30 mI) To the mixture was added 1.65 g of polyphosphoric acid, and the mixture was heated under reflux for 30 minutes. After cooling the reaction solution, the organic layer was separated from polyphosphoric acid, and the organic layer was diluted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain a 2: 3 mixture of product and raw materials. Was. The obtained mixture was dissolved in 20 ml of methanol, 9 ml of a 40% aqueous solution of hydroxylated water was added, and the mixture was reacted at 70 ° C. for 4 hours. After cooling, the reaction solution was extracted with a black form, the organic layers were combined, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was dissolved in tetrahydrofuran, and 0.50 g of di-tert-butyl dicarbonate was added, followed by stirring at room temperature for 1 hour. After evaporating the solvent, the residue was purified by silica gel column chromatography, and the obtained product was treated with 4moI ZL hydrochloric acid / ethyl acetate solution to give 7,8,9,10-tetrahydro-16H-floor. [2, 3-g] [3] 28 _mg of benzazepine hydrochloride was obtained as a colorless solid.

The compounds of Examples 23 to 25 were obtained in the same manner as in Example 5.

Example 23: 2-Ethyl-7,8,9,10-tetrahydro-6H-furo [2,3-g] [3] Benzozepine hydrochloride

Example 24: 6,7,8,9-Tetrahydro-5H-furo [2,3-h] [3] Benzozepine hydrochloride

Example 25: 7, 8, 9, 10-tetrahydro-6H-furo [3, 2-g] [3] benzazepine hydrochloride

Example 26

Dissolve 30 Omg of 4,5-bis (2-hydroxyethyl) benzo [b] thiophene in 1 OmI of tetrahydrofuran, cool to 120 ° C, and then add 540 mg of p-toluenesulfonic acid chloride, triethylamine 393 I and a catalytic amount of dimethylaminopyridine were added, and the mixture was stirred at room temperature for 113 hours. Thereafter, 54 Omg of p-toluenesulfonic acid chloride and 393 jUI of triethylamine were further added, and the mixture was stirred at room temperature for 24 hours. After the reaction solution was filtered and washed with getyl ether, the filtrate was washed successively with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. The organic layer is dried over magnesium sulfate, the solvent is distilled off, the residue is purified by silica gel column chromatography, concentrated to a certain extent, dioxane 3 OmI is added, and the solvent amount is reduced to about 15 mI under reduced pressure. It was concentrated until it became. 3.00 g of potassium carbonate was added to this solution, and a mixed solution of benzylamine 516 juI and dioxane 10 ml was added dropwise over 1 hour under reflux with heating. After refluxing with heating for another 40 hours, the reaction solution was cooled and filtered. The filtrate is concentrated under reduced pressure. Purification by force gel column chromatography yielded 269 mg of 8-benzyl-1,7,8,9,10- 亍 trahydro-6H-thieno [3,2-g] [3] benzozepine, and was obtained in the same manner as in Example 1. Riff, 8, 9, 10-tetrahydro-16H-thieno [3, 2-g] [3] benzozepine hydrochloride was obtained.

Example 27

Using the same method as in Reference Example 15 and Example 26, 2-methoxy 4,5,6,7-tetrahydro-4-oxobenzo [b] thiophene-15-ethyl acetate was used to prepare 2-methoxy 7,8, 9,10-Tetrahydro-6H-thieno [3,2-g] [3] Benzozepine hydrochloride was obtained.

The chemical structural formulas and physicochemical properties of the compounds obtained in Reference Examples and Examples are shown in the following table.

The symbols in the table have the following meanings.

Rf .: Reference example number

Ex .: Example number

Ac: Acetyl

Me: Methyl

Et: Ethil

Pr: propyl

iPr: Isopropyl

Allyl: Allyl

Ph: Fanir

N Station: DMSO-d ₆ unless nuclear magnetic resonance scan Bae spectrum (otherwise, TMS internal standard> [delta]:

Halla οε

90CZO / ZOdf / X3d 9tLtL0 / Z0 O Table 5

Hereinafter, in addition to those described in the examples, the above-mentioned production methods, the production methods of the reference examples and the examples, ordinary production methods known to those skilled in the art, and modifications thereof are required. The compounds shown in Tables 6 and 7 can be obtained without using the same.

9 Halla CZ0 / Z0df / X3d 9 L L0 / Z0 OAV T / JP02 / 02306

33

(Pharmacological test example)

Hereinafter, the binding test of the compound (1, II) of the present invention to the 5- _HT2C receptor and the animal test using rats will be described in detail.

Example 28

Binding experiment for 5-HT _2C receptor

The binding experiments for the 5-HT _2C receptor were described in A. Pazos et al., Eur. J. Pharmacol., 106, 539-546 (1985) or S. havlikand SJ Peroutka, Brain Res., 584, 191-196. [ ³ H] 5-HT binding analysis was performed according to the method of (1992).

Using the above method, the drug concentration that inhibits 50% of the receptor-binding ligand (IC ₅₀ value) was determined, and the Ki value representing the affinity for the receptor was calculated by the following formula: Ki = IC ₅ . (1 + [shi] Z [Kd]) ([L]: ligand concentration, [Kd]: dissociation constant) The results are shown in Table 8. Table 8

5_HT _2C receptor binding experiment)

It has been reported that mCP P (1- (m-chlorophenyl) pidazine) is a 5-HT _2C receptor agonist (Life Science, 43, 1297 (1993), etc.). Example 29

Animal experiment using rat: Rat penis erection-inducing action

Induction of penile erection by 5-HT _2C receptor stimulation and its test method have been reported (Berendsen & Broekkamp, Eur. J. Pharmacol., 135, 179-184 (1987)). According to the above test method, the test compound was orally administered to 5 male Wistar rats, and immediately after administration, the number of penile erections for 30 minutes was measured and compared with the vehicle administration group (distilled water administration). From the comparison results, the minimum effective dose at which a statistically significant response of the test compound was observed was determined.

Table 9 shows the results. Table 9

Erectile penis elicitation (mgZk g, p o)

Test compound Minimum effective dose

Example 4 1.0

Example 1 3 0.3

Example 1 4 3.0

Example 213.0

mC PP 3.0 As described above, in the compound of the present invention (1, II), a compound having an affinity for the 5-HT _2C receptor equal to or higher than that of m CPP, which is a 5-HT _2C receptor agonist, was observed. Furthermore, the compounds of the present invention (1, II) were also observed to have an activity equal to or higher than that of mCPP in erecting penile erections in rats.

From the above, it was confirmed that the compound of the present invention (1, II) was an excellent 5-HT _2C receptor agonist. Industrial applicability

The compound of the present invention (1, II) was confirmed by pharmacological tests to be an excellent 5-HT _2C receptor agonist. Therefore, the compounds (I, II) of the present invention are useful for treating central nervous system diseases such as sexual dysfunction, obesity, bulimia, anxiety, anxiety, depression or sleep disorders involving 5-HT _2C receptor.

Claims

The scope of the claims

1. A 5-HT _2c receptor agonist comprising, as an active ingredient, a benzozepine derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings

R ¹ , R ² and R ³ : the same or different, optionally substituted lower alkyl, optionally substituted lower alkenyl, acyl, mono-, mono-substituted hydrocarbon Group, one SH, one S—optionally substituted hydrocarbon group, amino, mono- or di-lower alkylamino, acylamino, halo, nitro or cyano in which the nitrogen may be substituted by lower alkyl

2. The 5-HT _2c receptor agonist according to claim ^1, wherein R ¹ and R ³ are the same or different and are 1 H, lower alkyl or halo, and R ² is lower alkyl or halo. _c

3. wherein R ¹ Gaha opening, R ² is lower alkyl or C port, R ³ is - according is H range of the second Claims 5-HT ₂ c receptor Agonisu Bok.

4. 6,7-Dichloro-2,3,4,5-tetrahydro-1H-3-benzobenzepine, 7-Bromo-6-chloro-2,3,4,5-tetrahydro-1H-3-benzoazepine or 6- HT _2c receptor Agonisu Bok - chloro 7-methyl one 2, 3, 4, 5-tetrahydro-1 H- 3- base Nzoazepin or a pharmaceutically acceptable 5 of claims Section 3, wherein the salts.

5. The 5-HT2 ₍ : receptor agonist according to claim 1, which is a therapeutic agent for sexual dysfunction.

6. erectile dysfunction treatment in the claims which drugs range of paragraph 5, wherein 5-HT ₂ c receptor Agoni scan Bok.

7. 5-HT _{2 according to} claim 1 for the manufacture of a therapeutic agent for sexual dysfunction. Receptor Use of agonists.

8. 5-HT _{2 according to} claim 1. A method for treating sexual dysfunction, comprising administering to a patient a therapeutically effective amount of a receptor agonist.

9. A benzazepine derivative represented by the following formula (II) or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings

R ¹¹ and R ³³ : one of them is mono-, lower-alkyl, amino, mono- or di-lower-alkylamino, acylamino, halo, nitro or cyano which may have lower alkyl on nitrogen, and the other is lower alkyl , Amino, mono- or di-lower alkylamino, acylamino, halo, nitro or cyano which may have lower alkyl at nitrogen

R ²² : lower alkyl, mono-, mono-lower alkyl, amino, mono- or di-lower alkylamino, acylamino, nitrogen, nitro, cyano or cyano in which nitrogen may be substituted by lower alkyl.

Further, R ²² may combine with R ¹¹ or an adjacent R ³³ to form a heteroalkyl ring which may be substituted with lower alkyl, mono- or mono-lower alkyl,

2) When R ^{22 is} ΟΗ or methoxy, R ¹¹ and R ³³ are the same or different and represent a group other than ΟΗ, methoxy, bromo or nitro

3) When R ¹¹ is chloro, R ²² represents a group other than chloro)

10. The method according to claim 9, wherein one of R ¹¹ and R ³³ is —Η, lower alkyl or halo, the other is lower alkyl or halo, and R ²² is lower alkyl or halo. Compound.

1 1. R ¹¹ is H, R ²² is lower alkyl or H, R ³³ is ー 10. The compound according to claim 10, wherein

1 2.7-bromo-6-chloro-2,3,4,5-tetrahydro-1-H-3-benzobenzopine or 6-chloro-7-methyl-1,2,3,4,5-tetrahydro-1 12. The compound according to claim 11, which is H-3-benzozepine, or a pharmaceutically acceptable salt thereof.

1 3. A pharmaceutical composition comprising the compound according to claim 9 and a pharmaceutically acceptable carrier.