JP2008037800A - Benzoazepine compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new benzoazepine compound having vasopressin antagonism. <P>SOLUTION: This benzoazepine compound represented by the general formula (1) [R<SP>1</SP>is H; R<SP>2</SP>is -O-R<SP>4</SP>or -N(R<SP>5</SP>)-O-R<SP>6</SP>; or R<SP>1</SP>and R<SP>2</SP>together represent a =N(R<SP>7</SP>)→O; R<SP>3</SP>is a lower alkyl; R<SP>4</SP>is 2-carboxy-tetrahydroxypyran ring which may have a protecting group; R<SP>5</SP>is a lower alkyl: R<SP>6</SP>is H or R<SP>4</SP>]. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a benzazepine compound.

As a compound having a vasopressin antagonistic action, for example, a benzazepine compound described in Patent Document 1 is known.
Japanese Patent Publication No. 7-76214

  An object of the present invention is to provide a novel benzazepine compound having a vasopressin antagonistic action.

  The present inventors have found that a benzoazepine compound represented by the following general formula (1) has a vasopressin antagonism while conducting various studies on the benzoazepine compound. The present invention has been completed based on such findings.

This invention provides the invention which concerns on the benzazepine compound and pharmaceutical which are shown to the following items 1-4.
Item 1. General formula (1)

[Wherein R ¹ represents a hydrogen atom.
R ² represents a —O—R ⁴ group or a —N (R ⁵ ) —O—R ⁶ group.
R ¹ and R ² together represent a ═N (R ⁷ ) → O group.
R ³ represents a lower alkyl group.
R ⁴ is a group

Indicates.
R ⁵ represents a lower alkyl group.
R ⁶ represents a hydrogen atom or an R ⁴ group (R ⁴ is the same as described above).
R ⁷ represents a lower alkyl group which may have a hydroxyl group or —OR ⁴ group (R ⁴ is the same as above) as a substituent.
R ⁸ , R ⁹ and R ¹⁰ each represent a hydroxyl group which may have a protecting group.
R ¹¹ represents a carboxyl group which may have a protecting group. ]
Or a salt thereof.
Item 2. A pharmaceutical comprising the benzazepine compound or a salt thereof according to Item 1 as an active ingredient.
Item 3. Item 3. The medicine according to Item 2, which is used as a vasopressin antagonist.
Item 4. Item 3. The medicine according to Item 2, which is used as a vasodilator, blood pressure lowering agent, water diuretic or platelet aggregation inhibitor.

Benzazepine Compound Each group represented by the general formula (1) is more specifically as follows.

The lower alkyl group is a linear or branched C _1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, Examples thereof include n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl group.

In the hydroxyl group which may have a protecting group, examples of the protecting group include a lower alkanoyl group. The lower alkanoyl group is a linear or branched C _1-6 alkanoyl group, and examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl groups. it can.

  In the carboxyl group which may have a protecting group, examples of the protecting group include a lower alkyl group. The lower alkyl group is the same as the lower alkyl group exemplified above.

  The benzazepine compound represented by the general formula (1) of the present invention or a salt thereof can be produced in the same manner as described in Examples 1 to 8 below.

  The benzazepine compound represented by the general formula (1) of the present invention or a salt thereof includes stereoisomers, optical isomers, and solvates (hydrates, ethanolates, etc.).

  The salt of the benzazepine compound represented by the general formula (1) of the present invention is a pharmaceutically acceptable salt, for example, an alkali metal salt (for example, sodium salt, potassium salt, etc.) and an alkaline earth metal. Metal salts such as salts (for example, calcium salts, magnesium salts, etc.); ammonium salts; organic base salts (for example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt) And tris (hydroxymethyl) aminomethane salt).

  Such salts can be readily formed by reacting the compound of the present invention with a corresponding pharmaceutically acceptable basic compound. Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

  Further, the benzoazepine compound of the general formula (1) of the present invention can be easily converted into an acid addition salt by allowing a pharmaceutically acceptable acid to act, and the present invention also includes this acid addition salt. . In the above, examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and nitric acid, acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, and tartaric acid. , Citric acid, malonic acid, methanesulfonic acid, benzoic acid, trifluoroacetic acid, benzenesulfonic acid, formic acid, toluenesulfonic acid and other organic acids, amino acids (eg, arginine, aspartic acid, glutamic acid, etc.) .

Pharmaceuticals The benzazepine compounds and salts thereof of the present invention are usually used in the form of general pharmaceutical preparations. The pharmaceutical preparation is prepared by a conventional method using diluents or excipients such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and the like that are usually used.

  The form of the pharmaceutical preparation using the compound of the present invention can be appropriately selected according to the therapeutic purpose. Examples of the form of the pharmaceutical preparation include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, ointments and the like, and in particular, injections, eye drops, etc. Aqueous solution formulations are preferred.

  For example, when an injection is prepared using the compound of the present invention, it is preferable that solutions, emulsions and suspensions are sterilized and isotonic with blood. In addition, when using the compound of the present invention in the form of these solutions, emulsions and suspensions, all those commonly used in this field as diluents can be used. Examples of such diluents include water, aqueous lactic acid solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like. In this case, an isotonic agent such as sodium chloride, glucose, mannitol or glycerin sufficient to prepare an isotonic solution may be added to the pharmaceutical preparation, and a normal pH adjusting agent, dissolving Adjuvants, buffers, soothing agents and the like may be added.

  When preparing an injection using the compound of the present invention, a benzazepine compound represented by the general formula (1) or a salt thereof, a buffer, an isotonic agent, water for injection, and a pH adjuster as necessary. And can be prepared by conventional methods.

  Examples of the buffer include carbonate, borate, phosphate, citrate, tris (hydroxymethyl) aminomethane, malate, and tartrate. The base can be added alone.

  Examples of the pH adjuster include basic compounds such as sodium hydroxide and acids such as hydrochloric acid.

  Furthermore, if necessary, colorants, preservatives, fragrances, flavoring agents, sweetening agents, and other pharmaceuticals may be incorporated into the pharmaceutical preparation.

  The content of the benzazepine compound represented by the general formula (1) of the present invention or a salt thereof in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.01 to 70 in the pharmaceutical preparation. It is good to set it as weight%.

  There is no restriction | limiting in particular about the administration method of said pharmaceutical formulation, It administers by the method according to various formulation forms, a patient's age, sex, other conditions, a patient's symptom grade, etc. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it is administered alone or mixed with a normal fluid such as glucose or amino acid, and administered intravenously, or if necessary, administered intramuscularly, intradermally, subcutaneously or intraperitoneally.

  The dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the patient's age, sex and other conditions, the degree of disease, etc., but is usually an active ingredient benzoazepine compound represented by the general formula (1) or The salt is administered in an amount of 0.001 to 100 mg, preferably 0.001 to 50 mg, per 1 kg of body weight per day, divided into 1 to several times.

  Since the dosage varies depending on various conditions, a dosage smaller than the above range may be sufficient, or a dosage exceeding the above range may be necessary.

  The patents, patent applications and literature cited in the present invention are inserted for reference.

  The benzazepine compound and its salt of the present invention have an excellent vasopressin antagonistic action.

  The benzazepine compound and its salt of the present invention have, for example, vasopressin antagonistic action, vasodilatory action, blood pressure lowering action, hepatic glucose release inhibitory action, mesangial cell proliferation inhibitory action, water diuretic action, platelet aggregation inhibitory action, etc. It is useful as a vasodilator, antihypertensive agent, diuretic, platelet aggregation inhibitor, hypertension, edema (eg, cardiac edema, hepatic edema, renal edema, cerebral edema, etc.), ascites, heart failure (eg, severe heart failure) Etc.), renal dysfunction, vasopressin secretion syndrome (SIADH), cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, polycystic kidney disease (PKD) and the like.

  The present invention will be further clarified by the following examples.

Example 1
(2S, 3S, 4S, 5R, 6R) -3,4,5-Tris- (2,2-dimethylpropionyloxy) -6-{(S) -1- [4- (2-methylbenzoylamino)- Synthesis of benzoyl] -2,3,4,5-tetrahydro-1H-benzo [b] azepin-5-yloxy} -tetrahydropyran-2-carboxylic acid methyl ester

  2.6 g (6.5 mmol) of N- [4-((R) -5-hydroxy-2,3,4,5-tetrahydrobenzo [b] azepine-1-carbonyl) phenyl] -2-methylbenzamide ( Compound obtained in Reference Example 28 of JP-A-9-168396), 5.1 g (14 mmol) of mercury (II) bromide and 7.0 g of molecular sieves 4A were suspended in 26 ml of 1,2-dichloroethane, and 55-60 Stir at ℃ for a while. The suspension was cooled to room temperature and (2S, 3S, 4S, 5R, 6R) -6-bromo-3,4,5-tris- (2,2-dimethylpropionyloxy) -tetrahydropyran-2- Carboxylic acid methyl ester 6.7g (13 mmol) was added, and it stirred at 60 degreeC for 3.5 hours. The reaction solution was cooled to room temperature, and insoluble materials were removed by filtration. The residue was washed with 125 ml of dichloromethane, and the filtrate and the washings were combined, washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After filtering the dried product, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30 → 30: 70). The purified product was concentrated under reduced pressure to give colorless amorphous solid (2S, 3S, 4S, 5R, 6R) -3,4,5-tris- (2,2-dimethylpropionyloxy) -6-{(S) -1- [4- (2-Methylbenzoylamino) -benzoyl] -2,3,4,5-tetrahydro-1H-benzo [b] azepin-5-yloxy} -tetrahydropyran-2-carboxylic acid methyl ester 2 0.4 g (43% yield) was obtained.

¹ H-NMR (DMSO-d ₆ , 100 ° C.) δ ppm: 1.09 (9H, s), 1.10 (9H, s), 1.11 (9H, s), 1.54-2.00 ( 3H, m), 2.14-2.43 (1H, m), 2.36 (3H, s), 3.67 (3H, s), 3.92-4.44 (1H, m), 4 .54 (1H, d, J = 10.0 Hz), 4.98-5.20 (3 H, m), 5.26 (1 H, d, J = 7.8 Hz), 5.44 (1 H, t, J = 9.3 Hz), 6.74 (1H, dd, J = 1.0 Hz, J = 7.8 Hz), 7.06 (1H, dt, J = 1.5 Hz, J = 7.5 Hz), 7 .11-7.30 (5H, m), 7.31-7.45 (3H, m), 7.49-7.60 (2H, m), 10.01 (1H, bs).

Example 2
(2S, 3S, 4S, 5R, 6R) -3,4,5-Tris- (2,2-dimethylpropionyloxy) -6-{(S) -1- [4- (2-methylbenzoylamino)- Synthesis of benzoyl] -2,3,4,5-tetrahydro-1H-benzo [b] azepin-5-yloxy} -tetrahydropyran-2-carboxylic acid

  (2S, 3S, 4S, 5R, 6R) -3,4,5-Tris- (2,2-dimethylpropionyloxy) -6-{(S) -1- [4- (2-methylbenzoylamino)- Benzoyl] -2,3,4,5-tetrahydro-1H-benzo [b] azepin-5-yloxy} -tetrahydropyran-2-carboxylic acid methyl ester 2.0 g (2.4 mmol) in tetrahydrofuran (THF) 30 ml And dissolved in a mixed solvent of 3 ml of water, and the resulting solution was cooled to 0 ° C. To this was added 120 mg (2.9 mmol) of lithium hydroxide, and the mixture was stirred at the same temperature for 10 hours. Further, 24 mg (0.6 mmol) of lithium hydroxide was added and stirred at the same temperature overnight. To the reaction solution, 7 ml of 1N hydrochloric acid and 100 ml of water were added, and extracted with diethyl ether (100 ml × 2 times). The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After filtering the dried product, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: ethanol = 10: 10: 1). The purified product was concentrated under reduced pressure to give colorless amorphous solid (2S, 3S, 4S, 5R, 6R) -3,4,5-tris- (2,2-dimethylpropionyloxy) -6-{(S) -1- [4- (2-Methylbenzoylamino) -benzoyl] -2,3,4,5-tetrahydro-1H-benzo [b] azepin-5-yloxy} -tetrahydropyran-2-carboxylic acid 1.7 g (Yield 86%) was obtained.

¹ H-NMR (DMSO-d ₆ , 100 ° C.) δ ppm: 1.07 (9H, s), 1.09 (9H, s), 1.10 (9H, s), 1.51-2.06 ( 3H, m), 2.14-2.42 (1H, m), 2.36 (3H, s), 2.68-3.45 (1H, m), 3.91-4.58 (1H, m), 4.38 (1H, d, J = 10.0 Hz), 4.95-5.27 (4H, m), 5.39 (1H, t, J = 9.3 Hz), 6.74 ( 1H, dd, J = 0.75 Hz, J = 7.8 Hz), 7.06 (1H, dt, J = 1.5 Hz, J = 7.5 Hz), 7.11-7.30 (5H, m) , 7.31-7.46 (3H, m), 7.47-7.64 (2H, m), 10.01 (1H, bs), 12.08-13.31 (1H, br).

Example 3
(2S, 3S, 4S, 5R, 6R) -3,4,5-trihydroxy-6-{(S) -1- [4- (2-methylbenzoylamino) -benzoyl] -2,3,4 Synthesis of 5-tetrahydro-1H-benzo [b] azepin-5-yloxy} -tetrahydropyran-2-carboxylic acid

  (2S, 3S, 4S, 5R, 6R) -3,4,5-Tris- (2,2-dimethylpropionyloxy) -6-{(S) -1- [4- (2-methylbenzoylamino)- Ethanol solution (30 ml) of 3.1 g (3.8 mmol) of benzoyl] -2,3,4,5-tetrahydro-1H-benzo [b] azepin-5-yloxy} -tetrahydropyran-2-carboxylic acid The mixture was cooled to 0 ° C., 15 ml of 5N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 days. The reaction solution was diluted by adding 100 ml of 90% ethanol, and DOWEX® 50WX8 was added little by little and stirred to obtain pH = 4. The obtained mixture was filtered, and the residue was washed with ethanol and water, and the filtrate and the washing solution were combined and concentrated under reduced pressure. 200 ml of water was added to the residue, ethanol was added until a homogeneous solution was obtained, and then concentrated under reduced pressure. The residue was purified by medium pressure column chromatography (ODS-S-50A, methanol: 5% acetic acid = 55: 45), and the purified product was concentrated under reduced pressure. The residue was dissolved in ethanol, water was added, and the insoluble matter produced was collected by filtration, dried and dried as a colorless amorphous solid (2S, 3S, 4S, 5R, 6R) -3,4,5-trihydroxy-6 -{(S) -1- [4- (2-Methylbenzoylamino) -benzoyl] -2,3,4,5-tetrahydro-1H-benzo [b] azepin-5-yloxy} -tetrahydropyran-2- 1.3 g (61% yield) of carboxylic acid was obtained.

¹ H-NMR (DMSO-d ₆ : D ₂ O = 4: 1, 100 ° C.) δ ppm: 1.31-2.17 (4H, m), 2.30 (3H, s), 2.67-3 .57 (4H, m), 3.66 (1H, d, J = 9.5 Hz), 3.75-4.66 (1H, m), 3.38 (1H, d, J = 7.3 Hz) 4.95-5.19 (1H, m), 6.77 (1H, d, J = 7.5 Hz), 7.05 (1H, dt, J = 1.3 Hz, J = 7.5 Hz), 7.11-7.25 (5H, m), 7.26-7.37 (2H, m), 7.41-7.67 (2H, m), 7.48 (1H, d, J = 8) .5 Hz).

Example 4
Synthesis of 2-methyl-N- (4- {5-[(Z) -methylimino] -2,3,4,5-tetrahydrobenzo [b] azepine-1-carbonyl} phenyl) benzamide-N-oxide

2-Methyl-N- [4- (5-oxo-2,3,4,5-tetrahydrobenzo [b] azepine-1-carbonyl) phenyl] benzamide (JP-A-6-80641, raw material of Example 1 Compound) 3.99 g (10.0 mmol), 8.52 g (0.1 mol) of N-methylhydroxylamine hydrochloride and 8.13 ml (0.1 mol) of pyridine are added to 200 ml of methanol, and 20 g of A unit filled with molecular sieves 3A 1/16 was attached, and the mixture was stirred with heating under reflux for 2.5 hours. The reaction mixture was cooled to room temperature, and the resulting insoluble material was collected by filtration. The filtrate was processed according to Example 5 described later. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1 → 30: 1). The purified product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate: methanol = 10: 10: 1 → 10: 10: 2). The purified product is concentrated under reduced pressure, and the residue is recrystallized from methanol to give 2-methyl-N- (4- {5-[(Z) -methylimino] -2,3,4,5-tetrahydrobenzoic acid as white powder. [B] Azepine-1-carbonyl} phenyl) benzamide-N-oxide (3.26 g, yield 76%) was obtained.
Melting point: 262-265 ° C.

Example 5
Synthesis of 2-methyl-N- (4- {5-[(E) -methylimino] -2,3,4,5-tetrahydrobenzo [b] azepine-1-carbonyl} phenyl) benzamide-N-oxide

The filtrate of Example 4 was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1 → 30: 1). The purified product was concentrated under reduced pressure, and the residue was subjected to medium pressure column chromatography (silica ultrapack SI-B (trade name) manufactured by Yamazen Co., Ltd., dichloromethane: ethyl acetate: methanol = 5: 5: 1 → 5: 5. : Purified in 2). The purified product was concentrated under reduced pressure, and the residue was recrystallized from isopropyl alcohol to give colorless needles of 2-methyl-N- (4- {5-[(E) -methylimino] -2,3,4,5 31 mg (yield 1.6%) of -tetrahydrobenzo [b] azepine-1-carbonyl} phenyl) benzamide-N-oxide were obtained.
Melting point: 184-188 ° C.

Example 6
Synthesis of N- {4- [5- (N-hydroxy-N-methylamino) -2,3,4,5-tetrahydrobenzo [b] azepine-1-carbonyl] phenyl} -2-methylbenzamide

109 mg of 2-methyl-N- (4- {5-[(Z) -methylimino] -2,3,4,5-tetrahydrobenzo [b] azepine-1-carbonyl} phenyl) benzamide-N-oxide. 26 mmol) was suspended in 5 ml of ethanol, 52 mg (1.3 mmol) of sodium borohydride was added to the resulting suspension, and the mixture was stirred with heating under reflux for 1 hour. To the resulting mixture was further added 52 mg (1.3 mmol) of sodium borohydride, and the mixture was stirred for 2 hours while heating under reflux. After cooling to room temperature, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The dried product was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high flash column chromatography (dichloromethane: methanol = 100: 1 → 40: 1). The purified product was concentrated to dryness under reduced pressure to obtain 110 mg of white powder (yield 100%). N- {4- [5- (N-hydroxy-N-methylamino) -2,3,4,5-tetrahydrobenzo [b] azepine- of white powder was recrystallized from ethanol-water (3: 7). 1-Carbonyl] phenyl} -2-methylbenzamide was obtained.
Melting point 189-192 [deg.] C.

Example 7
The following compounds are prepared in the same manner as in Examples 1, 2, and 3.

High resolution FABMS;
Calculated value for C ₃₂ H ₃₆ O ₉ N ₃ (M + H): 606.2451, found: 606.2445.

Example 8
The following compounds (8-1) and (8-2) are produced in the same manner as in Examples 4 and 5.
(8-1)

High resolution FABMS;
Calculated value of C ₂₆ H ₂₆ O ₄ N ₃ (M + H): 444.1923, measured value: 444.1923
(8-2)

High resolution FABMS;
C ₂₆ H ₂₆ O ₅ N ₃ Calculated (M + H): 460.1872, Found: 460.1852.

Example 9
Binding inhibition experiment (rat V2 _- receptor)
Various concentrations of V ₂ -receptor-rich kidney cell membrane solution diluted appropriately with 100 mM Tris-HCl buffer (pH = 8.0) containing 5 mM MgCl ₂ , 1 mM EDTA and 0.1% BSA A test compound and a certain amount of [ ³ H] AVP were added and reacted at 4 ° C. for 2 hours. 5 mM MgCl ₂ was cooled 10 volumes of ice, 1 mM EDTA and 100mM Tris -HCl buffer containing 0.1% BSA After finishing (pH = 8.0) was added to the reaction, Whatman (Whatman) GF / B filter, and washed with 10 mM Tris-HCl buffer (pH = 8.0) containing 5 mM MgCl ₂ and 1 mM EDTA, and then bound [ ³ H] AVP and free [ ³ H ] Separated from AVP. After transferring to a scintillation vial, Aquasol-2 was added, and the specific activity was measured with a scintillation counter. In order to determine nonspecific binding, binding in the presence of unlabeled AVP (final concentration 1 μM) was also examined. After calculating the binding rate of [ ³ H] AVP in the presence of each test compound, regression analysis was performed to determine the concentration (IC ₅₀ ) of each compound that inhibits the binding of [ ³ H] AVP by 50%.

  The results are shown in Table 1. In Table 1, each measured value was expressed as an average value ± standard error.

Claims (4)

General formula (1)

[Wherein R ¹ represents a hydrogen atom.
R ² represents a —O—R ⁴ group or a —N (R ⁵ ) —O—R ⁶ group.
R ¹ and R ² together represent a ═N (R ⁷ ) → O group.
R ³ represents a lower alkyl group.
R ⁴ is a group

Indicates.
R ⁵ represents a lower alkyl group.
R ⁶ represents a hydrogen atom or an R ⁴ group (R ⁴ is the same as described above).
R ⁷ represents a lower alkyl group which may have a hydroxyl group or —OR ⁴ group (R ⁴ is the same as above) as a substituent.
R ⁸ , R ⁹ and R ¹⁰ each represent a hydroxyl group which may have a protecting group.
R ¹¹ represents a carboxyl group which may have a protecting group. ]
Or a salt thereof.   The pharmaceutical which contains the benzazepine compound or its salt of Claim 1 as an active ingredient.   The medicament according to claim 2, which is used as a vasopressin antagonist.   The medicament according to claim 2, which is used as a vasodilator, an antihypertensive agent, a diuretic or a platelet aggregation inhibitor.