HU197726B - Process for production of derivatives of bensoic acid and medical compositions containing them - Google Patents

Abstract

Benzazepinone derivs. of formula (I) and their pharmaceutically acceptable salts are new (where R1 = H, alkyl, alkanoyl, alkenyl, aroyl, heteroaroyl or CONX1X2; R2 and R3 = alkyl or cycloalkyl; or NR2R3 = pyrrolidinyl, piperidinyl or morpholinyl; R4 and R5 = H, halo, alkyl, alkoxy, aryloxy, aralkoxy, aralkyl, OH, alkanoyloxy, OCONX1X2, OCHF2, CF3, NX3X4, S(O)malkyl or S(O)maryl; n = 2 or 3; m = 0-2; X1 and X2 = H, alkyl, aryl or heteroaryl; or NX1X2 = N contg. heteroaryl; X3 and X4 = alkyl, alkanoyl, aroyl, heteroaroyl, or carbamoyl; provided that if R4 = alkyl at the 7-position, it must have a tert. C bonded to the ring). - Specifically claimed is e.g. (cis)-3-acetoxy-1-(2-(dimethyl amino)ethyl)-1,3,4,5 -tetrahydro-4 -(4-methoxyphenyl)-2H-1 -benzazepin -2-one (Ia), etc.

Description

The present invention relates to novel benzazepine derivatives of the formula I and their acid addition salts. The new compounds have a valuable vasodilating effect.

Symbols used in formula (I) and throughout the description have the following meanings:

R 1 is hydrogen, (C 1 -C 4) -alkyl, (C 2 -C 7) -alkanoyl, (C 1 -C 4) -alkylaminocarbonyl, or benzoyl substituted by halogen and nitro;

R ₂ and R ₃ are each independently C 1 -C 4 alkyl, or R ₂ and R ₃ form a pyrrolidinyl group together with the nitrogen atom to which they are attached;

R ₄ is hydrogen, halogen,

(1-4C) alkyl, (1-4C) alkoxy, phenyl (1-4C) alkoxy, (1-4C) alkylaminocarbonyloxy, di (1-4C) alkylamino -carbonyloxy or trifluoromethyl;

R ₅ is hydrogen, halogen,

C 1-4 alkoxy or trifluoromethyl, and n is 2 or 3 with the proviso that when R ₄ is a 7-position alkyl, it must be attached to the ring by a tertiary carbon atom.

U.S. Patent 3,562,257 discloses vasodilating benzothiazepines, which are typically represented by the diltiazem internationally known as the diltiazem containing an acetyloxy group in the 3-position.

The terms "alkyl group" and "alkoxy group" may refer to both straight and branched groups.

The term "alkanoyl" refers to a group represented by the formula alkyl-C (O). Such alkanoyl groups having from 2 to 5 carbon atoms are preferred.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

The compounds of the formula I form acid addition salts with inorganic and organic acids. These acid addition salts are often useful for separating products from reaction mixtures by forming the salt in a medium in which it is insoluble. The free base can then be recovered by neutralization with a base such as sodium hydroxide. Any other salt may then be formed from the free base and the appropriate inorganic or organic acid. By way of example, salts with hydrogen halides, in particular hydrochloride and hydrobromide, sulfate, nitrate, phosphate, borate, acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, salicylate, methanesulfonate, benzenesulfonate and toluenesulfonate.

The carbon atoms at the 3- and 4-positions of the benzazepine nucleus of the compounds of formula I are asymmetric carbon atoms. The compounds of Formula I therefore exist in enantiomeric and diastereomeric forms and as a raffle mixture thereof. All of these are within the scope of the present invention. It is believed that the compounds of formula (I) which are in the d-cis configuration are most effective and therefore preferred. The compounds of the formula I and their pharmaceutically acceptable salts can be used as cardiovascular agents. These compounds act as vasodilators and are particularly useful as antihypertensive agents. Administration of a composition comprising a compound of the present invention (or a combination thereof) may reduce the blood pressure of a hypertensive mammal (e. G. Em20). Daily doses of from about 0.1 mg to about 100 mg / kg body weight / day, preferably from about 1 mg to about 50 mg / kg body weight / day, are suitable for reducing blood pressure and can be administered in single or divided doses. The active ingredient is preferably administered orally, but parenteral routes such as subcutaneous, intramuscular or intravenous routes may also be employed.

As a result of the vasodilator activity of the compounds of the formula I, it is believed that such compounds, in addition to being antihypertensive agents, are also useful as antiarrhythmic, antianginal, antiasthmatic agents and in limiting myocardial infarction.

The compounds of the present invention may also be formulated in combination with a diuretic, a beta 40 -adrenergic agent or an angiotensin converting enzyme inhibitor. Suitable diuretics are thiazide diuretics such as hydrochlorothiazide and bendroflumethiazide, suitable beta-adrenergic agents nadolol, and suitable angiotensin converting enzyme inhibitor captopril ^45.

In the preparation of compounds of formula (I) / first a compound of formula (II)

The 2-nitrotoluene derivative is reacted with a compound of formula (Ia)

Y is alkyl. With benzylidene malonate. The reaction may be carried out in a polar non-protic solvent (such as dimethylformamide) in the presence of a strong base such as sodium hydride to give a compound of formula (IV).

Reduction of the compound of formula (IV) results in the corresponding compound of formula (V). The reduction may be accomplished by catalytic hydrogenation (e.g., palladium on charcoal precipitated) or by the use of a chemical reducing agent (e.g., iron II sulfate or metal ion).

-2197726

Reaction of an amine of formula (V) with an alkali metal alkanolate (e.g., sodium methanolate) and an alcohol (e.g. methanol) yields the corresponding benzazepine (VI).

Thus, the reaction of a compound of formula VI with a strong base (such as lithium diisopropylamide or potassium hexamethyldisilazide) in an ethereal solvent such as tetrahydrofuran at low temperature in the presence of anhydrous oxygen gas gives the corresponding compound of formula VII.

Alternatively, a compound of Formula VII may be prepared by first cooling a compound of Formula VI in a solvent such as tetrahydrofuran to a very low temperature (e.g., about -78 ° C) and using a strong base (e.g., lithium). diisopropylamide or potassium hexamethyldisilazide). Treatment of the compound with triethyl phosphite in the presence of anhydrous oxygen gas provides the desired compound of formula VII.

Decarboxylation of a compound of formula VII can be accomplished by reacting the compound with lithium iodide in excess of hot pyridine to give a mixture of isomers of formula (VIIIa) and (VIIIb).

Generally, the preferred cis isomer is the predominantly isomer formed in the above reaction. The isomers may be separated by methods known in the art, such as crystallization or chromatography. Alternatively, the reactions described below may be carried out using a diastereomeric mixture (a mixture of compounds of formula (VIIIa) and (VIIIb)). The mixture of isomers can be separated at any stage of the reaction sequence.

Reaction of a compound of formula (VIIIa) or (VIIIb) with an alkali metal hydride (such as sodium hydride) in an inert solvent such as dimethylformamide or dimethylsulfoxide, followed by reaction with a compound of formula (IX) It provides a compound of formula (X) or the corresponding trans isomer, i.e., a compound of formula (I) wherein R 1 is hydrogen.

Compounds of formula (X) (or the corresponding trans isomers) may be acylated or alkylated by conventional means to give products of formula I wherein R 1 is other than hydrogen. For example, a compound of formula (X) (or the corresponding trans isomer) may be reacted with, for example, a compound of formula XI in the presence of a base. Alternatively, acylation may be carried out using an acid anhydride.

Preferred substituents on each of the substituent groups of the benzazepine derivatives of formula (1) are: R, acetyl; n = 2; R ₂ and R _{3 are} methyl; R _{4 is} hydrogen or halogen (especially chloro at position 7) and R _{5 is a} methoxy group.

The following examples are specific embodiments of the present invention.

Example 1:

cis-3-Acetoxy-1- [2- (dimethylamino) ethyl] -7-chloro-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1-benzazepine 2-one, monohydrochloride.

Method I.

A) [2- (5-Chloro-2-nitro-phenyl) -1- (4-methoxy-phenyl) -ethyl] -malonic acid dimethyl ester.

of dimethyl ester of 4-methoxybenzylidene-malonic acid (0.16 mol) and 60% sodium hydride (9.6 g, 0.24 mol) in dry dimethylformamide (350 ml) was added dropwise over 2 hours with stirring. a solution of 5-chloro-2-nitrotoluene (30 g, 0.176 mol) in dimethylformamide (30 ml) was added. The reaction mixture was stirred at room temperature for 6 hours and then quenched with 15.4 mL (0.26 mol) of acetic acid. The solvent was removed in vacuo and the residue was triturated with water. The yellow solid was filtered off and triturated with methanol to give 50.3 g of a white solid, m.p. 128.5-130.5 ° C.

B) 2- (2-Amino-5-chlorophenyl) -1- (4-methoxyphenyl) ethyl malonic acid dimethyl ester.

g (0.095 mol) of [2- (5-chloro-2-nitrophenyl) -1- (4-methoxyphenyl) ethyl] -malonic acid dimethyl ester and 184.5 g (0.663 mol) of crystalline iron II) Sulfate To a solution of 1.2 L of methanol: water (1:10) is added 142.5 ml of concentrated ammonium hydride solution under reflux for 30 minutes. The reaction mixture was refluxed for 20 minutes and then cooled to room temperature. After addition of ethyl acetate and Celite, the mixture was filtered through Celite. The filtrate was shaken with ethyl acetate and water and separated. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The product was recrystallized from isopropanol to give 28.22 g of the title compound, m.p. 114-116 ° C.

C) 7-Chloro-4- (4-methoxyphenyl) -3- (methoxycarbonyl) -1,3,4,5-betahydro-2H-1-benzazepin-2-one.

To a solution of 23.2 g (59.2 mmol) of [2- (2-amino-5-chlorophenyl) -1- (4-methoxyphenyl) ethyl] malonic acid dimethyl ester in 200 ml of methanol is added 16 ml of (69.97 mmol) of 25% sodium methanolate in methanol was added. The solution was refluxed under argon for 3 hours. The reaction mixture was cooled to room temperature and treated with 200 ml of 1 N hydrochloric acid. The white precipitate was filtered off and washed with water, methanol and dried in vacuo. 19.5 g of title 3 are thus obtained

M.p. 189-190.5 ° C.

D) 3-Hydroxy-7-chloro-4- (4-methoxyphenyl) -3- (methoxycarbonyl) -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one.

Oxygen was bubbled through 7.0 g (19.46 mmol) of 7-chloro-4- (4-methoxyphenyl) -3- (methoxycarbonyl) -1,3,4,5-tetrahydro-2H-. To a solution of 1-benzazepin-2-one in 100 ml of anhydrous tetrahydrofuran at 0 ° C was added 87.64 ml (58.76 mmol) of a 0.67 M solution of potassium hexamephil disilazole in toluene over 15 minutes. The reaction was continued for 1 hour at 0 ° C with continuous oxygen bubbling. The reaction was quenched with 75 mL of 5% potassium bisulfate solution, followed by addition of solid sodium sulfite and 10 mL of methanol. The reaction mixture was stirred for 30 minutes and extracted twice with ethyl acetate. The combined organic layers were washed with 1 N hydrochloric acid and saturated sodium bicarbonate solution and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was recrystallized from isopropanol

4.5 g of the title compound are obtained.

E) cis-3-Hydroxy-7-chloro-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one.

0.5 g (1.33 mmol) of 3-hydroxy-7-chloro-4- (4-methoxyphenyl) -3- (methoxycarbonyl) -1,3,4,5-tetrahydro-2H-1- benzazepin-2-one and lithium iodide (0.178 g, 1.33 mmol) in anhydrous pyridine (20 mL) was heated under reflux under argon until complete conversion to the product by TLC.

The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in chloroform and diluted with 1 N hydrochloric acid! extracted twice, then once with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was triturated with diethyl ether to give 0.22 g of cis product.

F) cis-1- [2- (Dimethylamino) ethyl] -3-hydroxy-7-chloro-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1 - benzazepin-2-one monohydrochloride.

0.83 g (2.612 mmol) of cis-3-hydroxy-7-chloro-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one 26.12 A solution of 60% sodium hydride (0.11 g, 2.74 mmol) in anhydrous dimethylformamide (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour under argon, and 2.30 ml (3.92 mmol) of 1.7 N toluene (dimethylamino) ethyl chloride solution was added, followed by stirring at 75 ° C for 2 hours. The solvent was evaporated in vacuo and the residue was shaken with ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with 1 N hydrochloric acid and dried over magnesium sulfate. The aqueous phase is mixed with 6N sodium hydroxide solution to bring the pH to 11. The product was extracted three times with ethyl acetate and dried over magnesium sulfate. The solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (4 ml) and diethyl ether (5 ml) and the solution was stirred at 0 ° C with 1.2 equivalents of 1.39 N hydrochloric acid in diethyl ether. The solid was filtered off with diethyl ether. wash to give 0.65 g of the title compound.

G) cis-3-Acetoxy-1- [2- (dimethylamino) ethyl] -7-chloro-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1 benzazepin-2-one monohydrochloride.

0.62 g (1.5 mmol) of 1- [2- (dimethylamino) 10-ethyl] -3-hydroxy-7-chloro-4- (4-methoxyphenyl) -1,3,4,5 A solution of tetrahydro-2H-1-benzazepin-2-one monohydrochloride in 25 ml of anhydrous acetic anhydride was heated at 110 ° C under argon until the starting material was judged to be completely reacted. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and 2 mL of saturated hydrochloric acid in diethyl ether was added. The resulting white precipitate was filtered off and dried; yield 0.5 g. The reaction was repeated to give an additional 0.27 g of product. mp 207.5-209 ° C.

Results of elemental analysis a

C ₂₃ H ₂₈ N ₂ Cl ₂ O ₄ .0.7 H ₂ O:

Found: C, 57.55; H, 6.17; N, 5.84;

Cl, 14.77;

Found: C, 57.54; H, 5.86; N, 5.63;

Cl, 14.92.

II. Method.

II. Method A is identical in detail to Method I above except for Parts D and E:

D) 3-Hydroxy-7-chloro-4- (4-methoxyphenyl) -3- (methoxycarbonyl) -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one.

7-Chloro-4- (4-methoxyphenyl) -3- (methoxycarbonyl) -1,3,4,5-tetrahydro-2H-40-benzazepin-2-one g (41.7 mmol) 780 A solution of tetrahydrofuran (ml) was cooled to -78 ° C and a solution of potassium hexamethyldisilazide (147 ml, 167 mmol) was added. The mixture was stirred for 1 hour, and then 28.7 mL (166.7 mmol) of triethyl phosphite was added ^{to 45} and bubbled with oxygen gas rapidly dry the resulting solution. The temperature of the reaction mixture was then raised to 0 ° C and stirred for an additional hour. The oxygen 5 C feed was then discontinued and the reaction was quenched with 500 mL of acetic acid. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate. The organic solution was washed thoroughly with 1 N hydrochloric acid, saturated sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. Evaporation of the dried organic solution gave a solid which was triturated with hexane to give 14.8 g of the title compound.

⁶⁰ E) cis-3-Hydroxy-7-chloro-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one.

16.4 g (43.7 mmol) of 3-hydroxy-7-chloro-4- (4-methoxyphenyl) -3- (methoxycarbonyl) -1,3,4,5-tetrahydro-2H-1- benzazepin-2-one and 23.7 g (174.6 mmol) of lithium iodide in 290 mL of 1% water

A solution of -4197726 in pyridine was refluxed under argon until complete conversion (about 1.5 hours) was achieved by thin layer chromatography. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1 N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The solution was dried over magnesium sulfate and evaporated. The residue was recrystallized from ethyl acetate to give 6.8 g of pure cis product.

Example 2:

cis-3-Acetoxy-1- [2- (dimethylamino) ethyl] -4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one- monohydrochloride.

A) [1- (4-McThoxyphenyl) -2- (2-nitrophenyl) ethyl] -malonic acid dimethyl ester.

(4-Methoxybenzylidene) -malonic acid dimethyl ester (360 mmol) was dissolved in anhydrous dimethylformamide (700 mL) under argon and a 60% sodium hydride dispersion in mineral oil (21.6 g, 540 mmol) was added. The suspension was then stirred at room temperature with 33.9 mL (400 mmol) of 2-nitrotoluene and a catalytic amount of tert-butanol was added. After stirring for 16 hours, the reaction was quenched with 3 L of 1N hydrochloric acid and extracted with diethyl ether. The combined organic layers were dried over sodium sulfate and evaporated. The resulting 171 g of a dark oil was chromatographed on 1.5 kg of 60-200 mesh silica gel with hexane: ethyl acetate 4: 1 to give 22 g of high purity product and 22 g of further slightly impure material, as confirmed by TLC.

B) [2- (2-Amino-phenyl) -1- (4-methoxy-phenyl) -ethyl] -malonic acid dimethyl ester.

Dimethyl ester of [1- (4-methoxyphenyl) -2- (2-nitrophenyl) ethyl] malonic acid (g) in methanol: acetic acid (5: 1, 450 ml) was hydrogenated at atmospheric pressure for 16 hours, followed by The crude product was recrystallized from isopropanol to give 13 g of the desired product. The evaporated mother liquor was chromatographed on LPS-1 silica gel with hexane: ethyl acetate 7: 3 to give an additional 2.24 g of product.

C) 4- (4-Methoxyphenyl) -3- (methoxycarbonyl) -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one.

11.97 g (33.5 mmol) of [2- (2-aminophenyl) -1- (4-methoxyphenyl) ethyl] malonic acid dimethyl ester and 9.2 mL (40.2 mmol) A solution of 25% sodium methanolate in 80 ml of methanol was refluxed for 1.5 hours and then cooled to room temperature. An excess of 1 N hydrochloric acid was added and the resulting precipitate was filtered to give 9.18 g of pure material, m.p. 217-219 ° C.

D) 3-Hydroxy-4- (4-methoxyphenyl) -3- (methoxycarbonyl) -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one.

Dry oxygen gas was bubbled through for 30 minutes 13 g (40.2 mmol) of 4- (4-methoxyphenyl) -3- (methoxycarbonyl) -1,3,4,5-tetrahydro-2H-1-benzazepine-2- on a solution of 130 ml of anhydrous tetrahydrofuran under ice-water cooling. 180 mL (120.5 mmol) of a 0.67 M solution of potassium hexamethyldisilazide in toluene are then added over a further 7 minutes with continuous oxygen supply. After stirring for a further 2.5 hours, the oxygen stream was stopped and the reaction was quenched with 200 mL of 5% potassium bisulfate solution. Then, 15 g of solid sodium sulfite followed by 100 ml of methanol are added and the mixture is stirred for an additional 30 minutes. The mixture was extracted twice with ethyl acetate, and the combined organic layers were washed three times with 1N hydrochloric acid, once with saturated sodium bicarbonate solution, then with brine, and finally dried over sodium sulfate. After evaporation, 15 g of crude product were obtained. triturate with diethyl ether / hexane to give 9.3 g of high purity product.

E) cis-3-Hydroxy-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one.

5.26 g (14.6 mmol) of 3-hydroxy-4- (4-methoxyphenyl) -3-methoxycarbonyl-1,3,4,5-tetrahydro-2H-1-benzazepine-2- and a solution of 19.6 g (147 mmol) of anhydrous lithium iodide in 150 ml of anhydrous pyridine are refluxed for one hour. After evaporation, the crude product is dissolved in ethyl acetate, washed with 6N hydrochloric acid solution, saturated sodium bicarbonate solution and dried over sodium sulfate. After evaporation and trituration with diethyl ether, 2.81 g of a substantially pure cis isomer is obtained, m.p.

173.5-175.5 ° C (dec.).

F) cis-1- [2- (Dimethylamino) ethyl] -3-hydroxy-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-benzazepin-2-one monohydrochloride.

1.0 g (3.53 mmol) of cis-3-hydroxy-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 35 ml of anhydrous To a solution of formamide in water was added 0.15 g (3.71 mmol) of a 60% solution of sodium hydride in oil and the mixture was stirred for one hour. Subsequently, 3.1 ml (5.3 mmol) of a 1.7 M solution of (, Ν-dimethyl- (2-chloroethyl) -amine in toluene was added and the mixture was heated at 75 ° C for 1.5 hours. The reaction mixture is then concentrated in vacuo and the residue is taken up in ethyl acetate and treated with ethyl acetate ^. shake with n hydrochloric acid. The organic layer was washed twice more and with aqueous hydrochloric acid, the combined aqueous layers were basified to pH 11 and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate and evaporated. The resulting crude product (1.17 g) was dissolved in a minimal amount of chloroform and acidified with saturated hydrochloric acid in diethyl ether at 0 ° C to give 1.27 g of an off-white powder.

G) cis-3-Acetyloxy-1- [2- (dimethylamino) ethyl] -4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1-benzazepine-2 one monohydrochloride.

-5197726

Column I

4. 4- (Trifluoromethyl) benzylidene-malonic acid dimethyl ester

1.27 g (2.83 mmol) of cis-1- [2- (dimethylamino) ethyl] -3-hydroxy-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro In 2H-1, zazepin-2-one monohydrochloride was suspended in acetic anhydride (28 ml) and heated at 100 ° C for 3 hours under argon. The resulting solution was evaporated and the residue was dissolved in ethyl acetate. After crystallization started, diethyl ether saturated with hydrochloric acid was added and the mixture was filtered. This gives 1.25 g of the desired product as an off-white powder, m.p. 215-216 ° C.

Elemental Analysis for: C ₂₃ H ₂₉ CIN ₂ O ₄ .0.4 H ₂ O: Calculated: C, 62.76; H, 6.82; N, 6.36.

Cl, 8.05;

Found: C, 62.76; H, 6.65; N, 6.40;

Cl, 7.97.

Example 3:

trans-3-Acetoxy-1- [2- (dimethyl-1-amino) ethyl] -4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1-benzazepine-2 one monohydrochloride.

A) trans-3-Hydroxy-4- (4-methoxyphenyl) -1,

3,4,5-tetrahydro-2H-l-benzazepin-2-one.

The mother liquor obtained by trituration of crude cis-3-hydroxy-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (see Example 2E) in diethyl ether 1 silica gel in hexane:

Chromatography of ethyl acetate (70:30) to give the title trans isomer, m.p. 168-170 ° C.

B) Trans-1- [2- (Dimethylamino) ethyl] -3-hydroxy-4- (4-methoxyphenyl) -1,3,4,5-tetahydro-2H-1-zazepine -2-one.

Following the procedure of Example 2 (F), but replacing the corresponding cis isomer with 0.57 g (2.01 mmol) of trans-3-hydroxy-4- (4-methoxyphenyl) -1,3,4, Using 5-tetrahydro-2H-1-benzazepin-2-one afforded 0.66 g of the title compound as an oil.

C) trans-3-Acetoxy-1- [2- (dimethylamino) ethyl] -4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1-benzazepine-2 one monohydrochloride.

Following the procedure of Example 2 (G), but replacing the corresponding cis isomer monohydrochloride salt with trans-1- [2- (dimethylamino) ethyl] -3-hydroxy-4- (0.654 g, 1.83 mmol). Using (4-methoxyphenyl) -1,3,4,5-tetra-hydro-2H-1-benzazepin-2-one, 0.5 g of the title compound is obtained by trituration with ethyl acetate and methanol / isopropanol. after recrystallization as a white crystalline solid. The product melts at 254-256.5 ° C.

Elemental Analysis for: C ₂₃ H ₂₉ ClN ₂ O ₄ .0.2 H ₂ O: Calculated: C, 63.31; H, 6.79; N, 6.42.

Cl, 8.12;

Found: C, 63.31; H, 6.90; N, 6.29;

Cl, 8.13.

4-8. example:

Example 1, Example II. but using the compounds listed in column I instead of (4-methoxybenzylidene) malonic acid dimethyl ester. are obtained.

5. Benzylidene-malonic acid dimethyl ester

6. 2-Methoxybenzylidene-malonic acid di20 methyl ester

7. 3-Methoxybenzylidene-malonic acid dimethyl ester

8. 4-Chlorobenzylidene-malonic acid dimethyl

-ester

II. column cis-3-Acetoxy-1- [2- (dimethylamino) ethyl] -7-chloro-1,3,4,5-tetrahydro-4- [4- (trifluoromethyl) phenyl] -2H-1-benzazepin-2-one monohydrochloride; mp

225.5-227 ° C (dec.).

cis-3-Acetoxy-1- [2- (dimethylamino) ethyl] -4-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one monohydrochloride ; mp 247-250 ° C (dec.). cis-3-Acetoxy-1- [2- (dimethylamino) ethyl] -7-chloro-4- (2-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1-benzazepine 2-one monohydrochloride; m.p. 250-252 ° C (dec.).

cis-3-Acetoxy-1- [2- (dimethylamino) ethyl] -7-chloro-4- (3-methoxyphenyl) -1,3,4,5-tetrahydro- 2H-1-benzazepin-2-one monohydrochloride; mp 225-226 ° C cis-3-Acetoxy-1- [2- (dimethylamino) ethyl] -7-chloro-4- (4-chlorophenyl) -1,3,4,5 -tetrahydro-2H-1-benzazepin-2-one methanesulfonate (1: 1) salt; mp 250-250.5 ° C.

9-13. example:

Example I, Example II. but using 5-chloro-2-nitrotoluene instead of

Uses the compounds listed in Column I45; columns.

Column I

9. 6-Methyl-2-nitro50 -toluene

10. 2-Nitro-5- (trifl-methyl) -toluene

II. column cis-3-Acetoxy-1- [2- (dimethyl-1-amino) -ethyl] -6-methyl-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H- 1-benzazepin-2-one monohydrochloride; mp 176-178 ° C (shrinkage at 172 ° C).

cis-3-Acetoxy-1- [2- (dimethylamino) ethyl] -4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-7- (trifluoromethyl) ) -2H-1-benzazepin-2-one monohydrochloride; 230-232 ° C (dec.; shrinks at 227 ° C).

-6197726

11.6-Chloro-2-nitro-cis-3-Acetoxy-1- [2- (di-toluene-methylamino) -ethyl] -6-chloro-4- (4-methoxy-phenyl) - 1,3 4,5-Tetrahydro-2H-1-benzazepine-2-π-monohydrochloride; mp 151-153 ° C (shrinks at 148 ° C).

12. 4-Chloro-2-nitro-cis-3-acetoxy-1- [2- (di-toluene-methylamino) -ethyl] -8-chloro-4- (4-methoxy-phenyl) -1,3 4,5-Tetrahydro-2H-1-benzazepin-2-one monohydrochloride; mp 173-176 ° C (shrinks at 164 ° C).

13.5-Benzyloxy-2-nitro-cis-3-acetoxy-7-benzyltoluene oxy-1- [2- (dimethylamino) ethyl] -4- (4-methoxyphenyl) -1,3,4 5-Tetrahydro-2H-1-benzazepin-2-one monohydrochloride; mp 117-120 ° C (shrinks)

107 ° C).

14. 2-Nitro-6- (trifluorocis-3-Acetoxy-1- [2- (dimethyl) -toluene methylamino) ethyl] -4- (4-methoxyphenyl) -1, 3,4,5-Tetrahydro-6- (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride; mp 222-224 ° C (dec.).

Example 15:

cis-3-Acetoxy-1- [2- (dimethylamino) ethyl] -7-hydroxy-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1-benzazepine 2-one, monohydrochloride.

0.5 g (0.87 mmol) of cis-3-acetoxy-7-benzyloxy-1- [2- (dimethylamino) ethyl] -4- (4-methoxyphenyl) -1,3,4 To a solution of 5-tetrahydro-2H-1-benzazepin-2-one monohydrochloride (see Example 13) in methanol (30 mL) was added palladium on charcoal (150 mg, 10%) and hydrogen in Parr hydrogen (50 psi). Hydrogenate under shaking for 5 hours. The catalyst was filtered off under argon, washed with methanol and the combined filtrates evaporated. The residue (which begins to solidify) is triturated under diethyl ether and the evaporation is repeated. The solid was dried under vacuum for a few hours to give 0.40 g of the title compound, m.p. 229-231 ° C (decomposition preceded by gradual shrinkage).

Elemental Analysis for: C ₂₃ H _{2 g} N ₂ O ₅ .HCl · 1.5 H ₂ O: Calculated: C, 58.04; H, 6.58; N, 5.89;

Cl, 7.45;

Found: C, 58.29; H, 6.33; N, 5.70;

Cl, 7.63.

Example 16:

cis-1- [2- (Dimethylamino) ethyl] -7-chloro-3- (2-chloro-4-nitrobenzyloxy) -4- (4-methoxyphenyl) ) -1,3,4,5-Tetrahydro-2H-1-benzazepin-2-one methanesulfonate (1: 1) salt.

0.80 g (2.06 mmol) of cis-1- [2- (dimethylamino) ethyl] * 3-hydroxy-7-chloro-4- (4-methoxyphenyl) 2H-1-benzazepine-2 (see Example 1F), 0.65 g (3.2 mmol) of 2-chloro-4-p-nitrobenzoic acid, 0.52 g (2.5 mmol) of dicyclohexylcarbodiimide and 0.04 g of 4- (dimethyl) -amino) -pyridine is added. The solution precipitates dicyclohexylurea. Allow to stand overnight at room temperature and filter the reaction mixture. The filtrate was washed once with 10 ml of 10% potassium carbonate solution, twice with 5 ml of 5% potassium carbonate solution, 5 ml of water and 5 ml of saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and the solvent is distilled off.

1.3 g of a pale yellow solid are obtained. The mixture was purified by chromatography on 50 g of silica gel with a 1: 1 mixture of dichloromethane: ethyl acetate to give 1.0 g of the cis ester with little trans ester. The mixture was slurried in diethyl ether (5 mL), cooled and filtered to give 0.9 g of an almost colorless solid. The remaining trace amount of trans + is removed by suspending the material in + 3 mL of isopropanol and stirring for 1 hour at room temperature. Filtration and washing with isopropanol and diethyl ether gave 0.76 g of the free base, m.p. 164-166 ° C. The material was dissolved in 10 mL of warm ethyl acetate and combined with a solution of 0.135 g of methanesulfonic acid in 5 mL of ethyl acetate to give the methanesulfonic acid salt. The resulting solution was gradually diluted with diethyl ether to give a colorless crystalline product. After cooling overnight, the solid was filtered, washed with diethyl ether and dried. Weight: 0.84 g. Melting point: 215-217 ° C.

Elemental analysis for C ₂₈ H ₂₇ N ₃ Cl ₂ O ₆ · CH ₃ SO ₃ H: Calcd: C, 52.09; H, 4.67; N, 6.28;

Cl, 10.61; S, 4.8;

Found: C, 51.87; H, 4.62; N, 6.14;

Cl, 10.59; S, 4.81.

Example 17:

cis-1- [2- (Dimethylamino) ethyl] -7-chloro-4- (4-methoxyphenyl) -2-oxo-1H-1-benzazepin-3-ylmethylcarbamate monohydrochloride .

0.80 g (2.06 mmol) of cis-1- [2- (dimethylamino) ethyl] -3-hydroxy-7-chloro-4- (4-methoxyphenyl) -1,3,4,5 To a suspension of tetrahydro-2H-1-benzazepin-2-one (see Example 1F) in dichloromethane (6 mL) was added methyl isocyanate (1.2 g, 21 mmol) and the resulting solution was allowed to stand at room temperature for 22 hours. TLC indicated the presence of a small amount of starting material. Acetonitrile (6 ml) and methyl isocyanate (2 g) were added and the mixture was left at room temperature for an additional 20 hours.

-7197726 ^{13 after all} . The solution was evaporated to give a solid (1.1 g) which was dissolved in ethyl acetate (35 ml), extracted twice with water (5 ml), dried over magnesium sulfate, filtered and the solvent was evaporated to give 0.93 g of a solid. This material was suspended in 5 mL of hexane to give 0.79 g of a solid after filtration. This material was suspended in diethyl ether (5 mL), cooled and filtered. The resulting solid (0.62 g) was dissolved in ethanol (3 mL) and, after addition of 0.26 mL of 5.7 N HCl in ethanol, was gradually diluted with about 50 mL of diethyl ether. 0.61 g of crystalline product is obtained, m.p. 238-240 ° C (dec.).

Elemental Analysis for: C ₂₃ H ₂₈ N ₃ ClO ₄ · HCl · H ₂ O: Calculated: C, 56.21; H, 6.15; N, 8.55;

Cl, 14.43;

Found: C, 56.42; H, 6.14; N, 8.58.

Cl, 14.48.

The following compounds within the scope of the present invention are also provided:

cis-3-Acetoxy-1- [2- (dimethylamino) ethyl] -7-methylthio-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1-benzazepine -2-one, cis-3-acetoxy-1- [2- (dimethylamino) ethyl] -7-methylthio-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H -1-benzazepin-2-one, cis-3-azetoxy-1- [2- (dimethylamino) ethyl] -7-methoxy-4- (4-methoxyphenyl) -1,3,4,5 tetrahydro-2H-l-benzazepin-2-one monohydrochloride; mp 215-217 ° C (dec), shrinkage at 205 ° C;

cis-3-acetoxy-1- [2- (dimethylamino) ethyl] -4- (4-methoxyphenyl) -7-pivaloyloxy-1,3,4,5-tetrahydro-2H-1-benzazepine 2-one, cis-3-ethoxy-1- [2- (dimethylamino) ethyl] -7- (N, N-dimethylcarbamoyloxy) -4- (4-methoxyphenyl) -1,3, 4,5-Tetrahydro-2H-1-benzazepin-2-one, cis-3-acetoxy-1- [2- (dimethylamino) ethyl] -7-chloro-4- (4-methylthiophenyl) - 1,3,4,5-Tetrahydro-2H-1-benzazepin-2-one, cis-1- [2- (dimethylamino) ethyl] -3-methoxy-4- (4-methoxyphenyl) - 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one monohydrochloride; mp 223-224 ° C (dec.);

cis-3-acetoxy-1- [2- (dimethylamino) ethyl] -7- (N-methylcarbamoyloxy) -4- (4-methoxyphenyl) -1,

3,4,5-Tetrahydro-2H-1-benzazepin-2-one monohydrochloride; m.p. 216-218 ° C (dec.) (shrinks at 212 ° C);

cis-3-acetoxy-1- [2- (dimethylamino) ethyl] -4- (4-methoxyphenyl) -7-pivaloyloxy-1,3,4,5-tetrahydro-2H-1-benzazepine 2-one monohydrochloride; mp 198-200 ° C (dec.), (shrinkage at 160 ° C);

* cis-3-acetoxy-1- [2- (dimethylamino) ethyl] -7- (N, N-dimethylcarbamoyloxy) -4- (4-methoxyphenyl) -1H-benzazepine-2- one monohydrochloride; 178-181 ° C (bubbling), (shrinks at 168 ° C);

cis-3-acetoxy-4- (4-methoxyphenyl) -1- (2- (1-pyrrolidinyl) ethyl] -1,3,4,5-tetrahydro-7- (trifluoromethyl) -2H- 1-benzazepin-2-one monohydro8 chloride, m.p. 228-230 ° C (dec.), (Shrinkage at 225 ° C);

cis-3-acetoxy-1- [3- (dimethylamino) propyl] -7-chloro-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one monohydrochloride; mp 212-215 ° C (dec), (shrinkage at 200 ° C);

d-cis-3-acetoxy-1- [2- (dimethylamino) ethyl] -7-chloro-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one monohydrochloride; mp 252-254 ° C (dec);

1-eis-3-acetoxy-1- [2- (dimethylamino) ethyl] -7-chloro-4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-1 benzazepin-2-one monohydrochloride; 253-255 ° C (dec.);

d-cis-3-acetoxy-1- [2- (dimethylamino) ethyl] -4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-7- (trifluoromethyl) - 2H-l-benzazepin-2-one monohydrochloride; mp 257-259 ° C (dec);

1-cis-3-acetoxy-1- [2- (dimethylamino) ethyl] -4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-7- (trifluoromethyl) In 2H-1, zazepin-2-ol monohydrochloride; mp 258-260 ° C (dec.).

Claims (5)

PATENT CLAIMS C 1-4 alkyl, C 1-4 alkoxy, phenyl (C 1-4 alkoxy), (C 1-4 alkyl) aminocarbonyloxy, di (C 1-4 alkyl) amino -carbonyloxy or trifluoromethyl, R ₅ is hydrogen, halogen, C 1-4 alkoxy, or trifluoromethyl, and n is 2 or 3; with the proviso that when R ₄ is a 7-position alkyl, it must be attached to the ring with a tertiary carbon atom - or an acid addition salt thereof, characterized in that for the preparation of compounds of formula I wherein R Villa) and / or a compound of formula VIIIb - R ₄ and R ₅ above - with a compound of formula IX - R ₂ , R ₃ and n are as defined for formula I - and halogen is fluorine , chlorine, bromine or iodine, optionally reacting the resulting 3-hydroxy compound of formula (I) with a compound of formula (XI): -8197726 R 1 is the same group as defined in formula (1) but different from hydrogen and, if desired, the resulting compound of formula (I) is converted to the acid addition salt. A process for the preparation of a benzazepine derivative of the Formula I wherein R 1 is hydrogen, C 1-4 alkyl, C 2-7 alkanoyl, C 1-4 alkylaminocarbonyl, or halogen; nitro substituted benzoyl; R ₂ and R ₃ are each independently C 1-4 alkyl, or R ₂ and R _{3 are} pyrrolidinyl together with the nitrogen to which they are attached; R ₄ is hydrogen, halogen, 2. A process according to claim 1 for the preparation of compounds of formula I wherein R1 is hydrogen, characterized in that the appropriate starting compounds are reacted. 3. A process according to claim 1 for the preparation of compounds of formula I wherein R 1 is C 1-4 alkyl, wherein the appropriate starting compounds are reacted. A process for the preparation of a compound of formula (I) according to claim 1 wherein R 1 is C 2 -C 7 alkanoyl, wherein the appropriate starting compounds are reacted. A process for the preparation of a compound of formula (I) according to claim 1 wherein R 1 is an acetyl group, which comprises reacting the appropriate starting compounds. 6. A process for the preparation of a compound of formula (I) according to any one of claims 1 to ₃ , wherein R ₂ and R ₃ are each C 1 -C 4 alkyl, wherein the corresponding starting compounds are reacted. 7. Process for the preparation of a compound of formula (I) according to any one of claims 1 to ₃ , wherein R ₂ and R ₃ are methyl, wherein the appropriate starting compounds are reacted. 8. Figures 1-5. Process for the preparation of a compound of formula (I) according to any one of claims 1 to ₃ , wherein R ₂ and R ₃ form a pyrrolidinyl group together with the nitrogen to which they are attached, characterized in that the corresponding starting compounds are reacted. 9. Figures 1-8. Process for the preparation of a compound of formula (I) according to any one of claims 1 to ₄ , wherein R ₄ is hydrogen, characterized in that the appropriate starting compounds are reacted. A process for the preparation of a compound of formula (I) according to claim 1 wherein R ₄ is a halogen atom, which comprises reacting the appropriate starting compounds. 11. Figures 1-8. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 6 wherein R ₄ is a chlorine atom attached at the 7-position of the benzazepine ring system, wherein the appropriate starting compounds are reacted. 12. A process according to any one of claims 1 to 6 for the preparation of compounds of formula I wherein R ₅ is C 1 -C 4 alkoxy, characterized in that the appropriate starting compounds are reacted. 13. A process for the preparation of a compound of formula (I) according to any one of claims 1 to ₅ , wherein R ₅ is a methoxy group attached to the 4-position of the phenyl group, characterized in that appropriate starting compounds are reacted. 14. A process according to any one of claims 1 to 6 for the preparation of compounds of formula I wherein n is 2, wherein 20 starting materials were reacted. 15. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 3, wherein n is 3, which comprises reacting a suitable Ki25 starting compound. The process of claim 1, wherein cis-3-acetoxy-1- (2- (dimethylamino) ethyl) -7-chloro-4- (4-methoxyphenyl) -1,3,4,5- The tetrahydro-2H-1-benzazepin-2-one or its acid addition salt is prepared by reacting the appropriate starting compounds. The process of claim 1, wherein cis-3-acetoxy-1- (2- (dimethylamino) ethyl) -4- (4-methoxyphenyl) -1,3,4,5-tetrahydro-2H- 1-benzaze35 pin-2-one or an acid addition salt thereof by reacting the appropriate starting compounds. The process according to claim 1, which is trans-3-acetoxy-1- (2- (dimethylamino) ethyl) -4- (4,4-methoxyphenyl) -1,3,4,5-tetrahydro-2H-. 1-benzazepin-2-one or an acid addition salt thereof by reacting the appropriate starting compounds. The process according to claim 1, wherein cis-3-acetoxy-1- (2- (dimethylamino) ethyl) -4- (4-methoxyphenyl) -7- (trifluoromethyl) -1,3, 4,5-Tetrahydro-2H-1-benzazepin-2-one or an acid addition salt thereof by reacting appropriate starting materials. 20. The method of claim I, wherein cis-3-acetoxy-1- (2- (dimethylamino) ethyl) -7-methoxy-4- (4-methoxyphenyl) -1,3,4,5 -tetrahydro-2H-1-benzazepin-2-one or an acid addition salt thereof, characterized in that the appropriate starting compounds are reacted. ⁵ 21. A method comprising (I) benzazepine derivative - defined in R ,, _{R2, R3, R4, R5} and n in claim 1 - pharmaceutical compositions containing the acid addition salt elfogadató or a pharmaceutical preparation, characterized in that 1-20. The active ingredient produced by the process according to any one of claims 1 to 6, together with the usual excipients, is processed into a pharmaceutical composition.