FI77234B - FOERFARANDE FOER FRAMSTAELLNING AV BENZAZEPINDERIVAT. - Google Patents

Description

1 77234

Betsazepine for the preparation of benzazepine derivatives

Finnish patent application 821742 contains e.g. The benzazepine derivatives of the general formula (I) and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids, are described. These compounds have valuable pharmacological properties, in particular a heart rate-lowering effect.

In the general formula I

E is an n-propylene group substituted with an alkyl group having 1 to 3 carbon atoms, G is an ethylene group,

R1 and R2, which may be the same or different, are hydroxy, alkyl, alkoxy or phenylalkoxy groups in which the alkyl moiety may in each case have 1 to 3 carbon atoms, or one of R1 and R2 is also a hydrogen atom or R1 together with R2 is 1- or an alkylenedioxy group having 2 carbon atoms, R3 and R4, which may be the same or different, are hydrogen or halogen atoms, hydroxy groups, alkyl or alkoxy groups each having 1 to 4 carbon atoms, trifluoromethyl or cyano groups or one of R3 and R4 may also be a nitro group or R3 together with R4 is an alkylenedioxy group having 1 or 2 carbon atoms, R5 is a hydrogen atom, alkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, in which the alkyl moiety in each case contains 1 to 3 carbon atoms , or a methylamino or ethylamino group substituted on the alkyl moiety by a trifluoromethyl group, and 2 77234 R0 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkenyl group having 3 to 5 carbon atoms and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids.

In the context of the definitions of the groups R 1 to R 8 and E, the following meanings are possible:

R1 is a methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, 1-methoxyethoxy, 2-phenylethoxy or 3-phenylpropoxy group, R2 is a hydrogen atom, methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 2-phenylpropoxy or 2-phenylpropoxy group, R3 or R 4, which may be the same or different, are hydrogen, fluorine, chlorine, bromine or iodine, methyl, ethyl, propyl, isopropyl, n-butyl, hydroxy, methoxy, ethoxy , a propoxy, isopropoxy, n-butoxy, trifluoromethyl or cyano group or one of R3 and R4 may also be a nitro group, R5 is a hydrogen atom, methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy , propoxy, isopropoxy, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, ethylpropylamine o-, methylpropylamino or / 3,0,0-trifluoroethylamino group, R6 is a hydrogen atom, methyl, ethyl, propyl, isopropyl, allyl, buten-2-yl, buten-3-yl, pentenyl group ,

R1 together with R2 and / or R3 together with R4 are in each case a methylenedioxy or ethylenedioxy group, E is 1-methyl-n-propylene, 2-methyl-n-propylene, 1-ethyl-n-propylene, -ethyl-n-propylene or a 2-propyl-n-propylene group.

3 77234

More preferred compounds of general formula I are those in which E is an ethylene, n-propylene, n-butylene or 2-methyl-n-propylene group, G is an ethylene group,

R1 is an ethyl, hydroxy, benzyloxy or alkoxy group having 1 to 3 carbon atoms, R2 is a hydrogen atom, a methyl, hydroxy or methoxy group, or R1 and R2 together form a methylenedioxy group, R3 is a hydrogen, fluorine, chlorine or bromine atom, trifluoromethyl -tyl, nitro, alkyl or alkoxy group each having 1 to 4 carbon atoms, R4 is a hydrogen, chlorine or bromine atom, a methyl, methoxy or cyano group, or R3 and R4 together form a methylenedioxy group, R5 is a hydrogen atom, hydroxy -, methoxy, amino, dimethylamino or 6,0 β-trifluoromethylamino group and

Rg is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an allyl group and their acid addition salts, especially their physiologically acceptable acid addition salts with inorganic or organic acids.

Particularly preferred compounds of general formula I 77234 4 are those in which E is an n-propylene group, G is an ethylene group,

R 1 is a methoxy group, R 2 is a methoxy group or and R 6 together form a methylenedioxy group, R 1 is a methoxy or trifluoromethyl group, a chlorine or bromine atom, R 1 is a methoxy group, a hydrogen, chlorine or bromine atom or R 1 and R 2 together form methylenedioxy group,

R 1 is a hydrogen atom, an amino or methoxy group, and R 6 is a hydrogen atom, a methyl, ethyl, n-propyl or allyl group, and their physiologically acceptable acid addition salts with inorganic or organic acids.

According to the invention, it has now been found that the benzazepine derivatives of the general formula I can also be prepared by the following methods:

a) Oxidation of the benzazepine O of general formula (II)

R2 5 5 77234 wherein R. - R., E and G have the same meaning as above.

1 6

The oxidation is performed with ruthenium tetroxide in a suitable solvent or solvent mixture such as chloroform / water, methylene chloride / water or carbon tetrachloride / water at temperatures between 0 and 100 ° C, preferably between 20 and 50 ° C. However, the reaction is most preferably carried out in a two-phase system such as methylene chloride / water, chloroform / water or carbon tetrachloride / water with a catalytic amount of ruthenium dioxide in the presence of a suitable oxidant such as sodium periodate to form ruthenium tetroxide in situ.

b) For the preparation of compounds of general formula I in which R 1 is in the 7-position:

Cyclize a compound of general formula (III) «3 * 1 cv cv * -1 - ° R 2 in which - R 1, E and G are as defined above,

R 9 'is the same as R 1 above or an amino protecting group such as a benzyl group or an acetyl group, for example an acetyl, benzoyl or ethoxycarbonyl group, and X represents a group suitable for ring closure.

6 77234

Suitable groups X are, for example, a carboxy or nitrile group, an ester group such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or benzyloxycarbonyl group, a thioester group such as ethylthiocarbonyl, phenylthiocarbonyl, phenylthiocarbonyl or pyridylthiocarbonyl group a carbonyl or trifluoroacetoxy carbonyl group or an amide group such as an aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl or phenylaminocarbonyl group.

The reaction is optionally carried out in the presence of a suitable condensing agent, optionally in a pressure vessel, in a solvent such as xylene, dimethyl glycol ether, tetralin or sulfane at elevated temperatures, for example between 100 and 250 ° C, but most preferably between 140 and 180 ° C. However, the reaction can also be carried out without a solvent.

Suitable condensing agents are, for example, N, N'-dicyclohexylcarbodiimide, thionyl chloride, phosphate, such as diethyl chlorophosphonate or bis (O-nitrophenyl) phenylphosphonate, phosphorane, such as (2.2, 2-trifluoroethoxy) triphenylphosphorane, N-alkylpyridinium salt such as N-methyl-2-chloropyridinium iodide or N-methyl-2-fluoropyridinium tosylate, Ν, Ν'-dicyclohexylcarbodiimide / 4-dimethylamino-pyridine, chlorosulfonyl-isocyanate or also, when R 1 'does not represent a hydrogen atom, Ν, Ν'-carbonyldiimidazole.

In addition, it may be advantageous for any HO or NH 4 groups present during the reaction to be protected with protecting groups, for example acetyl, benzoyl, ethoxycarbonyl. or benzyl groups.

If X in the compound of the general formula III represents a 7,77234 nitrile or amide group, the reaction is most preferably carried out by converting the corresponding compound by alkaline or acid hydrolysis, for example with methanol / hydrochloric acid or ethanol / sodium hydroxide at each boiling point of the reaction mixture.

Any protecting groups used during the reaction are then cleaved off, for example the acyl group, most preferably. hydrolytically in the presence of an acid or a base or in the presence of a benzyl group, preferably hydrogenolytically, for example with a hydrogenation catalyst such as hydrogen or platinum.

The compounds of general formula I obtained according to the invention can be:; converts to its acid addition salts, in particular to its physiologically acceptable acid addition salts with inorganic or organic acids. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid.

: The compound of the general formula III used as starting material is obtained by chloromethylation of the compound K of the general formula I \ CO33 'pr'-v, in which

R 1, R 2 and E have the same meaning as above and 8 77234 Y is a protected hydroxy group, for example an acetoxy, benzoyloxy or 4-nitrobenzyloxy group, which is then reacted with an alkali cyanide, the group Y being converted into a suitable leaving group such as chlorine, bromine or iodine; , to a methylsulfonyloxy or 4-methylphenylsulfonyloxy group and then reacted with an amine of general formula (V)

Rj R6 '"' 0 ^ (V, R5 where R1 - Rv and G have the same meaning as above, and

J O

optionally then hydrolyzed and / or esterified or amidated.

The compound of the general formula II used as starting material is obtained by alkylation of a correspondingly substituted benzazine derivative (see European Patent Application 82 103 931.0,.

The following examples further illustrate the invention:

Example 1 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl] -3- (N-methyl-N- (2- (3,4 -dimethoxy-phenyl) -ethyl) -amino / propane 0.22 g of 1- (7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl) -3- (N -methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane is dissolved in 10 ml of methylene chloride and added to a solution of 0.5 g of sodium periodate 9,77234 and 10 mg of ruthenium dioxide monohydrate and 10 mg of ruthenium dioxide monohydrate (25 ml of methylene chloride and 25 ml of water). The mixture is stirred for 30 minutes, the organic phase is separated, dried over magnesium sulphate, filtered and evaporated in vacuo. The residue obtained is purified on a thick-layer plate (PSC pre-plates, E. Merck, Damstadt, Kiselgel 60 G 254 + 366; layer thickness: 1 mm) when the propellant is methylene chloride + 10% ethanol + 1% ethanolic ammonia.

Yield: 35 mg (15.3% of theory), m / e e 456

Example 2 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl] -3- (N-methyl-N- (2- (3 (4-Dimethoxy-phenyl) -ethyl) -amino] -propane dihydrochloride 0.1 g of N- [3- (N'-methyl-N '- (2- (3,4-dimethoxy-phenyl) -ethyl) The amino salt of -amino-propyl] -2- (2-hydroxycarbonylmethyl-4,5-dimethoxyphenyl) ethylamine is heated for 2 hours at 200 ° C in 5 ml of sulfolane. After cooling, dilute with 50 ml of water and extract several times with 30 ml of methylene chloride. The organic extracts are combined, washed twice with water, dried over magnesium sulphate, treated with activated carbon / bleaching earth, filtered and evaporated in vacuo. The residue is dissolved in acetone and the dihydrochloride is precipitated with ethereal hydrochloric acid.

Yield: 80 mg (75.1% of theory),

Melting point: 136 ° C (dec.).

Example 3 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-10,72234 3-yl] -3- (N-methyl-N- (2- (3t-4 Dimethoxy-phenyl) -ethyl) -amino] -propane 0.1 g of N- [3- (N'-methyl-N '- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propyl The sodium salt of β- (2-hydroxycarbonylmethyl-4,5-dimethoxy-phenyl) -ethylamine is heated at 180 ° C for 1.5 hours. The melt is cooled, dissolved in methylene chloride and purified on a thick layer plate (PSC plates, E. Merck, Darmstadt, Kieselgel 60 F 254 + 366; layer thickness: 1 mm) with methylene chloride as chloride: chloride + 10% ethanol + 1% ethanolic ammonia .

Yield: 20 mg (21.9% of theory), m / e = 456

Example 4 1- [7,8-Dimethoxy-3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl] -3- (N-roethyl-N- (2- (3,4 (dimethoxy-phenyl) -ethyl) -amino] -propane 0.1 g of N- [3- (N'-methyl-N '- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] - propyl / -2- (2-hydroxycarbonylmethyl-4,5-dimethoxy-phenyl) -ethylamine sodium salt is refluxed for 2 hours in 20 ml of xylene, the solvent is distilled off in vacuo and the residue is purified on a thick-layer plate (PSC plates, E. Merck, Darmstadt , Kieselgel 60 F 254 + 366, layer thickness: 2 mm) when the propellant is methylene chloride + 10% ethanol + 1 S ethanolic ammonia Yield: 65 mg (71.2% of theory), m / e = 456

Example 5 1- [718-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzataepin-2-on-3-yl] -3- (N-methyl-N- (2- (3,4-dimethoxy- phenyl - (-, ethyl) ·> amino] -propane 11,77234 0.1 g N- [3- (N'-methyl-N '- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino N-propyl / -2- (2-hydroxycarbonylmethyl-4,5-dimethoxyphenyl) -ethylamine sodium salt and 0.1 g of Ν, di'-di-cycloocarboxyimide are mixed hours at room temperature in 10 ml of absolute tetrahydrofuran. The precipitated N, N1-dicyclohexylurea is filtered off with suction after cooling in an ice bath, washed with a small amount of tetrahydrofuran and the filtrate is evaporated in vacuo.

The product is further purified according to Example 3.

Yield: 60 mg (65.7% of theory), m / e = 456

Example 6 1- [7,8-Dimethoxy-3,4,4-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- (N-methyl-N- (2- (3,4-dimethoxy) (phenyl) -ethyl) -amino / propane 0.1 g of N- [3- (N'-methyl-N1- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propyl] -2 The sodium salt of - (2-hydroxycarbonyl-1-4,5-dimethoxy-phenyl) -ethylamine and 0.1 g of N, N'-carbonyldiimidazole are stirred for 8 hours at room temperature in 10 ml of absolute tetrahydrofuran. Dilute with 40 ml of acetic acid ester and shake twice with 2N sodium hydroxide and once with water to remove imidazole, dry over magnesium sulphate and evaporate in vacuo. The residue is further purified according to Example 3.

Yield: 55 mg (60.2% of theory), m / e = 456

Example 7 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzathiepin-2-on-3-yl] -3- (N-methyl-N- (2- (3,4-dimethoxy-phenyl) ) -ethyl) -amino] -propane 12 77234 0.2 g of N- [3- (N'-methyl-N '- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propyl N- (4,5-Dimethoxy-2-methoxycarbonylmethyl-phenyl) -ethylamine is heated at 180 ° C for 1.5 hours. The reaction product is further purified according to Example 3. Yield: 60 mg (32.1% of theory), m / e = 456

Example 8 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl] -3- (N-methyl-N- (2- (3,4-dimethoxy) (phenyl) -ethyl) -amino] -propane 1.25 g of N- [3- (N'-methyl-N '- (2- (3,4-dimethoxy-phenyl) -1-ethyl) -amino] -propyl] 2- (4,5-Dimethoxy-2-hydroxycarbonylmethyl-phenyl) -ethylamine is dissolved in 100 ml of methanol and hydrochloric acid gas is bubbled into the solution for 8 hours. It is then refluxed for a further 18 hours, evaporated in vacuo and the residue taken up in a mixture of methylene chloride and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and evaporated in vacuo.

; - The residue obtained is further purified according to Example 3.

Yield: 170 mg (14.9% of theory), m / e = 456

According to Examples 1-8, most preferably Example 2, the following compounds can be prepared: 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl] -3 - [N-Methyl-N- (2- (4-methoxy-phenyl) -ethyl) -amino] -propane hydrochloride Melting point: 175-177 ° C 12,7,8-methylenedioxy-1,3,4, 5-Tetrahydro-2H-3-benzazepin-2-yl--3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -1,137,234

ethyl) amino / propane hydrochloride Melting point: 210-212 ° C

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine

2-on-3-yl / -3- (N-methyl-N- (2- (3,4-methylenedioxy-phenyl) -ethyl) -amino] -propane hydrochloride Melting point: 191-193 ° C

1- [7,8-Dimethoxy-1H-3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl] -3- [N- (2- (3,4-dimethoxy-phenyl) -] ethyl) amino / -propane-hydrochloride

Melting point: 152-154 ° C

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl] -3- [N-allyl-N- (2- (3,4 (dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride

Melting point: 153-155 ° C

1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl] -3- (N-propyl-N- (2- (3,4 (dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride Melting point: 80 ° C (dec.) 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2 -is-

3-yl--3- (N-methyl-N- (2- (3,4-dichloro-phenyl) -ethyl) -amino] -propane dihydrochloride Melting point: 161 ° C

1- [7-Hydroxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl] -3- (N-methyl-N- (2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane Melting point: 157-158 ° C

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-berffazepin-2-on-3-yl] -3- (N-methyl-N- (2- (3,4 -dimethylphenyl) - 14 77 234

ethyl) amino / propane dihydrochloride melting point: 170-172 ° C

1- / 7,8-dimethyl-l, 3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl / -3- / N-methyl-N- (2- (3,4 (dimethoxy-phenyl) -ethyl) -amino] -propane-dihydrochloride Melting point: 1S4-157 ° C

1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl] -3- [N-methyl-N- (2- (4-dimethylamino) (phenyl) -ethyl) -amino / propane dihydrochloride Melting point: 193-196 ° C

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl] -3- (N-methyl-N- (2- ( 4-Amino-3-chloro-5-trifluoromethyl-phenyl) -ethyl) -amino] -propane IR spectrum (methylene chloride): 3410, 3510 cm -1 (NH 4) 1650 cm -1 (CO) 1610, 1520 cm -1 (C = C) 2800 cm -1 (N-alkyl) 2830 cm -1 (OCH 3) UV spectrum (ethanol): λmax: 241 nm (0.33) 285 nm (0.10) 310 nm (0,08) 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl] -3- (N-methyl-N- ( 2- (4-amino-3,5-dichloro-phenyl) ethyl) amino / -propane

Melting point: 94-104 ° C

L / 7.8-d.imetoksi-l, 3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl / -3- / N-methyl-N- (2- (4 -amino-3,5-dibromo-phenyl) -ethyl) -amino] -propane Melting point: 108-112 ° C

1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-is] 77234 on-3-yl] -3- (N-methyl-N- (2- (4 (amino-3-chloro-5-fluorophenyl) ethyl) amino] propane m / e = 463/465 (C 1 H 2 ClFN-10; 463.99)

Claims (4)

A process for the preparation of pharmaceutically usable benzazepine derivatives of the formula I CH2CH2V R6 3 (I) I NENGV r2 ° T where E is an optionally substituted with a 1 to 3 carbon atom alkyl group -propyl group, G is an ethylene group, R 2 and R 2, which may be the same or different, are hydroxy groups, alkyl, alkoxy or phenyl alkoxy groups having 1-3 carbon atoms in the alkyl part, respectively, or one of the groups R is also a hydrogen atom, or together with the group R2 is a 1- or 2-carbon atom alkylene dioxide group, R 2 and R 2, which may be the same or different, are hydrogen or halogen atoms, hydroxy groups, alkyl or alkoxy groups, with respectively, 1-4 carbon atoms, trifluoromethyl or cyano groups or one of the groups R 2 and R 2 may also be a nitro group or R 2 together with the group R 4 a 1- or 2-carbon alkylene dioxide group, R , enalkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, in which the alkyl moiety of e case contains 1-3 carbon atoms, or the alkyl moiety has a methylamino or ethylamino group substituted with a trifluoromethyl group, and R 2 is a hydrogen atom, alkyl group having 1-3 carbon atoms or alkenyl group having 3-5 carbon atoms, especially their physiologically suitable acid addition salts, with inorganic or organic acids, characterized in that a) a benzazepine of the general formula (II) 77634 R R 2, where R 2 - R 9, E and G are the same as above, are oxidized with ruthenium tetroxide in a solvent or b) a compound of the general formula (III) - R 3 i6 '/ hx' ** CH 2 -CH 2 -NENG- (III) W 2 c 2x H _ Rs where R 1, - R 2, E and G are the same as above, R - is the same as R, above or a protecting group for amino group, OD and X is a group suitable for cyclization, cyclized, and optionally a highly obtained compound of the general formula (I) is transferred to its acid addition salt, especially its physical give suitable acid addition salts, with inorganic or organic acid. Process according to Claim 1a, characterized in that the ruthenium tetroxide used for the oxidation is formed in the reaction mixture. 3. A process according to claims 1a and 2, characterized in that the oxidation is carried out at temperatures 0 to 100 ° C, preferably at temperatures between 20 and 50 ° C. Method according to claim 1b, characterized.