DD215541A5 - PROCESS FOR THE PREPARATION OF BENZAZEPINE DERIVATIVES - Google Patents

Abstract

The present invention provides novel processes for the preparation of Benzazepinderivaten of the general formula I, in which R deep 1 to R deep 6, E and G are defined as in claim 1, namely the oxidation of a corresponding Benzazepinderivates with ruthenium tetroxide and the cyclization of a corresponding ring-open Connection. The compounds of general formula I have valuable pharmacological properties, in particular a heart rate-lowering effect.

Description

Berlin, 22 · 3, 84 - AP C 06 D / 256 668 0 63 0.18 11

Process for the preparation of benzazepine derivatives Field of application of the invention

The invention relates to ^! a process for the preparation of benzazepine derivatives having valuable pharmacological properties, in particular having a heart rate-lowering effect «

The compounds according to the invention are used as medicaments »

Characteristic of the known technical solutions

In the European application 82 103 931.0, which is published on 24 Nov. 1982 under Publication No. 0 065 229, u, a are benzazepine derivatives of the general formula

^CH 2 ^CH 2 _X

M-E-N-G

and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids, which have valuable pharmacological properties, in particular a heart rate-lowering action,.

63 018 11

/ - .... '·. - la - '. , . ·. - In the above general formula I means

E is an ethylene, n-propylene or n-butylene group which is optionally substituted by an alkyl group having 1 to 3 carbon atoms,

G is an optionally substituted by an alkyl group having from V to 3 carbon atoms methylene or ethylene group,

R ₁ and R ₂ , which may be identical or different, hydroxy groups, alkyl, alkoxy or Pheny1alkoxygruppen in which the alkyl moiety may each contain 1 to 3 carbon atoms, or one of the radicals R ₁ or R- also a hydrogen

atom or R. together with R _{2 is} an alkylenedioxy group having 1 or 2 carbon atoms,

R ₃ and R ₄ , which may be identical 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 R ₃ or R ₄ also a nitro group or R ₃ together with R _{4 represents} an alkylenedioxy group having 1 or 2 carbon atoms,

Rc is a hydrogen atom, an alkyl, hydroxy, alkoxy, amino, alkylamino, Diälkylamino-, alkanoylamino, alkoxycarbonyl - >> ^ amino or bis (alkoxycarbonyl) amino group, in which the alkyl moiety each contain 1 to 3 carbon atoms can, or one in the alkyl part by a trifluoromethyl group sub-

substituted methylamino or ethylamino group> and

R _{6 represents} a hydrogen atom, an alkyl, phenylalkyl, alkanoyl or alkoxycarbonyl group in which the alkyl moiety may contain in each case 1 to 3 carbon atoms, or an alkenyl group having 3 to 5 carbon atoms.

For the meanings mentioned in the definition of the radicals R ₁ to R _c , E and G e.ingangs is, for example

R ₁ represents the methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy or 3-phenylpropoxy group,

for R ₂ those of the hydrogen atom, the methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 2 Phehylpropoxy or 3-phenylpropoxy group,

; R ^ and R ₄ , which may be identical or different, those of the hydrogen, fluorine, chlorine, bromine or iodine atom, the methyl, ethyl, propyl, isopropyl, η-butyl, Hydroxy, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, trifluoromethyl or cyano group or for one of the radicals R ₃ or R ₄ also those of the nitro group,

R _{5 is} hydrogen, methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, amino, methylamines, ethylamino, propylamino, isopropylamino, Dimethylamino, diethylamine ©, dipropylamino, methylethylamino, ethylpropylamino, ', methylpropylamine, formylamino, acetylamino, propionylamino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, bis (ethoxy) carbonyl) amino or β, β, β-trifluoroethylamino group,

for R, those of the hydrogen atom, the methyl, ethyl, propyl,

Isopropyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, allyl, buten-2-yl, buten-3-yl, pentenyl, formyl, acetyl, propionyl, Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or isopropoxycarbonyl group, Ί-

for R ₁ together with R ₂ and / or R ₃ together with R _{4 in} each case those of the methylenedioxy or ethylenedioxy group,

for E, the ethylene, n-propylene, n-butylene, 1-methylethylene, 2-ethyl-ethylene, 1-propyl-ethylene, 1-methyln-propylene, 2-methyl-n-propylene , 1-ethyl-n-propylene, 3-ethyl-n-propylene, 2-propyl-n-propylene or 2-methyl

p-butylene group and _. _r . .. ·, .. · ...._.

for G, the methylene, ethylidene, propylidene, n-butylidene, 2-methyl-propylidene, ethylene, 1-methyl-ethylene, 2-ethyl-ethylene, 1-propyl-ethylene or 2 Methyl ethylene group into consideration.

Preferred compounds of the above general formula I are those in which

Έ- the ethylene, n-propylene, n-butylene or 2-methyl-n-propylene group,

G is the ethylene or 1-methyl-ethylene group,

R is a methyl, hydroxy, benzyloxy or alkoxy group having 1 to 3 carbon atoms,

R _{2 is} a hydrogen atom, a methyl, hydroxy or methoxy group, or R. and R ₂ together denote the methylenedioxy group,

R _{3 is} a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, nitro, alkyl or alkoxy group having in each case 1 to 4 carbon atoms,

R _{4 is} a hydrogen, chlorine or bromine atom, a methyl, methoxy or cyano group or R. and R, together the methylenedioxy group,

R _{5 represents} a hydrogen atom, a hydroxy, methoxy, amino, acetylamino, ethoxycarbonylamino, bis (ethoxycarbonyl) amino, dimethylamino or β, β, β-trifluoroethylamino group and

R, a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an allyl or benzyl group, and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids.

63 018 11

'.-. '- · - ⁵ -.: ...

Particularly preferred compounds of the above general formula. I are the ones in which

E the n-propylene group, G the ethylene group »

R _{1 is} the methoxy group »

R _{2 is} the methoxy group or R ₁ and R ₂ together are the methylenedioxy group,

R _{3 is} the methoxy or ^4- trifluoromethyl group, a chlorine or bromine atom,

R _{4 is} the methoxy group, a hydrogen, chlorine or bromine atom or R, and R. together form the methylenedioxy group,

R _{5 is} a hydrogen atom, an amino or methoxy group and

R _{6 represents} a hydrogen atom which is methyl, ethyl, n-propyl or allyl, and their physiologically tolerable acid addition salts with inorganic or organic acids,

Object of the invention

The aim of the invention is to provide a simple and economical process for the preparation of Benzazepinderivaten, are achieved with the high yields.

63 018 11

- 5a -

Explanation of the essence of the invention

The invention has for its object to find »suitable starting compounds and reaction conditions for the preparation of Benzazepindsrivaten.

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

a) oxidation of a Benzazepine of the general formula

 - 6 -

^R 1 <R ₆

· ^ΙΙΙ)

R-

.V

in the

R ₁ to Rg, E and G are as defined above.

The oxidation is carried out 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 1ÖO ° C, preferably at temperatures between 20 and 50 ° C. However, the reaction is 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 oxidizing agent such as sodium periodate, which generates ruthenium tetroxide in situ.

b) For the preparation of compounds of the general formula I in which R _{1 is} in the 7-position;

Cyclization of a compound of the general formula

^R 1 ^^ >> ^ CH: - CH - N - E - N - G - // ¹ ^ , (HD

H .''R ₁

R ₁ to Rt, E and G are as defined above,

Rg 'has the meanings mentioned above for R, or a protective group for an amino group such as a benzyl group or an acyl group, e.g. the acetyl, benzoyl or ethoxycarbonyl group, and

X represents a group suitable for ring closure.

For example, X represents the carboxy or nitrile group, an ester group such as the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or benzyloxycarbonyl group, a thioester group such as the ethylthiocarbonyl, phenylthiocarbyphenyl or pyridylthiocarbonyl group, an acyloxycarbonyl group such as the acetoxycarbonyl or trifluoroacetoxycarbonyl group or an amide group such as 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 sulfolane at elevated temperatures, e.g. at temperatures between 100 and 250 C, but preferably at temperatures between 140 and 180 ° C performed. However, the reaction can also be carried out without a solvent.

Suitable condensing agents include, for example, N, N'-dicyclohexylcarbodiimide, thionyl chloride, a phosphate such as diethyl chlorophosphonate or bis (O-nitrophenyl) phenylphosphonate, a phosphorane such as (2,2,2-trifluoroethoxy) -triphenylphosphorane, an N-alkyl- pyridinium salt such as N-methyl-2-chloropyridinium iodide or N-methyl-2-fluoropyridinium tosylate, N, N-dicyclohexylcarbodiimide / ^ -dimethylamino-pyridine, chlorosulfonyl isocyanate or even when R 'is not a hydrogen atom, N , N'-carbonyldiimidazole into consideration.

Furthermore, it may be advantageous if any existing HO or NH ₂ ~ groups during the reaction by protecting groups, for example by acetyl ^, benzoyl, Äthoxycarbonyl- 'or benzyl groups protected.

If ix in a compound of the general formula III denotes a nitrile or amide group, the reaction is preferably carried out in such a way that a corresponding compound is obtained by means of alkaline or acidic hydrolysis, e.g. is converted by means of methanol / hydrochloric acid or ethanol / sodium hydroxide each at the boiling point of the Reaktiohsgemisches, in a corresponding carboxy compound, which is then cyclized. .

The protective radicals optionally used during the reaction are then removed again, e.g. Acyl radicals preferably hydrolytically in the presence of an acid or base or Behzylreste preferably hydrogenolytically, e.g. with hydrogen in the presence of a hydrogenation catalyst such as palladium / carbon or platinum.

The compounds of the general formula I obtained according to the invention can be converted into their acid addition salts, in particular into their physiologically tolerated acid addition salts, with inorganic or organic acids. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid.

A compound of the general formula III used as starting material is obtained by chloromethylation of a compound of the general formula

63 018 11

- 9 COCH,

- N

E-Y

, (IV)

in the

R, R and E are as defined above and Y is a protected hydroxy group, e.g. B. the acetoxy, benzoyloxy or 4-nitrobenzoyloxy group, further reaction with an alkali metal cyanide, conversion of the radical Y into a suitable leaving group as in the chloro, bromo or oxyatom, the Methylsulfonyloxy- or 4-Methylphenylsulfonyloxygruppe and subsequent Reaction with an amine of the general

formula

R

R _c - NH - G b

in the ^J

R_ to R ₆ and G are as defined above, and, if appropriate, subsequent hydrolysis and / or esterification or amidation,

A compound of the general formula II used as starting material is obtained by alkylation of an appropriately substituted benzazepine derivative (see European application 82 103 931.0 of May 6, 1982).

63 018 11

·. , , - ίο -. . "

embodiment

The following examples are intended to explain the invention in more detail:

example 1

l / _t "" 7,8-dimethoxy-l, 3j, 4 _f 5-tetrahydro-2H-3-benzazepin-2-on-3-yl ^ -3- £ ~ N-methyl- (2- (3 , 4-dimethoxy-phenyl) -ethyl) -atnirio / '] 7-propane ... ..... , ,, · ....,. , ... , "..". ";

0.22 g of l- £ "" 7, 8-dimethoxy-2,3,4,5-tetrahydro-lH-3-benzazepine-3-yl37-3- / 7 "N-methyl-N- (2 * ( 3,4-dimethoxy-phenyl) -ethyl) -amino-y-propane are dissolved in 10 ml of methylene chloride and added to a solution of 0.5 g of sodium hydroxide and 10 mg of ruthenium dioxide monohydrate in 25 ml of methylene chloride and 25 ml of water The mixture is stirred for 30 minutes, the organic phase is separated off, dried over magnesium sulfate, filtered and concentrated in vacuo The residue obtained is passed through a thick-layer plate (PSC precoat plate, silica gel 60 F 254 + 366, layer thickness: 1 mm) with the mobile phase methylene chloride + 10 % ethanol + 1 % ethanolic ammonia cleaned «

Yield? 35 mg (15.3 % of theory), m / es 456

Example 2

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl ₎ -7-3- / N-methyl-N- (2 - (3,4-'dimethoxy-phenyl) -ethyl) -

63 018 11

₁ 7-propane dihydrochloride

0.1 g of N - ^ "3 - /" N ⁱ -methyl-N '- (2-C3,4-dimetho-1-yl-phenyl) -ethyl) -amino _> J7-propyl_7-2- (2- hydroxycarbonylmethyl-4 _J 5-dimethoxyphenyl) -ethyl-amine-sodium salt are heated in 5 ml of sulfolane 2 hours at 200 ⁰ C. After cooling, it is diluted with 50 ml of water and extracted several times with 30 ml of methylene chloride. The organic extracts are combined, washed twice with water, dried over magnesium sulfate, treated with charcoal / bleaching earth, filtered and concentrated in vacuo. The residue is dissolved in acetone and ethereal hydrochloric acid is by precipitating the dihydrochloride Yield: 80 mg (75.1% of theory), Melting point: 136 ⁰ C (dec *) ·

, '''''' · I. ·: Example 3

l - ^ "7,8-dimethoxy-l, 3 _i 4,5-tetrahydro-2H-3-benzazepin-2-one-3-ylJ7-3 - /""N-me thyl-N- (2- ( 3,4-dimethoxy-phenyl) -ethyl) -amino- J7-propane .

0.1 g of N- / f "3- / ~ N'-methyl-N ^t - (2- (3,4-dimethoxyphenyl) -ethyl) -amino _> _7 ^r -propyl_J7-2- (2-hydroxycarbonylmethyl -4,5-dimethoxyphenyl) -ethyl-amine, sodium salt 1.5 hours are heated to 180 ⁰ C, the melt is cooled * dissolved in methylene chloride and (a thick film plate PSC-finished .platte-., Kieselgei 60 F 254 + 366; layer thickness: 1 mm) with the eluent methyl chloride + 10 % ethanol + 1 % ethanolic ammonia, yield: 20 mg (21.9 % of theory), m / e = 456

63 018 11

- 11a -

Example 4

l- _^> "" 7 ₁ 8-dimethoxy-l, _{3,4,5-tetrahydro-2H-3-ben2azepin-2-on-3-yl>} J7-3- / f "N'-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino-7- propane

0.1 g N- / 3- ~ / ~ N ^t N ^-methyl-1 - (2- _(3-t 4 diniethoxy-phenyl) -ethyl) -aminoJ7-Pf * _opyl> J7-2- (2-hydroxycarbohylmethyl -4,5-dimethoxyphenyl) ethyl-amine sodium salt is refluxed in 20 ml of xylene for 2 hours. The solvent is distilled off in vacuo and the residue is passed through a thick-layer plate (PSC precoat plate, silica gel 60 F 254 + 366; 2 mm) with the mobile phase methylene chloride + 10 % ethanol + 1 % ethanolic ammonia.

Yield: 65 mg (71.2 % of theory);

m / e = 456

- 12 -

Beispiel'5

1-7, 8-dimethoxy-1, 3,4, S-

3 - / N-methyl-N- (2- (3,4-dimethoxy-phenyl) ethyl) amino / -propane,

0.1 g of N- £ 3- / N '-methyl-N' - (2- (3,4-dimethoxyphenyl) -ethyl) -amino / -propyl / -2- (2-hydroxycarbonylmethyl-4,5 -dimethoxy-phenyl) -ethyl-amine-sodium salt and 0.1 g of N, N'-dicyclohexylcarbodiimide are stirred in 10 ml of absolute tetrahydrofuran for 10 hours at room temperature. The precipitated N, N'-dicyclohexylurea is filtered off with suction after cooling in an ice bath, washed with a little tetrahydrofuran and the filtrate is concentrated in vacuo. The product is further purified analogously to Example 3

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

Example 6 -

1-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl7- ⁱ - 3- / N-methyl-N- (2- (3, 4-dimethoxy-phenyl) -ethyl) -amino-7-propane

0.1 g of m-3- (3-methyl-N '- (2- (3,4-dimethoxyphenyl) ethyl) -amino-propyl / -2- (2-hydroxycarbonylmethyl-4,5 -dimethoxy-phenyl) -ethylamine-sodium salt and 0.1 g of Ν, Ν'-carbonyldiimidazole are stirred in 10 ml of absolute tetrahydrofuran for 8 hours at room temperature. It is diluted with 40 ml of ethyl acetate and shaken twice with 2N sodium hydroxide solution and once with water to remove the imidazole, dried over magnesium sulfate and concentrated in vacuo. The residue is further purified analogously to Example 3

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

;. '. -:. ; ; ; -: .. ';; - 13 .- .. <;''._; -. ^:; ··: Example 7 ''. ^':::'. , , ,

1-7,8-dimethoxy-1,3,4-s-tetrahydro-HS-benzazepine-5-s-yl- 3-Zn-methyl-N- (2- (3,4-dimethoxy-phenyl) ethyl) propane--aminoy

0.2 g of N - ^ - N'-methyl-N * - (2- (3,4-dimethoxyphenyl) -ethyl) -amino-propyl / -2- (4, S-dimethoxy) - Methoxycarbonylmethyl-phenyl) -ethylamine are heated to 180 ⁰ C for 1.5 hours. The reaction product Mird further purified analogously to Example 3. Yield: 60 mg (32.1% of theory), m / e = 456.

Example 8

¹ "D ' 8-Diniethoxy-1,3,4,5-tetrahydro- ^k- 2H * 3-benzazepine" -2-on-3-yl7- S-ZN-methyl-N "(2- (3, 4-dimethoxy-phenyl) ethyl) amino / -propane

1.25 g of N- / 3- ^ N'-methyl-N * - (2- (3,4-dimethoxyphenyl) ethyl) amino / propyl 7-2- (4, S-dimethoxy) -hydroxycarbonylmethyl -phenyl) -ethyl- {.: Ami η are dissolved in 100 ml of methanol and refluxing is passed 8 hours hydrochloric acid gas. The mixture is then refluxed for a further 18 hours, concentrated in vacuo and the residue taken up in methylene chloride / saturated sodium bicarbonate solution. The organic phase is separated off, dried over magnesium sulfate and concentrated under reduced pressure and the residue obtained is further purified analogously to Example 3. Yield: 170 mg (14.9% of theory), m / e = 456

Analogously to Examples 1 to 8, the following compounds can be prepared:

- 14 -

1-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-o-3-yl-7-3- / N-methyl-N- (2- (4- methoxy-phenyl) -ethyl) -aminoy-propane hydrochloride. ,

Melting point: 175-177 ° C. ,

T-Z7,8-methylenedioxy-1,3,4, S-tetrahydro-HS-benzazepine - ^ -on-S-yiy-3- / N-methyl-N- (2- (3,4-dimethoxyphenyl ) -ethyl) -aminopropane hydrochloride. Melting point: 21O-212 ° C

1- fl , 8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl-7-.3- ^ N-methyl-N- (2- (3,4-) methylenedioxy-p'-phenyl) -ethyl) -amino / -propane-hydrochloride Melting point: 191-193 ° C.

1- ^ 7,8-Dirnethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl7-3-j / N- (2- (3,4-dimethoxy-phenyl ) -ethyl) -amino / -propane hydrochloride Melting point: 152-154 ° C

1- ^ 7,8-dimethoxy-1,3,4, S-tetrahydro ^ HS-benzazepin ^ -on-S-yl / -3- ^ N -allyl-N- (2- (3,4-dimethoxy-) phenyl) -ethyl) -aminoy-propane hydrochloride Melting point: 153-155 ° C.

1 - ^, 8-Dimethoxy-1, 3,4, 5-tetrahydro-2H-3-benzazepin-2-one-3-yl-7-3- / N-propyl-N- (2- (3,4 -dimethoxyphenyl) -ethyl) -aminoj-propane hydrochloride

Melting point: 80 ° C (dec.).

1-7,8-dimethoxy-1,3,4, B-

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-one-S-S-YLJ-ZN'-methyl-N- (2- (3, 4-dimethoxy-phenyl) -ethyl) -amino? -

propane

Melting point: 157-158 ° C.

- 15 -

1-7.8-dimethoxy-1,3,4, S-

3- ^ N-methyl-N- (2- (3,4-dimethyl-phenyl) -ethyl) -aminoZ-propane

dihydrochloride

Melting point: 17O-172 ° C

1- £ 7 ", 8-dimethyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl7-3- / N" -methyl-N- (2- (3, 4-dimethoxy-phenyl) -ethyl) -aminopropanedihydrochloride ^ Melting point: 154-157 ° C.

1- ^ 7,8-Dimethoxy-l, 3,4,5-tetrahydro ^ 2H-3-benzazepin-2-one-3-yl7-3 - ^ - methyl-N- (2- (4-dimethylamino-phenyl ) ethyl) - ami n £ / -propandihydrochlorid melting point: 193-196 C. ⁰

1-7,7-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl7-3- ^ N -methyl-N- (2 * (4-a-amino) 3-chloro-5-trifluoromethyl-phenyl) ethyl) -aminoy-propane IR spectrum (methylene chloride)

UV spectrum (ethanol): λ max:

3410 , 3510 cm" (NH ₂ ) 1650 cm (CO) 1610 , 1520 cm (C = C) 2800 cm (N-alkyl) 2830 cm (OCH ₃ ) 241 nm (0, 33) 285 nm (0 / 10) 310 nm (0, 08)

1-7.8-dimethoxy-1,3,4, S-

S - ^ - methyl-N- (2- (^ -amino-Sis-dichloro-phenyl) -ethyl) -amino? -

propane

Melting point: 94-1O4 ° C.

T- ^ J, 8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl7-3- / N-methyl-N- (2 ^ (4-amino) 3,5-dibromo-phenyl) -ethyl) -aminoy-

pfopan

Melting point: 1O8r-112 ° C,

- 16 -

1-7,7-Dimethoxy-1,3,4-S-3- / N-methyl-N- (2- (4-amino-3-chloro-5-fluoro-phenyl) -ethyl) -amino -

propane

m / e = 463/465 (C ₂₄ H ₃₁ ClFN ₃ O _3; 463.99)

Claims (9)

E is an optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted ethylene, n-propylene or n-butylene group, G is an optionally substituted by an alkyl group having 1 to 3 carbon atoms methylene or ethylene group, R ₁ urid R ₂ , which may be identical or different, hydroxy groups, alkyl, alkoxy or phenylalkoxy groups, in which the alkyl moiety may each contain 1 to 3 carbon atoms, or one of the radicals R ₁ or R _{2 is} also a hydrogen atom or R ₁ together with R _{2 represents} an alkylenedioxy group having 1 or 2 carbon atoms, 63 018 11 R "and R., Which may be identical 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 the radicals R, or R. also a nitro group or R ₃ together with R. an alkylenedioxy group having 1 or 2 carbon atoms, R _{5 is} a hydrogen atom, an alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino or bis (alkoxycarbonyl) amino group in which the alkyl moiety can contain in each case 1 to 3 carbon atoms, or a substituted in the alkyl moiety by a trifluoromethyl group methylamino or ethylamino group, and. Rg represents a hydrogen atom, an alkyl, phenylalkyl, alkanoyl or alkoxycarbonyl group in which the alkyl moiety may each contain from 1 to 3 carbon atoms, -or denote an alkenyl group of from 3 to 5 carbon atoms, and of their acid addition salts, in particular of their physiologically acceptable acid addition salts with inorganic or organic acids, characterized in that a) a benzazepine of the general formula  '' ': · -' '. '· "" R. "6 - E - N - G 63 018 11 in the R. to R ₆ , E and G are as defined above, is oxidized with ruthenium tetroxide in a solvent, or. · b) a compound of the general formula ^ N-E-N-G , (III) in dar R ₁ to Rg, E and G are as defined above, R ₆ ^{1 has} the meanings mentioned for R ₆ or a protective group for an amino group and X represents a group suitable for ring closure, is cyclized and, if desired, converting a compound of the general formula I thus obtained into its acid addition salt, in particular into its physiologically tolerated acid addition salt, with an inorganic or organic acid, 2 · Method according to item la, characterized in that the ruthenium tetroxide used for the oxidation is formed in the reaction mixture. 63 018 11 - 20 - 3 · The method according to the points la and 2, characterized in that the oxidation is at temperatures between O and 100 ⁰ C but preferably _1, carried out at temperatures between 20 and 50 ° C · 4, process according to item Ib, characterized in that the reaction is carried out at temperatures between 100 and 250 ^° C, but preferably at temperatures between 140 and 180 ⁰ C, 5 # Method according to points Ib and 4, characterized in that the reaction is carried out in a solvent, 6, process according to the points Ib ₁ 4 and 5, characterized in that the reaction is carried out in the presence of a condensing agent » 7, process according to the points Ib and 4 to 6, characterized in that existing OH and NH groups are protected during the reaction by Schutzreete, which are subsequently cleaved again. 8, process according to item 6, characterized in that as condensing agent N, N'-oicyclohexylcarbodiimide, thionyl chloride, a phosphonate, phosphorane or N-alkylpyridinium salt, N, N'-dicyclohexylcarbodiimide / ^ -dimethylaminopyridine, chlorosulfonyl isocyanate or else when _Rf ' is not hydrogen, N, N ^I -carbonyl-diimidazole is used. 63 018 11 9 * Process according to item 7, characterized in that the protecting groups used are acyl groups which are subsequently hydrolytically split off · Ip. Process according to item 7, characterized in that benzyl groups are used as protective radicals, which are subsequently removed by hydrogenolysis »