DD263525A5 - METHOD FOR PRODUCING NAPHTHALINE AND INDAN DERIVATIVES - Google Patents

Abstract

Naphthalene and indane derivatives of the formula <IMAGE> in which the substituents have the meaning given in the description, their enantiomers, their diastereomers and their acid addition salts with inorganic or organic acids which have useful pharmacological properties, in particular a heart rate-reducing action. The novel compounds can be prepared by processes known per se.

Description

Process for the preparation of naphthalene and indane derivatives

Field of application of the invention

The invention "relates to a process for the preparation of naphthalene and indan derivatives, which have valuable pharraakoiogisohe Eigenacliaften, in particular a heart rate-lowering effect ·

Characteristic of the known country of technology

In EP-A-0.177.960 are already Tetrahydronapivthaiine, which is substituted in the 2-position by an optionally substituted by an acyl substituted hydroxy group sia-i described. These compounds have a pronounced calcium-antagonistic action and can therefore be used as medicaments, in particular for the control or prevention of angina pectoris, ischemia, arrhythmias and hypertension.

Object of the invention

The aim of the invention is the search for new compounds with valuable pharmacological properties.

Explanation of the essence of the invention ,

Surprisingly, it has now been found that the new naphthalene and Indanderivate of formula I.

'2'η ^λ ENG

UU =! - h

2 6 3 5 2

their enantiomers, their diastereomers and their Sa'ureaddiLionssalze, in particular their physiologically acceptable acid addition salts with inorganic or organic acids, other valuable pharmacological properties, in particular a heart rate-lowering effect and a depressing effect on the (^ need of the heart.

The present invention thus relates to the novel tetrahydronaphthalene and indane derivatives of the above formula I, their enantiomers, their diastereomers, their acid addition salts, in particular for the pharmaceutical use of their physiologically acceptable acid addition salts with inorganic or organic acids, processes for their preparation and medicaments containing these compounds ,

In the above general formula I, η is the number 1 or 2,

A is a carbonyl group and R ^ is a hydrogen atom or

^R 8

A represents a group of the formula -CH- in which Rg represents a hydrogen atom, a hydroxy, alkanoyloxy or alkoxycarbonyloxy group, and Ry represents a hydrogen atom or R ^ and Rg together form another bond,

E is a straight-chain alkylene group optionally substituted by an alkyl group and having 3 or 4 carbon atoms,

G is a straight-chain alkylene group having 2 to 5 carbon atoms optionally substituted by an alkyl group,

R _{1 represents} a hydrogen or halogen atom, a trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy or phenylalkoxy group,

2 ^ 3525

1 * 2 is a hydrogen atom or halogen atom, a hydroxy, alkoxy, phenylalkoxy or alkyl group, or

R ^ and ϊ * 2 together represent an alkylenedioxy group having 1 or 2 carbon atoms,

R _{3 is} a hydrogen atom, an alkyl group or an alkenyl group having 3 to 5 carbon atoms,

R 4 is a hydrogen or halogen atom, an alkyl, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, bis (alkylsulfonyl) amino, N-alkyl-alkylsulfonylamino, cyano, Alkylmercapto, alkylsulfinyl or alkylsulfonyl group or an optionally substituted by an alkyl, phenylalkyl, 2-hydroxyethyl, 3-hydroxyn-propyl ·, 2-hydroxy-n-propyl, alkylsulfonyl, cyanoalkyl, alkoxycarbonyl, Hydroxycarbonyalkyl, alkoxycarbonylalkyl, trifluoromethyl, difluoromethyl or trifluoromethylsulfonyl substituted hydroxy group,

Rr is a hydrogen or halogen atom, an alkyl, hydroxy, alkoxy, nitro, cyano or trifluoromethyl group or

R4 and R5 together represent an alkylenedioxy group having 1 or 2 carbon atoms and

R _{6 is} a hydrogen or halogen atom, an alkyl or alkoxy group, wherein all the above-mentioned alkyl or alkoxy groups each contain 1 to 3 carbon atoms and the above-mentioned alkanoyl groups may each contain 2 or 3 carbon atoms.

For the meanings mentioned in the definition of the radicals at the outset, for example

2 * 3525

for R _1, that of the hydrogen, fluorine, chlorine or bromine atom, the methyl, ethyl, n-propyl, isopropyl, trifluoro methyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy , Nitro, amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamines, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino , Methyl-isopropylamino, ethyl-n-propylamino, benzyloxy, 1-phenylethoxy, 1-phenylpropoxy, 2-phenylethoxy or 3-phenylpropoxygrafpe,

) 10 for R ₂ those of the hydrogen, chlorine or bromine atom, the methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 2-phenylpropoxy or 3-phenylpropoxy group or, together with R _1, that of the methylenedioxy or ethyleneoxy group,

for R 3 those of the hydrogen atom, the methyl, ethyl, n-propyl, isopropyl, allyl, crotyl or n-pentene-2-yl group,

for R 4 those of the hydrogen, fluorine, chlorine, bromine or iodine atom, the methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, Amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, Ethyl n-propylamino, acetylamino, propionylamino, methoxycarbonylaraino, ethoxycarbonylamino, n-propoxycarbonylamino, methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, bis (methylsulfonyl) amino, bis (ethyl sulfonyl) -amino, N-methyl-methylsulfonylamino, cyano, methylmercapto, ethylmercapto, n-propylmercapto, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, methylsulfonyl, ethylsulfony1-. n-propylsulfonyl, benzyloxy, 1-phenylefchoxy, 2-phenylethoxy,

2 * 3525

2-phenylpropoxy, 3-phenylpropoxy, 2-hydroxyethoxy, 2-hydroxy-n-propoxy-3-hydroxy-n-propoxy, methylsulfonyloxy, ethylsulfonyloxy, isopropylsulfonyloxy, methoxycarbonyloxy, ethoxyearbonyloxy -, Isopropoxycarbonyloxy-, Hydroxyoarbonylmeifchoxy ·, 2- (hydroxycarbonyl) -ethoxy-, Methoxyoarbonylmethoxy-, üthoxyoarbonylmethoxy-, isopropoxycarbonyl methoxy, 2- (methoxycarbonyl) ethoxy, 2- (n-propoxycarbonyl) ethoxy, cyanoethoxy, 2 Cyanoethoxy, 3-cyano-n-propoxy, trifluoromethoxy or difluoromethoxy group,

for Rc those of the hydrogen, chlorine or bromine atom, the methyl, ethyl, n-propyl, isoprcpyl, -hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, nitro, cyano or trifluoromethyl group or R. and R, - together that of the methylenedioxy or ethylenedioxy group,

for Rg that of the hydrogen, chlorine or Broraatoms, the methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy or isopropoxy group,

for Ry that of the hydrogen atom or together with R _Q that of another bond,

A represents the methylene, hydroxymethylene, acetoxymethylene, propionyloxymethylene, methoxycarbonyloxymethylene, ethoxycarbonyl-oxymethylene, n-propoxycarbonyloxymethylene or carbonyl group,

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

for ethylene, 1-methyl-ethylene, 1-ethyl-ethylene, 1-propyl-ethylene, 2-methyl-ethylene, 2-ethyl-ethylene,

n-propylene, n-butylene, n-pentylene, 1-methyl-n-propylene, 1-methyl-n-butylene, 1-methyl-n-pentylene ·, 1-ethyl-n-propylene , 2-ethyl-n-propylene or 1-ethyl-n-buf cylengruppe into consideration.

For example, in addition to the compounds mentioned in the examples, mention may also be made of the following compounds which * fall under the abovementioned formula I:

6,7-dimethoxy-2- [3 - ((2- (4-methylphenyl) -ethyl) -methylamino) -propyl] -1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((2- (3-methylphenyl) ethyl) methylamino) propyl] -l, 2,3,4-tetrary-ronaphthalin,

6,7-dimethoxy-2- [3 - ((2- (3-methoxyphenyl) -ethyl) -methylamine) -propyl] -l, 2, 3,4-tetrahydronaphth ~,

6,7-dimethoxy-2- [3 - ((2- (4-difluoromethoxyphenyl) ethyl) methylamino) -propyl] -I, 2, 3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((2- (4- (2-hydroxyethoxy) phenyl) ethyl) methylamino) propyl] -l, 2,3,4-tetrahydronaphthalene;

6,7-dimethoxy-2- [3 - ((3- (4-amino-3,5-dibromo-phenyl) -propyl) -methyl amino!) Propyl] - !, 2,3,4-tetrahydronaphthalene;

6,7-dimethoxy-2- [3 - ((2- (3,4-methylendioxvphenyl) ethyl) methylamino) propyl] - !, 2,3,4-tetrahydronaphthalene;

6,7-dimethoxy-2-C 3 - ((2- (3,4-dichlorophenyl) -ethyl) -methyl-amino) -; propyl] -1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((3- (4-cyanophenyl) -propyl) -methylamino) -propyl] -l-hydroxy-1,2,3,4-tetrahydronaphthalene,

2 * 3525

6,7-dimethoxy-2- [3 - ((2- (4-methylsulfonylphenyl) -ethyl) -methyl-amino) -propyl] -1-hydroxy-1,2,3,4-tetrahydronaphthalene,

6,7-di-methoxy-2- [3 - ((2- (4-methoxyphenyl) ethyl) methylamino) propyl] -1-hydroxy-1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((2-phenyl-ethyl) -methyl-amino) propyl] -l-hydroxy-1/2 ,. 3, 4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((3- (4-bromophenyl) propyl) methylamino) -propyl]] - l-hydroxy-l, 2,3,4-tetrahydronaphthalene;

6,7-di-methoxy-2- [3 - ((2- (4-methyl-phenyl) -ethyl) -methyl-amino) -propyl] -1-hydroxy-1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - {(2- (3-methylphenyl) ethyl) methylamino) -ρropyI] -I-hydroxy-1,2,3,4-tetrahydronaphthalene;

6,7-dimethoxy-2- [3 - ((2- (3-methoxyphenyl) ethyl) methylamino) propyl] naphthalene -l-hydroxy-l, 2,3,4-tetrahydr ^,

6,7-Dimethoxy-2- [3 - ((2- (4-trifluoromethylsulfonyloxyphenyl) - (ethyl) -methylamino) -propyl] -l-hydroxy-1,2,3,4-tetrahydronaphthalene.

6,7-dimethoxy-2- [3 - ((2- (4-cyanomethoxyphenyl) ethyl) methylamino) propyl] -1-hydroxy-1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((2- (4-di-fluoromethoxyphenyl) -ethyl) -methylamino) -propyl] -I-hydroxy-1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((2- (4-trifluoromethoxyphenyl) ethyl) methylamino) propyl] -1-hydroxy-1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((2- (4-methanesulfonylaminophenyl) ethyl) methylamino) propyl] -l-hydroxy-l, 2,3,4-tetrahydronaphthalene;

2 (53525

6,7-dimethoxy-2- [3 - (( 2- (4-methoxycarbonylaminophenyl) ethyl) methylamino) propyl] -1-hydroxy-1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((2- (4-ethoxycarbonylmethoxyphenyl) ethyl) methylamino) propyl] -1-hydroxy-1,2,3,4-tetrahydronaphthalene,

6,7-di (ethoxy-2- [3- ((2- (4-hydroxycarbonylmethoxyphenyl) ethyl) methylamino) propyl] -1-hydroxy-1,2,3,4-tetrahydronaphthalene,

6,7-Dimethoxy-2- [3 - ((3- (4-amino-3,5-dibromo-phenyl) -propyl) -methyl-amino) -propyl] -l-hydroxy-1,2,3,4- tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((2- (3,4-methylendioxypheny1) ethyl) methylamino) propyl] -l-hydroxy-l, 2,3, s-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((2- (3,4-dichlorophenyl) ethyl) methylamino) propyl] -l-hydroxy-l, 2,3,4-tetrahydronaphthalene;

6,7-dimethoxy-2- [3 - ((3- (4-cyanophenyl) propyl) methylamino) propyl] -1-oxo-1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((2- (4-methylsulfonyl-phenyl) -ethyl) -methyl-amino) -p.vopyl] -1-oxo-1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((2- (4-methoxyphenyl) ethyl) methylamino) propyl] -l-oxo-l, 2,3,4-tetrahydronaphthalene;

6., 7-Dimethoxy-2- [3 - ((2-phenyl-ethyl) -methyl-amino) -propyl] -1-oxo-1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((3- (4-bromophenyl) propyl) methylamino) propyl] -l-oxo-l, 2,3,4-tetrahydronaphthalene;

6,7-dimethoxy-2- [3 - ((2- (4-methylphenyl) ethyl) methylamino) propyl] -l-oxo-l, 2,3,4-tetrahydronaphthalene;

6,7-dimethoxy-2- [3 - ((2- (3-methylphenyl) -ethyl) -methylamino) -propyl] -1-oxo-1,2,1,4-tetrahydronaphthalene,

C, 7-dimethoxy-2- [3 - ((2- (3-methoxyphenyl) ethyl) methylamino) propyl] -1-oxo-1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((2- (4-trifluormethylsul £ onyloxyphenyl) ethyl) -methylamine) -propylJ-l-oxo-1,2,3,4-tetrahydronaphthalene;

6,7-dimethoxy-2- [3 - ((2- (4-cyanomethoxyphenyl) ethyl) methylamino) propyl] -l-oxo-l, 2,3,4-tetrahydronaphthalene;

6,7-dimethoxy-2- [3 - ((2- (4-difluoromethoxyphenyl) ethyl) methylamino) -propyl] -1-oxo-1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((2- (4-trifluoromethoxyphenyl) ethyl) methylamino) propyl] -1-oxo-1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2-C3 - ((2- (4-methanesulfonylaminophenyl) ethyl) methylamino) propyl] -l-oxo-l, 2,3,4-tetrahydronaphthalene;

6,7-dimethoxy-2- [3 - ((2- (4-methoxycarbonylaminophenyl) ethyl) methylamino) propyl] -1-oxo-1,2,3,4-tetrahydronaphthalene,

6,7-dimethoxy-2- [3 - ((2- (4-ethoxycarbonylmethoxyphenyl) ethyl) methylamino) propyl] -l-oxo-l, 2,3,4-tetrahydronaphthalene

6,7-dimethoxy-2- [3 - ((2- (4-hydroxycarbonylmethoxyphenyl) ethyl) methylamino) propyl] -l-oxo-l, 2,3,4-fcetrahydronaphthalin,

6,7-dimethoxy-2- [3 - ((3- (4-amino-3,5-dibromo-phenyl) -propyl) -methyl-amino) propyl] -l-oxo-l, 2,3,4- cetrahydronaphthalin,

525. '

- 10 -

6,7-Dimethoxy-2 - [3 - ((2- (3,4-methylenedioxyphenyl) ethyl) methylamino) propyl] -1-oxo-1,2,3,4-tetrahydronaphthalene and

6,7-dimethoxy-2- [3 - ((2- (3,4-dichlorophenyl) ethyl) -methvlamino) propyl] -l-oxo-l, 2,3,4-tetrahydronaphthalene. their enantiomers, their diastereomers and their acid additions,

Preferred compounds of the above formula I are the same as those in which

η is the number 1 or 2,

A is a carbonyl group and Ry is a hydrogen atom or

^R 8

A is a group of the formula -CH-, in which Rg is a hydrogen atom or a hydroxy group, and R _{7 is} a hydrogen atom or R ₇ and Rg together represent a further bond,

E is the n-propylene group,

G is the ethylene or n-propylene group, R _{1 is} a methyl or methoxy group, R _{2 is} a hydrogen atom or a methoxy group, R _{3 is} the methyl group,

R 4 is a hydrogen, chlorine or bromine atom, a hydroxy, 20-methoxy, cyano, cyanomethoxy, hydroxycarbonylmethoxy, methoxycarbonylraethoxy, ethoxycarbonylmethoxy, methyl, amino, acetylamino, methoxycarbonylamino, methyl

2 * 3525

- 11 -

sulfonyloxy, trifluoromethylsulfonyloxy, benzyloxy, methylsulfonylamino or bis (methylsulfonyl) amino group,

R _{5 is} a hydrogen, chlorine or bromine atom, a methoxy or nitro group and

Rg is a hydrogen, chlorine or bromine atom, their enantiomers, their diastereomers and their acid addition salts.

Particularly preferred compounds of the formula I are those in which

R ₁ to R ₃ , A, E, G and η are as defined above, R _{4 is} a methoxy group, R _{5 is} a methoxy group and

Rg is a hydrogen atom, their enantiomers, their diastereomers and their acid addition salts.

(15) According to the invention, the novel compounds are obtained by the following processes:

a) For the preparation of compounds of the formula I, in which R 7 and Rg each represent a hydrogen atom or together form another bond:

Reaction of a compound of the formula

(II)

63S2S

- 12 -

in the

R ₁ , R ₂ f η and E are as defined above,

^R 9

A _{1 represents} a group of the formula -CH-, in which Rg represents a nitrogen atom, and R _{7 represents} a hydrogen atom or R ₇ and R ₈ together represent another bond, and

X represents a nucleophilic leaving group such as a halo or sulfonyloxy group, e.g. a chlorine, bromine or iodine atom, the methanesulfonyloxy, p-toluenesulfonyloxy or ethoxysulfonyloxy group, with an amine of the formula

H-K-O /

in the

R ₃ to R ₆ and G are as defined above.

The reaction is conveniently carried out in a solvent or solvent mixture such as acetone, diethyl ether, methylformamide, dimethylformamide, dimethyl sulfoxide, benzene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane or in an excess of the compounds of the formulas II and / or III and optionally in the presence of a acid-binding agent, eg an alcoholate such as potassium tert-butylate, an alkali metal hydroxides such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine or pyridine, the latter also serving as a solvent , or a reaction accelerator such as potassium iodide depending on the reactivity of the nucleophilically exchangeable residue zwackmäßigerweise at temperatures

- 13 -

between 0 and 15O ⁰ C, preferably at temperatures between 50 and 120 ⁰ C / eg at the boiling temperature of the solvent used, carried out. However, the reaction can also be carried out without a solvent. However, the reaction is carried out particularly advantageously in the presence of a tertiary organic base or an excess of the amine of general formula III used.

b) reaction of a compound of the formula

in the

η, A, E, R-j ^ to R-j and Ry are as defined above, with a compound of the formula

Y -

^R 6

in the

R4 to Rg and G are as defined above and Y represents a nucleophilic leaving group such as a halogen atom or a su.lionyloxy group, e.g. a chlorine, bromine or iodine atom, the methanesulfonyloxy, p-toluenesulfonyloxyodar 3ϊthoxysuJ.fonyloxygruppe.

03 5 25

- 14 -

The reaction is conveniently carried out in a solvent or solvent mixture such as acetone, diethyl ether, methylformamide, dimethylformamide, dimethyl sulfoxide, benzene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane or in an excess of the compounds of formulas IV and / or V used and optionally in Presence of an acid-binding agent, eg an alcoholate such as potassium tert-butylate, an alkali hydroxide such as sodium or potassium hydroxide, an alkali carbonate such as potassium carbonate, an alkali metal amide

such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine or pyridine, the latter can also serve as a solvent, or a reaction accelerator such as potassium iodide depending on the reactivity of the nucleophilically exchangeable radical expediently at temperatures between 0 and 150 ⁰ C preferably at temperatures between 50 and 120 ⁰ C, for example at the boiling temperature of the solvent used, durcngeführt. However, the reaction can also be carried out without a solvent. However, the reaction is carried out particularly advantageously in the presence of a tertiary organic base or an excess of the amine of the formula IV used.

c) For the preparation of compounds of the formula I in which A

represents a group of the formula -CH-, in which Rg denotes a hydrogen atom or a hydroxyl group:

Reduction of a compound of the formula

2 ί 3 5- 2

- 15 -

in the

η and RjL to Rg are as defined above,

A _{2 is} a carbonyl group and Ry is a hydrogen atom or

A _{2 represents} a group of formula -CH-, in which Rq ei.-λ represents hydrogen atom or a hydroxy group, and R _{7 represents} a hydrogen atom,

E ¹ which for E or G ^{1 has} the meanings mentioned above for G, but in the radicals E or G, an adjacent to the ^ N-Rg group methylene group must be replaced by a carbonyl group.

The reduction is preferably carried out with a metal hydride such as lithium aluminum hydride or diborane or with a complex of borane and a thioether, for example with borane-dimethyl sulfide complex, optionally in the presence of a Lewis acid such as boron trifluoride in a suitable solvent such as diethyl ether or tetrahydrofuran at temperatures between 80 ⁰ C, but preferably at the boiling point of the solvent used, for example at temperatures between 35 and 65 ⁰ C performed,

If A ₂ in a compound of the formula VI used is a carbonyl group or R g is a hydroxyl group, the preparation of compounds of the formula I in which R 9 is a hydrogen atom is preferably carried out in the presence of a Lewis acid, for example with borane-dimethyl sulfide. Complex in the presence of boron trifluoride, or

If A ₂ in an inserted compound of the formula VI is the carbonyl group or R g is a hydroxyl group, the reduction is preferably carried out with lithium aluminum hydride for the preparation of compounds of the general formula I in which R 9 is a hydroxyl group.

'• ψ

63 5

- 16 -

d) For the preparation of compounds of the formula I, in which A represents the carbonyl group:

Oxidation of a compound of the formula

(VII).

5 in the

n, E, G and R ^ bi3 R _{6 are} as defined above.

The oxidation is preferably carried out with an oxidizing agent such as potassium permanganate, barium manganate, potassium dichromate or with a ketone in the presence of a base (Oppenauer method), for example with acetone / Alurainiumisopropylat or. Benzophenone / Kaliurc tert.butylat, in a suitable solvent such as water, water / dioxane, glacial acetic acid, water / acetic acid or toluene at temperatures between 0 and 150 ⁰ C performed. However, the oxidation with an inorganic oxidizing agent is preferably carried out at temperatures between 0 and 50 ⁰ C and the oxidation to Oppenauer preferably at the boiling temperature of the reaction mixture, for example at temperatures between 50 and 115 ⁰ C.

»E) For the preparation of compounds of the formula I in which R4 is an alkylamino, dialkylamino, amino anoylamino, alkoxycarbonylamino, alkylsulfonylamino, bis (alkylsulfonyl) amino, N-alkylalkylsulfonylamino, alkylmercapto Represents -, alkoxy, alkoxycarbonyloxy, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, phenylalkoxy, trifluoromethoxy, difluoropethoxy, cyanoalkoxy, alkylsulfonyloxy or trifluoromethylsulfonyloxy group:

- 17 -

Reaction of a compound of the formula

- 0

in the

R ₁ to R _3, R 5 to R 7, A, E, G and η are as defined above and

Rg represents a hydroxy, amino or alkylamino group having 1 to 3 carbon atoms, with a compound of the formula

Z - R

(IX)

in the

Z is a nucleophilic leaving group such as a halogen atom, e.g.

a chlorine, bromine or iodine atom, and

R ₁ Q represents an alkyl, alkanoyl, alkoxycarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, alkylsulfonyl, phenylalkyl, trifluoromethyl, difluoromethyl or cyanoalkyl group, wherein the abovementioned alkyl and alkoxy moieties each have 1 to 3 carbon atoms or the Alkanoyl moiety may contain 2 or 3 carbon atoms.

The reaction is conveniently carried out in a solvent or solvent mixture such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally also in the presence of an acid activating agent or a dehydrating agent, e.g. In the presence of ethyl chloroformate, thionyl chloride, phosphoric acid,

 2 <3S.2F. '

- 18 -

phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N ¹ -dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or Ν, Ν'-thionyldiimidazole, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base can also serve simultaneously as solvents such as triethylamine or pyridine, whilst the latter two may be carried out at temperature _v doors -25 to 250 ⁰ C, but preferably b'ii temperatures between -10 ^e C and the boiling de <_ solvent used ,

g) For the preparation of compounds of formula I in which R "7 and Rg together represent another bond?

Dehydration of a compound of the formula

OH 1

R-I I

in the n, E, G and R ^ to R ^ are as defined above.

The dehydration is expediently carried out in a solvent such as acetone, methanol, ethanol, tetrahydrofuran or dioxane and preferably in the presence of an acid such as hydrochloric acid or sulfuric acid, preferably in the presence of an alcoholic acid such as methanolic hydrochloric acid, at temperatures between 0 and 50 ° C, preferably at Room temperature, performed.

203525

- 19 -

In the reactions described above, optionally present reactive groups such as hydroxyl, amino or amino groups can be protected during the reaction by conventional protecting groups / which are cleaved again after the reaction.

For example, comes as a protective group for a hydroxy group, the trimethylsilyl, acetyl, benzoyl, benzyl or tetrahydropyranyl and

as protective group for an imino or amino group, the acetyl, benzoyl, ethoxycarbonyl or benzyl group into consideration.

The optional subsequent cleavage of a protective moiety used is preferably carried out hydrolytically in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ^° C., preferably at the boiling point of the reaction mixture. However, is preferably carried out by hydrogenolysis, the removal of a benzyl group, for example with hydrogen in the presence of a catalyst such as palladium / charcoal in a solvent such as methanol, ethanolamine (nol, ethyl acetate or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ⁰ C, but preferably at room temperature, and a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

If, according to the invention, a compound of the formula I in which R 1 represents a benzyloxy group, this can be converted into the corresponding hydroxy compound by means of debenzylation.

Subsequent debenzylation is preferably carried out in a solvent such as water, water / ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide.

26359.5 · '

- 20 -

carried out with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium / carbon at temperatures between 0 and 50 ^e C, but preferably at room temperature.

The compounds of the formula I obtained, which have at least one chiral center, can be separated by conventional methods into their diastereomers, for example by column chromatography, and into their enantiomers, for example by column chromatography on a chiral phase or by crystallization with optically active acids , eg with D- or L-monomethyl-wine, D- or L-diacetyltartaric acid, D- or L-tartaric acid, D- or L-lactic acid, D- or L-camphoric acid, D- or L-dibenzoyltartaric acid, D- or L- Camphersulfonic acid or D- or L-camphoric acid.

The resulting compounds of formula I can be further converted into their acid addition salts, in particular for their pharmaceutical use in their physiologically acceptable acid addition salts with inorganic or organic acids. Suitable acids are, for example, acidic, hydrobromic, sulfuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, fumaric or oxalic acids.

Some of the compounds of the formulas II to X used as starting materials are known from the literature or are obtained by processes known per se.

For example, a starting compound of the general formula II is obtained by reduction of a corresponding carboxylic acid of the formula

2 6 3S 25

- 21 -

- E - COOH

(XI)

in the

R ₁ , R ₂ / E and η are as defined above, or a corresponding ester to the corresponding alcohol and subsequent reaction with a halogenating agent such as phosphorus tribromide or hydrogen bromide. The carboxylic acid of the general formula XI required for this purpose is obtained by Michael addition of a corresponding acrylic ester to a compound of the formula

O π

- R

11

(XII)

2 η

in the

Rw Ro ^{un (} ^ ^nw * ^{e 9} i ⁿ 9 ^to 9 ^{s are} defined and

R. ₁ is a hydrogen atom or a lower alkoxy group. The compound of the formula XII required for this purpose is again obtained by reacting a corresponding ketone with a formic acid ester or a dialkyl carbonate in the presence of a strong base such as an alkali metal alcoholate or an alkali metal hydride.

2 * 3

- 22 -

A starting compound of the formula IV is obtained, for example, by reaction of a carboxylic acid of the formula XI with a corresponding amine in the presence of N, N'-carbonyldiimidazole and subsequent reduction of the amides thus obtained

A compound of the formulas VI, VII, VIII and X used as starting material is obtained by reacting a corresponding U-halogen compound with a corresponding amine.

The novel compounds of formula I and their physiologically acceptable acid addition salts with inorganic or organic acids have valuable pharmacological properties, especially at low central side effects particularly a heart rate lowering effect and a reduction of 0 ₂ "3edarfs of the heart"

Examples were the compounds

A a 6,7-Dimethoxy-2- / 5 - ((2- (3,4-dimethoxyphenyl) -ethyl) -methylamino) -propyl-7-1-Ö3CO-1,2,3,4-t-etrahydro-naphthalene,

B xs 6,7-Dimethoxy-2- / 3 - ((2- (3 »4-dimethoxyphenyl) -thyl) -methylamino) -propyl 7-1,2,3,4-tetrahydronaphthalene hydrochloride and

0 = 5,6-dimethoxy-2- / 3 - ((2- (3,4-dimethoxyphenyl) ethyl) methylaraino) -propyl-7-1-hydroxy-indan

examined for their biological properties as follows:

- 23 Effect on heart rate in rats:

The effect of the substances to be tested on the heart rate was investigated per dose in 2 rats with an average weight of 250-300 g. The rats were anesthetized with pentobarbital (50 mg / k9 i.p. and 10 mg / kg s.c.). The substances to be investigated were injected in aqueous solution into the jugular vein (0.1 ml / 100 g).

Blood pressure was measured by cannula attached to the carotid artery and the heart rate was recorded from an ECG (II or III lead) derived from needle electrodes. The heart rate of the animals in the control period was between 350 and 400 beats / minute (bpm).

The following table contains the found values:

substance Dose [mg / kg] Heart rate reduction, measured 5 minutes after substance administration [bpm] A B C 5.0 5.0 5.0 157 150 152

The compounds according to the invention have no toxic side effects at therapeutic doses. Thus, for example, in the case of an intravenous administration of the substance A and C, no toxic side effects could be observed, apart from a low sedation, even in a high dose of 10 mg / kg of η mice.

03 5 25

- 24 -

On account of their pharmacological properties, the compounds prepared according to the invention are suitable for the treatment of sinus-adenocardias of various origins and for the prophylaxis and therapy of ischemic heart diseases.

The dosage required to achieve a corresponding effect is two to two times daily 0.03 to 0.4 mg / kg body weight, preferably 0.07 to 0.25 mg / kg body weight. For this purpose, the compounds according to the invention of formula I and their physiologically acceptable acid addition salts with inorganic or organic acids, optionally in combination with other active substances, together with one or more inert conventional carriers and / or diluents, for. With corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, Y / asser, water / ethanol, water / Giycerin, water / sorbitol, water / Polyälhy-Isnglyfcolj propylene glycol, carboxymethylcellulose or fatty substances such as hard or whose suitable mixtures are to be incorporated into common pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, drops, ampoules, juices or suppositories «

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

63 5

- 25 -

Example A

6,7-dimethoxy-l-oxo ~ l, 2,3,4-tetrahydronaphthalene-2-carbaldehyde

187.5 g (0.909 mol) of 6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene are suspended in 4.0 l of diethyl ether and, while stirring, 123.4 g (1.1 mol) of potassium tert.butylate. After 30 minutes, 89 ml (1.1 kg) of ethyl formate are added dropwise to the resulting precipitate. After 5 hours, the blue-red suspension is mixed with 1 1 of water. The water phase is separated and acidified with concentrated hydrochloric acid, whereby a yellow precipitate precipitates. The hydrochloric acid phase is extracted 3 χ with methylene chloride, dried over magnesium sulfate and evaporated in vacuo.

Yield: 186.2 g (87.4% of theory), Melting point: 153-154 ⁰ C.

Example B

3- (6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydronaphthalen-2-yl) -propionic acid methyl ester

A mixture of 128.8 g (0.55 mol) of 6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carbaldehyde, 125 ml (1.38 mol) of methyl acrylate and 82.5 ml (0.6 mol) of triethylamine is heated under reflux for 6 hours. The mixture is then evaporated in vacuo and the residue obtained over 1600 g of aluminum oxide (neutral, activity ΙΙ-.τΐΙ) with methylene chloride and then with increasing proportions of ethanol (to 1%). Yield: 144.5 g (90% of theory), Melting point: 104-106 ⁰ C.

2 «3 5

-26-

Example C

3- (6,7-Dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) propionic acid

169 g (0.578 mol) of 3- (6,7-dimethoxy-l, 2,3,4-tetrahydronaphthalen-2-yl) -propionic acid methyl ester are suspended in 1.5 l of 8% sodium hydroxide solution and heated to reflux for 90 minutes. It is then poured onto ice and acidified with concentrated hydrochloric acid. The resulting precipitate is filtered off with suction.

Yield: 152.1 g (94.5% of theory), Melting point: 156-158 ⁰ C.

Example D

3- (6,7-D \ inethoxy-l-oxo-l, _2; 3,4-tetrahydronaphthalen-2-yl) -N- (2- (3,4-dimethoxyphenyl) ethyl) -N-methyl- propionamide

8.35 g (C, 03 mol) of 3- (6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) -propionic acid amide are suspended in 120 ml of ethyl acetate, with 4, 86 g (0.03 mol) of N, N-carbonyldiimidazole and stirred for ¹ to 60 minutes. 5.86 g (0.030 mol) of N-methyl-homoveratrylamine, dissolved in 30 ml of ethyl acetate, are added to this suspension. After one hour, 2 χ is extracted with 8% sodium hydroxide solution. The organic phase is dried over magnesium sulfate and evaporated in vacuo. Yield: 12.4 g (91% of theory), R E value: 0.8 (alumina, neutral, eluent: 3% ethanol in methylene chloride).

63 5 25

- 27 -

Example E

3- (6,7-dimetho) yl-oxo-1,2,4,4-tetrahydronaphthalene-2-yl) -N- (2- (4-benzyloxy) (p) -nyl) -ethyl) -N-methyl-propionic acid amide

Prepared analogously to Example D from 3- (6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-yl) -propionic acid, Ν, Ν'-carbonyldiimidazole and N-methyl- . 4-benzyloxyphenyl) -ethylamine yield: 91% of theory, melting point: 126-128 ⁰ C.

Example F

3- (6,7-Dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) N- (2- (4-nitrophenyl) ethyl) -N-methyl-propionic acid amide

Prepared analogously to Example D from 3- (6,7-dimethoxy-l-oxo-1,2,3,4-tetrahydronaphthalene-2-yl) propionic acid, Ν, Ν'-carbonyldiimidazole and N-methyl-2- (4 -nitrophenyl) ethylamine. Yield: 87.8% of theory, (melting point: 128-13O ⁰ C.

Example G

3- (6,7-Dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) N - (2- (4-aminophenyl) -ethyl) -N-methyl-propionic acid amide

10.0 g (0.023 mol) of 3- (6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) -N- (2- (4-nitrophenyl) -ethyl) - N-methyl) propionamide are dissolved in 120 ml of methanol in the presence of 1.0 g of 10% palladium / carbon at room temperature for 2 hours

2 <3 5 2

- 28 -

Hydrogenated 5 bar of hydrogen. The catalyst is then filtered off with suction and the methanol is distilled off in vacuo. Yield: 9.3 g (100% of theory),

R, value: 0.4 (alumina, neutral, eluent: 3% ethanol in methylene chloride).

Example H

5,6-dimethoxy-l-oxo-indan-2-carbaldehyde

Prepared analogously to Example A from 5,6-dimethoxy-l-oxo-indane. Yield: 81% of theory, Melting point: 145-147 ⁰ C.

Example I

3- (5,6-dimethoxy-l-oxo-indan-2-yl) -propionic acid methylester

Prepared from 5,6-dimethoxy-l-oxo-indan-2-carbaldehyde and acrylic acid methylester analogously to Example B. Yield: 38% of theory, Melting point: 59-62 ⁰ C.

Example K

3- (5,6-dimethoxy-l-oxo-indan-2-yl) propionic acid

Prepared from 3- (5, 6-dimethoxy-l-oxo-indan-2-yl) -propionic acid methyl ester analogously to Example C.

Yield: 60% of theory, melting point: 146-148 ^e C.

2 * 3525

- 29 -

Example L

3- (5,6-Dimethoxy-1-oxo-indan-2-yl) -N- (2- (3,4-dimethoxy-phe- pyl) -ethyl) -N- methyl-propionic acid amide

Prepared from 3- (5,6-dimethoxy-1-oxo-indan-2-yl) -propionic acid and N-methylhomoveratrylamine analogously to Example D. Yield: 83% of theory,

R _f value: 0.48 (alumina N; methylene chloride + 2%

ethanol)

Example M

6,7-dimethoxy-2- (3-methylaminopropyl) -l, 2,3, 4-tetrahydro naphthalene

a) 3- (6,7-Dimethoxy-1-oxo-1,1,3,4-tetrahydronaphthalen-2-yl) -N-methylpropionic acid amide

8.35 ο (0.03 mol) of 3- (6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydronaphthalin-2-yl) propionic acid are suspended in 120 ml of ethyl acetate, with 4 , 86 g (0.03 mol) of N, N-carbonyldiimidazole and stirred at ¹ 50 ⁰ C for 30 minutes. 4.65 g (0.15 mol) of methylamine are introduced into this suspension within 30 minutes. The mixture is then stirred for a further 30 minutes, the precipitate is filtered off with suction and washed with cold ethyl acetate.

Yield: 6.9 g (79% of theory), Melting point: 160-161 ⁰ C,

Calc .: C 65.96 H 7.27 N 4.81 Vessel: 66.15 7.29 4, 96

2 <3 5 2

30 -

b) 6,7-dimethoxy-2- (3-methylaminopropyl) -1,2,3,4-tetrahydro- naphthalene

6.7 g (0.013 mol) of 3- (6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) -N-methylpropionicuria are suspended in 80 ml of tetrahydrofuran. For this purpose, 3.26 g (0.023 mol) of boron trifluoride etherate under nitrogen and heated to 60 ⁰ C under nitrogen. At diaser temperature now 5.8 ml (0.058 mol) Borandiiaethylsulfidkomplex (10 molar solution) are added dropwise. The mixture is then heated under reflux for 5 hours. Methanol is added dropwise to the cooled reaction mixture, then 10 ml of methanolic hydrochloric acid are added and refluxed for a further 2 hours. The mixture is taken up after evaporation of the solvent in 2 molar sodium hydroxide solution., Shaken out with ethyl acetate. The organic phases are dried over magnesium sulfate in vacuo and the residue is purified over alumina (neutral, activity II-III) with methylene chloride and increasing portions of methanolic ammonia. Yield: 33% of theory,

Mobile phase: 3% ethanol in methylene chloride)

R value: 0.15 (alumina neutral,

Example N

6,7-dimethoxy-2- (3-bromopropyl-l) -l, 2,3,4-tetrahydronaphthalene

a) 3- (6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl) -propanol-1

Prepared analogously to Example Mb from 3- (6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthaiin-2-yl) -propionic acid. Yield: 84% of theory,

R _f value: 0.4 (ready-made silica tiles Macherey-Nagel, polygram, mobile phase: 3% ethanol in methylene chloride)

- 31 -

b) 6,7-Dimethoxy-2- (3-bromopropyl-l) -l, 2,3,4-tetrahydronaph Thalin _'

3.8 g (0.0152 mol) of 3- (6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl) -propanol-1 are dissolved in 40 ml of toluene

 Thereafter, 1.57 ml (0.0167 mol) of phosphorus tribromide dissolved in 5 ml of toluene are added dropwise within 30 minutes. It is stirred for 1 hour at room temperature. The mixture is treated with ice cooling with water and then extracted 3 times with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered off and evaporated in vacuo

 Yield: 4.4 g (92% of theory), R value: 0.9 (ready-made silica gel, Macherey-Nagel solvent: methylene chloride)

63 5

- 32 -

example 1

6.7 ~ Dimechoxy-2- [3 - ((2- (3,4-dimethoxyphenyl) -ethyl) -methylamino) -propyl] -1-hydroxy-1,2,3,4-tetrahydronaphthalene

To 1.60 g (0.042 mol) of lithium aluminum hydride in 150 ml of dry tetrahydrofuran are added 9.6 g (0.021 mol) of 3 / - (6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene). 2-yl) -N- (2- (3,4-dimethoxy-phenyl) -ethyl) -N-methyl-propionic acid amide dissolved in 50 ml of dry tetrahydrofuran. Thereafter, the mixture is heated under reflux for one hour, then treated with ice-water cooling with 1.6 ml of water, 1.6 ml of 15% sodium hydroxide solution and 5 ml of water. The precipitate is filtered off, washed with tetrahydrofuran and the filtrate evaporated in vacuo

 Yield: 5.0 g (50% of theory), oil, Rf value 0.61 (aluminum oxide, mobile phase: 3% ethanol in methylene chloride)

Ber. : C 70.40 H. 8,41 N 3,16 Found: 70,26 8,33 3,05

Example 2

6,7-dimethoxy-2- [3 - ((2- (3,4-dimethoxyphenyl) ethyl) methylamino) propyl] - !, 2,3,4-tetrahydro-naphthalen-hydrochloride

To a solution of 2.73 g (0.006 mol) of 3- (6,7-dimethoxy-loxo-1,2,4-tetrahydro-napht.halin-2-yl) -N- (2- (3, 4-dimethoxyphenyl) -ethyl) -N-methylpropionamide in 30 ml of absolute tetrahydrofuran are added under nitrogen to 0.74 ml (0.006 mol)

- 33 -

Added boron trifluoride etherate and then added dropwise 1.5 ml (0.015 mol) Borandimethylsulfidkomplex (10 molar.) Solution. The mixture is then heated under reflux for 6 hours. The cooled reaction mixture is added dropwise with methanol. Then 5 ml of methanolic hydrochloric acid are added and heated for a further 2 hours under reflux. The methanol and tetrahydrofuran is distilled off and the residue is neutralized after addition of water with 2 molar sodium hydroxide solution. The greasy precipitate is extracted with methylene chloride. The organic phase is dried over magnesium sulfate, evaporated in vacuo and the residue obtained is purified over 120 g of aluminum oxide (neutral, activity II-III) with methylene chloride and subsequent increasing amounts of ethanol (to 0.5%). From a solution in acetone is precipitated with methanoIischer hydrochloric acid, the hydrochloride.

Yield: 1.24 g (44.6% of theory), Melting point: 143-145 ⁰ C,

Ber.ι C 67.29 H 8.25 N 3.02 Found: 67.16 8.18 3.07

Example 3

6,7-Dimethoxy-2- [3- ((2- (3,4-diynethoxyphenyl) -ethyl) -methyl) -propyl] -1-oxo-1,2,3,4-tetrahydronaphthalene hydrochloride

² ^ A mixture of 4.43 g (0.01 mol) of 6,7-dimethoxy-2- [3 - ((2- (3,4-dimethoxyphenyl) ethyl) methylaraino) propyl] -1-hydroxy 1,2,3,4-tetrahydronaphthalene, 2.80 g (0.025 mol) of potassium tert -butylate, 9.10 g (0.05 mol) of benzophenone and 100 ml of toluene are refluxed for 4 hours. The cooled reaction mixture is washed 2 χ with water, then 3 χ extracted with 1% hydrochloric acid. The hydrochloric acid phases are combined and neutralized with concentrated sodium hydroxide solution.

2635 £ 5

- 34 -

The greasy precipitate is extracted with methylene chloride. The organic phase is dried over magnesium sulfate, evaporated in vacuo and purified over 300 g of aluminum oxide (neutral, activity II-III) with methylenectiloride and then increasing proportions of ethanol (to 0.5%). From a solution in acetone is precipitated with methanolic hydrochloric acid Hydrociiiorid. Yield: 1.7 g (33.6% of theory), m.p .: 16G-162 ° C,

Calc .: C 65.33 H 7.59 N 2.93 F .: 65.40 7.50 2.77

Example 4

6,7-dimethoxy-2- [3 - ((2- (4-benzyloxypheny1) ethyl) -methy1-amino) -propyl] -l, 2,3,4-tetrahydro-naphthalen-hydrochloride

Prepared analogously to Example 2 from 3- (6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) -N- (2- (4-benzyloxyphenyl) -ethyl) -N-methyl -propionsäureamid.

Yield: 21% of theory,

Melting point: 171-173 ^P C, calc .: C 72.99 H 7.90 N 2.75 V .: 73.10 8.07 2.71

Example 5

6,7-Dimethoxy-2- [3 - ((2- (4-aminophenyl) ethyl) methylamino) propyl] -2,3,4-tetrahydronaphthalene dihydrochloride

Prepared analogously to Example 2 from 3- (6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) -N- (2- (4-aminophenyl) -ethyl) -N -methyl-propionamide.

243525

- 35 -

Yield: 320 mg (23% of theory), melting point:> 220 ^° C.,

Calc .: C 63.29 H 7.97 N 6.15 Found: 63.10 7.91 6.08

Example 6

6,7-dimethoxy-2- [3 - ((2- (4-nitrophenyl) ethyl) methylamino) propyl] - !, 2,3,4-tetrahydro-naphthalen

A mixture of 1.0 g (0.0038 mol) of 6,7-dimethoxy-2- (3-methylaminopropyl) -1,2,3,4-tetrahydronaphthalene, 0.87 g (0.038 mol) 2- 4-Nitrophenyl) ethyl bromide and 1.1 ml (0.008 mol) of triethylamine is refluxed for 2 hours. The cooled reaction mixture is dissolved in a mixture of 2 molar sodium hydroxide solution and methylene chloride. The organic phase is separated, washed with water, dried over magnesium sulfate, evaporated in vacuo and purified over 120 g of alumina (neutral, activity II-III) with methylene chloride and then increasing proportions of ethanol (up to 0.8%)

 Yield: 210 mg (16% of theory), oil, R value: 0.69 (aluminum oxide, eluent: 2% ethanol in methylene chloride)

Calcd .: C, 69.88, H, 7.82, N, 6.79, Found: 69.87, 7.61, 6.67

Example 7

6,7-dimethoxy-2- [3 - ((2- (4-acetaminophenyl) ethyl) methylamino) propyl] - !, 2,3,4-tetrahydro-naphthalen-hydrochloride

0.76 g (0.002 mol) of 6,7-dimethoxy-2- [3 - ((2- (4-aminophenyl) -

- 36 -

ethyl) -methyl, lamino) -prupyl] "1,2,3,4-tetrahydronaphthalene and 0.3 ml (0.0022 mol) of triethylamine are dissolved in 10 ml of methylene chloride and 0.16 ml (0, After 30 minutes, the mixture is treated with water, and the aqueous phase is extracted with methylene chloride (3 ×) The organic phase is dried over magnesium sulphate and concentrated by evaporation in a vacuum from a solution of the residue obtained in acetone with ethereal salt solution the hydrochloride is precipitated

Yield: 0.25 g (27% of theory), Melting point: 129-131 ⁰ C,

Ber »: C 67,73 H 8,09 N 6,08 Cl 7,69 Found: 67,60 8,45 5,89 7,73

Example 8

6,7-Dimethoxy-2- [3 - ((2- (4-hydroxyphenyl) -ethyl) -methylamino) -propyl] -I, 2, 3, 4-tetrahydronaphthalene

9.1 g (0.019 mole) of 6,7-dimethoxy-2- [3 - {(2- (4-benayloxyphenyl) -. Ethyl) -methylamino) -propyl] -1,3,3,4-tetrahydronaphthalene are hydrogenated in 100 ml of glacial acetic acid in the presence of 1.2 g of 10% palladium / carbon for 5 hours at room temperature and 5 bar of hydrogen. The catalyst is then removed and the glacial acetic acid is distilled off in vacuo. The resulting residue is mixed with 10% sodium hydroxide solution and extracted 3 χ with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated in vacuo. Yield: 6.1 g (83% of theory), melting point: 90-91 ⁰ C,

Calc .: C, 75.16; H, 8.67; N, 3.65, Gef .: 75.00 x 8.79, 3.73

63 5 25

-37-

Example 9

6,7-Dimethoxy-2- [3- ((2- (4-methanesulfonyloxyphenyl) ethyl) methylamino) propyl] -1,2,3,4-tetrahydronaphthalene hydrochloride

0.96 g (0.0025 mol) of 6,7-dimethoxy-2- [3 - ((2- (4-hydroxyphenyl) -ethyl) -methylamine)) -propyl J-1,2,3,4-tetrahydro- Dissolved naphthalene werion in 5 ml of pyridine and added dropwise with stirring 0.27 ml (0.0035 mol) of methanesulfonic acid. After one hour, it is mixed with 10% sodium hydroxide solution. The aqueous phase is extracted 3 χ with methylene chloride. The organic phase is dried over magnesium sulfate and evaporated in vacuo and purified over 80 g of alumina (neutral, activity II-III) with methylene chloride. The residue obtained is taken up with ether and the hydrochloride is precipitated with ethereal hydrochloric acid

Yield: 0.38 g (31% of theory), m.p. 145-146 ⁰ C,

Ber. : C 60.29 H 7,2C <N 2,81 S 6,44 Cl 7,12 Found: 60,35 7,38 2,85 6,27 7,39

Example 10

6,7-Dimethoxy-2- [3 - ((2- (4-benzyloxyphenyl) -ethyl) -methylamino) -propyl] -1,3,3,4-tetrahydronaphthalene hydrochloride

Prepared analogously to Example 6 from 6,7-dimethoxy-2- (3-bromopropyl) -1,2,3,4-tetrahydronaphthalene and N-methyl- (4-benzyloxyphenyl) ethyl.lamine.

Yield: 43% of theory Melting point: 171-1.73 ° C

535

- 38 Example 11

6,7-Dimethoxy-2 - [3 - ((2- (4-trifluoromethanesulfonyloxyphenyl) ethyl) -methylamino) -propyl] -1,3,3,4-tetrahydronaphthalene hydrochloride

Prepared from 6, 7-Dimethoxy-2- [3 - ((2- (4 ~ hydroxyphenyl) - ethyl) methylamino) propyl] -l, 2, 3,4-tetrahydro-naphthalene, and Trifluormethansulfor.sjäurochlorid analogous to Example 9 .. Λ yield: 69% of theory,

Melting point: 135-137 ⁰ C,

Ber. C 54.39 H 6.03 N 2.54 Cl 6.42 S 5.81 F .: 54.34 6.28 2.74 6.69 6.05

Example 12

6,7-Dimethoxy-2- [3 - ((2- (4-cyanomethoxyphenyl) -ethyl) -methylamino) -propyl] -], 2,3,4-tetrahydronaphthalene-hyracene tartrate

Prepared from 6,7-dimethoxy-2- [3- ((2- (4-hydroxyphenyl) ethyl) methylamino) propyl] -1,2,3,4-tetrahydronaphthalene and chloroacetonitrile analogously to Example 16.

Yield: 31% of theory,

Melting point: 63-68 ⁰ C Calc .: C 62.92 H 7.04 N 4.89 Found .: 62.64 7.01 4.80

6352

- 39 Example 13

6,7-dimethoxy-2- [3 - ((2- (4-tr ifluormethoxypheny1) ethyl) methylamino) propyl] - _w 2,3,4-tetrahydro-naphthalen-hydrochloride

Prepared from 6,7-dimethoxy-2- (3-methylaminopropyl) -1,2,3,4-tetrahydronaphthalene and 2- (4-trifluoromethoxyphenyl) -ethyl bromide analogously to Example 6. Yield: 50% of theory, melting point: 124-125 ⁰ C

Ber. C 61.53 H 6.82 N 2.87 Cl 7.27 V .: 61.43 7.03 2.85 7.55

Example 14

6,7-Dimethoxy-2- [3 - ((2- (4-methanesulfonylaminophenyl) -ethyl) -methylamino) -propyl] -1,2,3,4-tetrahydronaphthalene hydrochloride

Prepared from 6,7-dimethoxy-2- [3 - ((2 ~ (4-aminophenyl) -ethyl) -methylamino) -propyl] -l, 2,3,4-tetrahydronaphthalene, and methanesulphonic acid chloride analog Example 7. Yield: 30% of theory, m.p .: 177-179 ° C

Calc .: C 60.40 H 7, 50 N 5.64 V .: 60.60 7.61 5.70

- 40 -

Example 15

6,7-dimethoxy-2- [3- ((2- (4-methoxycarbonylaminophenyl) ethyl) methylamino) propyl] -l, 2, 3,4-tetrahydro-naphthalene-hydrogen fumarate

Prepared from 6,7-dimethoxy-2- [3 - ((2- (4-aminophenyl) ethyl] -methylamino) -propyl] -1,3,3,4-tetrahydronaphthalene and methyl chloroformate analogously to Example 7. Yield : 23% of theory, melting point: 156-16O ⁰ C (decomp.) Calc .: C 64.73 H 7.24 N 5.03 Found .: 65.03 7.08 5.20

Example 16

6,7-dimethoxy-2- [3 - ((2- (4-ethoxycarbonylmethoxyphenyl) ethyl) methylamino) propyl] -l, 2,3,4-tetrahydro-naphthalen-hydrochloride

A mixture of 1.15 g (0.003 mol) of 6,7-dimethoxy-2- [3 - ((2- (4-hydroxyphenyl) -ethyl) -methylamino) -propyl3-l, 2,3, ^A- tetrahydronaphthalene, 0.34 g (0.003 mol) of potassium tert .but ^ -. 10 ml of dimethylsulfoxide at and is heated for 1 hour at 5O ⁰ C, Thereafter, 0.5 g is added (0.003 mol) of bromoacetic ester and again for 1 hour at 50 ⁰ C. The cooled reaction mixture is mixed with water and extracted with ethyl acetate. The organic phase wire ⁵ , dried over magnesium sulfate, evaporated in vacuo and over 60 g of silica gel (3 2-63 μπι, Fa.

Woelm) with methylene chloride and then increasing proportions of ethanol (up to 3%). From a solution in acetone, the hydrochloride is precipitated with methanolic hydrochloric acid.

- 41 -

Yield: 0.2 g (13 % of theory),

Melting point /: 134 - 136 ⁰ O

Ber ·: 0 66.45 H 7.97 U 2.77 Ql 7.01 Found: 6,, 31 7.91 2.74 7.15

Example 17

6,7-D: 1-ethoxy-2- / 3- ((2- (3,4-direthoxyphenyl)) - ethyl-1-methyl- amine) -propyl-7-1-2-dihydro-naphthalene hydrochloride

5.0 g (0.011 mol) of 6,7-dimethoxy-2- / 3 - ((2- (3,4-dimethoxyphenyl) ethyl) -raethylamino) -propyl-7-1-hydroxy-1,2,3 , 4-tetrahydronaphthalene are dissolved in 40 ml of acetone and treated with methanolic hydrochloric acid. It is stirred for 30 minutes at room temperature, then added dropwise with ether until a slight turbidity occurs and stirred again for 30 minutes. "The precipitate is filtered off with suction and dried. Yield: 4.8 g (92 % of theory), m.p .: 171-172 ⁰

H 7,6 ^ N 3,03 8,06 3,27

Ber ": C 67, 59 Found .: 67, 51 example 18

5,6-dimethoxy-2- / 3 - ((2- (3,4-dimethoxyphenyl) -ethyl) -methyl- amino) -propyl-1-hydroxy-indane.

Prepared from 3- (5, 6-Dioxyethoxy-1-oxo-indan-2-yl) -N- (2- (3,4-dimethoxyphenyl) ethyl) -H-methylpropionic acid amide analogously to Example 1

Yield: 58% of theory, Melting point: 83-85 ⁰ C

- 42-

2

Ber. : Gef .:

C 69.90 69.18

H 8,11 8,19

3.26 3.13

Example 19

5,6-dimethoxy-2- [3 - ((2- (3,4-dimethoxyphenyl) ethyl) -met'hylamino) propyl] -l-oxo-indan

Prepared from 5,6-dimethoxy-2- [3 - ((2- (3,4-dimethoxyphenyl) ethyl) methylamino) propyl] -1-hydroxyindane and benzophenone analogously to Example 3. Yield: 16% of the theory, melting point: 98-100 ^e C

N 3.02 2.95

Ber. : C 64, 20 71 H 7, 39 Found .: 64 80 7, 39 example

6,7-Dimethoxy-2- [3 - ((2- (4-hydroxycarbonylmethoxyphenyl) -ethyl) -methylamino) -propyl] -1,2,3,4-tetrahydronaphthalene

A solution of 7C0 mg (0.014 mol) of 6,7-dimethoxy-2- [3 - ((2- (4-ethoxycarbonylmethoxyphenyl) ethyl] methylamino) propyl] -1,2,3,4-tetrahydronaphthalene 4.1 ml of 0.1N sodium hydroxide solution are added dropwise in 10 ml of methanol, followed by stirring at room temperature for 25 minutes, and finally 4.1 ml of 0.1N hydrochloric acid are added to the solution and the mixture is extracted several times with ethyl acetate evaporated over K'agnesiumsulfat in vacuo.The residue is taken up in a little methylene chloride, filtered and the filtrate evaporated to dryness

 Yield: 4C mg (36% of theory),

2 (53

- 43 -

Melting point: 71 C H 7, 99 N 3, 17 Ber «: C 70 72 7, 74 3, 06 Vascular: 70 , 49 Example 21

6,7-dimethoxy-2/5 - ((2- (4- (N, N-bis-methanesulfonyl-amino) -pheny1) ethyl) methylamino) -propyi7 ~ 1,2,3 '4-tetrahydronaphtha lin hydrochloride _t

Prepared from 6,7-dimethoxy-2 ~ / 3 - ((2- (4-aminophenyl) -ethyl) -methylamine)) ~ propyl7-1,2,3 »4-tetrahydronaphthalene and methanesulfonyl chloride analogously to Example 14.

Yield: 15 % of theory,

Melting point: -106 - 108 ⁰ C (Zers ·)

Ber _e ? Ο 54.29 H 6.83 N 4.87

Gef .: 54.10 6.77 4.62

Example 22

6,7-Dimethylmethoxy-2- / 3 - ((3- (4-bromophenyl) -propyl) -methylamino) -propyl-7-1-2,4-tetrahydronaphthalene hydrogen fumarate

Prepared from 6,7-dimethoxy-2- (3-methylamino-propyl) -1,2,3,4-tetrahydronaphthalene and 3- (4-bromophenyl) -1-bromopropane analogously to Example 6, yield: 35 % of theory,

Melting point: 59 ⁰ C 42 H 6 65 N 2, 43 Ber .: .C 60 10 6 43 2, 40 Found .: 60

2 $ 3

- 44 -

Example 23

6,7-Dimethoxy-2- [3 - ((3- (4-cyanophenyl) -propyl) -methylamino) propyl] -2,3,4-tetrahydronaphthalene-hydrgenic fumarate

Prepared from 6,7-dimathoxy-2- (3-methylamino-pr.opyl) -1,2,3,4-tetrahydronaphthalene and 3- (4-cyano-phenyl) -1-bromopropane analogously to Example 6

Yield: 58% of theory, melting point from 57 ^° C. decomposition Calc .: C, 68.94. H 7,33 N 5,36 F .: 68,71 7,15 5,20

Example 24

6,7-Dimethoxy-2- [3 - ((2- (4-methylsulfonyl-phenyl) -ethyl) -methyl-amino) -propyl] -], 2, 3,4-tetrahydronaphthalene

Prepared from 6,7-dimethoxy-2- (3-methylaraino-propyl) -1,?, 3,4-tetrahydronaphthalene and 2- (4-methylsulfonylphenyl) -1-bromoethane analogously to Example 6. Yield: 10.4% of Theory, oil, R _f value: 0.63 (alumina, eluent: 3% ethanol

in methylene chloride) Calc .: C 67.32 H 7, 85 N 3.14 V: 67.14 7.98 3.25

Example 25

6,7-di-methoxy-2- [3 - ((3- (4-methoxy-phenyl) -propyl) -methyl-amino) -propyl] -! 2,3,3-tetrahydronaphthalene

Prepared from 6,7-dimethoxy-2- (3-methylamino-propyl) -

2 * 3525

- 45 -

1,2,3,4-tetrahydronaphthalene and 3- (4-methoxyphenyl) -1-bromopropane analogously to Example 6

 Yield: 68.7% of theory, melting point: 39 ° C.

5 Ber. : C 75, 87 H 8th , 82 N 3, 40 Gef .: 75, 69 8th , 94 3, 59 example 26

6,7-Dimethoxy-2- [3 - ((2-phenylethyl) methylamino) propyl] 1,2,3,4-tetrahydronaphthalene

Prepared from 2-phenyl-1-chloroethane and 6,7-dimethoxy-2- (3-methylamino-propyl-l, 2,3,4-tetrahydronaphthalene analog

Example 6.

Yield: 42% of theory,

Oil, Rj value: 0.42 (alumina, eluent: 2% ethanol '15 in methylene chloride)

Ber, s C 78.43 H 9.05 N 3.81 F .: 78.63 9.29 3.66

Example 27

5,6-Dimethcxy-2- [3 - ((4 ~ benzyloxyphenyl) ethyl) methylamino) propyl] -l-hydroxy-indan

Prepared from 3- (5 _f 6-dimethoxy-1-oxo-indan-2-yl) -N- (2- (4-benzyloxyphenyl) -ethyl) -N-methyl-propionic acid amide and lithium aluminum hydride analogously to Example 1. Yield: 90 % of theory, melting point: 80-83 ⁰ C

Calc .: C 75.76 H 7.84 N 2.95 F .: 75.58 8.01 2.79

-46 -

Example 28

6,7-Dimethoxy-2-Z3 - ((2- (4- (2-hydroxyethoxy) -phenyl) -ethyl ) -methylamino) -propyl7-1.2.3τ4? -Ϊ́θ trahydro onaphthalene-hydrarbonyl id

Prepared from 6,7-D: -ethoxy-2- / 3 - ((2- (4-ethoxycarbonylmethoxyphenyl) -ethyl) -methylamino) -propyl7-1,2,3,4-tetrahydronaphthalene and lithium aluminum hydride analogous to Example 1 Yield "43 % of theory,

Melting point: 141 - 143 ⁰ O

Ber ·: 0 2? 67 30 Found. " 67 20 example

H 8.25 N 3.02 Cl 7.64 8 28 3.04 7.65 _f

6,7-Dime thoxy-2- ^ ö - ((2 ~ (4- "-benzyloxyphenyl) 1-thyl) -methylamino) -propyl-7-1-hydroxy-1,2,3-tetrahydronaphthalene

Prepared from 3- (6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) -N- (2- (4-benzyloxyphenyl) -ethyl) -N-methylpropio. ,., Ätheamia and lithium aluminum hydride analogously to Example

Yields 53.6% of theory,

Melting point: 75 ⁰ O 77 H 7, 66 N 2, 66 Ber. "C 70 00 7, 52 CVJ 56 Gef .s 71

26352s

- 47 Example 30

6,7-Dimethoxy-2- / 5 - ((2- (4-hydroxyphenyl) -ethyl) -methyl-diamino) propyl-7-1-hydroxy-1,2,3,4-tetrahydronaphthalene

Herge is prepared from 6,7-dimethoxy-2-Z3 - ((2- (4-benzyloxy-phenyl) ethyl) -methylamino) -propyl-i-hydroxy-1,2,3,4-tetrahydronaphthalene and hydrogen analogously to Example 8, yield: 47.5% of theory »

H 8,33 N 3,51 8,43 3,53

Melting point ^ 97 ⁰ U 15 Ber.s C 72 14 Found #: 72 Example 31

6,7-Dimethoxy-2- / 3 - ((2- (4-metnanesulfonyloxy-phenyl) -ethyl ) -methylamino) -propyl-7-1-hydroxy-1,2,3,4-tetrahydropnaphthalene

Prepared from 6,7-dimethoxy-2 - / 3 - ((2- (4-hydroxypi, enyl) -ethyl) -methylaraino) -propyl-7-1-hydroxy-1,2,3,4-tetrahydronaphthalene and methanesulfonyl chloride analogously to Example 9 · Yield: 16.7 % of theory,

oil, R _f value: 0.4 (aluminum oxide, eluent: 5 % ethanol in methylene chloride)

Calc .: C 62.87 H, ', 39 H 2.93 Cl 6.71 V .: 62.05 7.50 2.75 6.88

2 * 3525

- 48 -

Example 32

6,7-Dimethoxy-2- [3 - ((2- (4-trifluoromethanesulfonyloxy-phenyl) -ethyl) -methyl-amino) -propyl] -1-hydroxy-1,2-d _; 3,4-tetrahydronaphthalene

Prepared from 6,7-dimethoxy-2- [3 - ((2- (4-hydroxy-phenyl) -ethyl) methylamino) ~ propyl] -l-hydroxy-l, 2, 3, 4-tetrahydronaphthalene and trifluoromethanesulfonyl chloride analogously to Example 9.

Yield: 54.8% of theory, m.p .: 119 "C

Ber .; C 56.49 H 6.07 N 2.63 Cl 6.03 Found: 56.36 6.01 2.49 6.86

Example 33

6,7-Dimethoxy-2- [3- (^ -H-ethoxycarbonylmethoxy-phenyl) -ethyl) -methyl-amino) -propyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene

Prepared from 6,7-dimethoxy-2- [3 - ((2- (4-hydroxyphenyl) -ethyl) -methylamino) -propyl] -1-hydroxy-1,2,3,4-tetrahydronaphthalene and ethyl bromoacetate analog Example 9. Yield: 29% of theory,

Oil, R _f value: 0.2 (alumina, eluent: 3% ethanol

in methylene chloride)

Calc .: C 69.25 H 8.09 K 2.88 F: 69.00 7.93 2.63

- 49 Example 34

6,7-dimethoxy-2- [3 - ((2- (4-hydroxycarbonylmethoxy-phenyl) - ethyl) methylamino) propyl] -l-hydroxy-l, 2, 3,4-tetrahydronaph thalii

Prepared from 6,7-dimethoxy-2- [3 - ((2- (4-hydroxy-phenyl) -ethyl) -methyl-amino) -propyl] -1-hydroxy-1,2,3,4-tetrahydronaphthalene and ethyl bromoacetate. Natronlauje analog

Example 20.

Yield: 37% of theory, melting point: 92 ^° C.

IIER. : C 68.25 H 7, 71 N 3.06 F .: 68.58 7.63 2.92

Example 35

6,7-dimethoxy-2- [3 - ((2- (4-benzyloxyphenyl) -ethyl) -methylamino) -propyl] -1-oxo-1,2,3,4-tetrahydronaphthalene hydrochloride

Prepared from 6,7 ~ dimethoxy-2- [3 "((2- (4-benzyloxyphenyl) ethyl) methylamino) propyl] -1-hydroxy-1,2,3,4-tetrahydronaphthalene and potassium tert-butylate / benzophenone analogously to Example 3.

Yield: 26% of theory,

Melting point: 191 ^° C.

Calcd .: C, 71.04, H, 7.31, N, 2.67, C, 6.76, V: 71.12, 7.24, 2.61, 6.87

- 50 Example 36

6.7 "Dircethoxy-2- [3 - ((2- (4-benzyloxyphenyl) ethyl) methylamino) propyl] -3,4-dihydronaphthalene hydrochloride

Prepared from 6,7-dimethoxy-2- [3- ((2- (4-beirizyloxyphenyl) -, ethyl) -methylamino) -propyl] -1-hydroxy-1,2,3,4-tetrahydronaphthalene and hydrochloric acid analogously to Example 17. Yield: 18.6% of theory, melting point: 185 ^° C.

Be.r. : C 73.28 H 7, 54 N 2.76 Cl 6.98 F .: 73.66 7.20 2.78 7.43

Example 37

6,7-di-methoxy-2- [3 - ((2- (4-hydroxyphenyl) -ethyl) -methylamino) propyl] -3,4-dihydronaphthalene

Prepared from 6,7-dimethoxy- [3 - ((2- (4-hydroxyphenyl) ethyl) methylamino) propyl] -1-hydroxy-1,2,3,4-tetrahydronaphthalene and hydrochloric acid analogously to Example 17.

Yield: 65% of theory,

Oil, Rf value: 0.83 (alumina, eluent: 5% ethanol

in methylene chloride) Ber. : C 75.56 H 8, 19 N 3.67 F .: 75.29 8.10 3.62

2 * 3525

- 51 Example 38

6,7-Di-methoxy-2- [3 - ((2- (4-methanesulfonyloxyphenyl) ethyl) methylamino) -propyl] -3,4-dihydronaphthalene hydrochloride

Prepared from 6,7-dimethoxy-2- [3 - ((2- (4-methanesulfonyloxyphenyl) -ethyl) -methylamine ») -propyl] -l-hydroxy-1,2,3,4-tetrahydronaphthalene and hydrochloric acid analogously to Example 17. Yield: 42.8% of theory, melting point: 81 ^° C. (sinters from 59 ^° C.)

Calc .: C, 58.41, H, 7.06, N, 2.72, Cl, 6.89, S, 6.2, 10, Fe, 58.60, 7, 7, 2.5, 7.00, 6.37

Example 39

6,7-Dimethoxy-2- [3 - ((2- (4-trifluoromethanesulfonyloxyphenyl) ethyl) -methylamine) propyl] -3,4-dihydronaphthaii η

Prepared from 6,7-dimethoxy-2- [3 - ((2- (4-trifluoromethanesulfonyloxyphenyl) -ethyl) -methylamino) -propyl] -l-hydroxy-1,2,4,4-tetrahydronaphthalene and hydrochloric acid analogously to Example 17th

Yield: 77% of theory,

Oil, Rf value: 0.92 (alumina, eluent: 3% ethanol

in methylene chloride) Calcd .: C, 58.47, H, 5.89, N, 2.73, Cl, 6.24, Found: 58.61, 5.88, 2.54, 6.75

263

- 52 Example 40

5,6-Dimethoxy- 2-V i - ((2- (4-methoxyphenyl) -ethyl) -methylamine) propyl-1-hydroxy-indan-oxalate

Prepared from 3- (5,6-dimethoxy-1-oxo-indan-2-yl) -N- (2- (4-methoxyphenyl) -ethyl; -methiethylpropionic acid and lithium aluminum hydride analogous to Example 1. Yield: 90% the theory

Melting point: 80-83 ⁰ C

Calc .: C 6'J, 79H 7, 21N 2.86 Found: 63.55 7.31 3.02

Example 41

5,6-Dimethoxy-2- [3 - ((2- (4-methoxyphenyl) -ethyl) -methylamine) propyl-D-oxo-indane hydrochloride

Prepared from 5,6-dimethoxy-2- [3 - ((2- (4-methoxyphenyl) ethyl) methylamino) propyl] -1-hydroxyindane and benzophenone analogously to Example 13.

Yield: 21% of theory,

Melting point: 193-194 ⁸ C

Calc .: C 66.42 H 7.43 N 3.23 Cl 8.17 G _G f: 66.30 7.58 3.39 8.30

Example 42

5,6-Dimethoxy-2-yl 3- ((2- (4-benzyloxy-phenyi-1) -ethyl) -methyl-1-amino) -propyl] -l-hydroxy-indan

Prepared from 3- (5,6-dimethoxy-1-oxo-indan-2-yl) -N- (2- (4-

3 5 2

- 53 -

benzyloxyphenyl) ethyl) -N-methylpropionsäüreamid and Lithiumaluminiii.r'.hydLid analogously to Example 1. Yield: 90% of theory, Melting point: 80-83 ⁰ C

Calc .: C 75.76 H 7.84 N 2.95 F .: 75.58 8.07 2.79

Example 43

5,6-Dimethoxy-2- (3 - ((2- (4-benzyloxyphenyl) -ethyl) -methylamino) -p.propyl] -1-oxo-indane hydrochloride

Prepared from 5,6-dimethoxy-2- [3 - ((2- (4-benzyloxyphenyl) ethyl) methylamino) propyl] -1-hydroxyindane and berizophenone analogously to Example 3.

Yield: 12% of theory,

Melting point: 189-191 ° C 15

Ber. : C 70 , 64 H 7 , 11 N 2 75 Cl 6 95 Gef .: 70 50 7 , 22 2 , 83 7 20 Example 44

5,6-Dimethoxy-2- [3 - ((2- (4-methylphenyl) -ethyl) -methylamino) propyl] -1-hydroxy-indan

Prepared from 3- (5,6-dimethoxy-1-oxo-indan-2-yl) -N- (2- (4-methylphenyl) -ethyl) -N-methylpropionic acid amide and lithium aluminum hydride analogously to Example 1.

Yield: 83% of theory, Melting point: 89-90 ⁰ C Calc .: C 75.16 H 8.67 N 3.65 Found .: 74.96 8.65 3.58

2 (3 5 2s, '

- 54 -

Example 45

5,6-Dimethoxy-2- [3 - ((2- (4-methylphenyl) -ethyl) -methylamino) -propyl-1-oxo-indane hydrochloride

Prepared from 5,6-dimethoxy-2- [3 - ((2- (4-methylphenyl) ethyl) methylamino) propyl] -1-hydroxyindane and benzophenone analogously to Example 3

Yield: 19% of theory, Melting point: 193-194 ⁰ C.

Calcd .: C, 68.96, H, 7.72, N, 3.35, Cl, 8.48, 1 C, F, 68.86, 7.72, 3.45, 8.63

Example 46

4-methyl-2- [3 - ((2- (3,5-dimethoxyphenyl) -ethyl) -methylamino) propyl] -l-hydroxy-indan-oxalate

Prepared from 3- (4-methyl-1-oxo-indan-2-yl) -N- (2- (3,5-dimethoxyphenyl) ethyl) -N-methylpropionic acid amide and lithium aluminum hydride analogously to Example 1

Yield: 90% of theory, Melting point: 82-83 ⁰ C

Calc .: C, 65.94; H, 7.45; N, 2.96; Found: 66.03, 7.55, 3.05

Example 47

4-methyl-2- [3 - ((2- (3,5-dimethoxyphenyl) ethyl) meth / lamino) propyl] -1-oxo-indan

Prepared from 4-methyl-2- [3 - ((2- (3,5-dimethoxyphenyl) -

2 «3 5.2

- 55 -

ethyl) -methylamino) -propyl] -l-hydroxy-indan and benzophenone analogously to Example 3.

Example 48

4-methyl-2-L3 - ((2-phenylethyl) methylamino) propyl] -l-hydroxy-indan-oxalate

Prepared from 3- (4-methyl-1-oxo-indan-2-yl) -N- (2-phenylethyl) -N-ratithylpropionamide and lithium aluminum hydride analogously to Example 1

Yield: 90% of the theory, melting point: 88-9O ⁰ C.

Ber. : C 69.71 H 7.5ό Ν 3.39 G .: 69.57 7.63 3.31

Example 49

4-methyl-2- [3 - ((2-phenylethyl) methyl) propyl] -3-oxoindane fumarate

Prepared from 4-methyl-2- [3 - ((2-phenyl-ethyl) -methyl-amino) · propyl] -l-hydroxy-indan and benzophenone analogously to Example 3. Yield: 5% of theory, Melting point: 118-121 ⁰ C

Calc .: C 71.37 H 7,14 N 3,20 Found: 71,19 7,33 3,31

- 56 -

Example 50

4-methyl-1-2- [3 - ((2- (3,4,5-tr-t-methoxyphenyl) -ethyl) -methylamino) -propyl] -1-hydroxy-indan

Prepared from 3- <4-methyl-1-oxo-indan-2-yl) -N- (2- (3,4,5-trimethoxyphenyl) -ethyl) -N-methylpropionamide and lithium aluminum hydride analogously to Example 1. Yield: 85% of the theory, melting point: 75-77 ⁰ C

Ber. : C ti, 40 K 7.41 N 2.78 V: 64.49 7.38 3.09

Example 51

4-methyl-2- [3 - ({2- (3,4,5-trimethoxyphenyl) ethyl) methylamino) -propyl] -1-oxo-indaη

Prepared from 4-methyl-2- [3 - ((2- (3,4,5-trimethoxyphenyl) -ethyl)] -methylamino) -propyl] -1-hydroxy-inaane and benzophenone analogously to Example 3.

Example 5 2

5,6-Dimethoxy-2- [3- ((2- (4-benzyloxyphenyl) -ethyl) -methyl-1-amino) -propyl] indene hydrochloride

Prepared from 5,6-dimethoxy-2- [3 - ((2- (4-benzyloxyphenyl) ethyl) methylamino) propyl] -1-hydroxyindane and hydrochloric acid analogously to Example 17

Yield: 88% of theory, melting point: 181-183 ⁰ C.

2 * 3525

- 57 -

Ber .: C 72 93 H 7, 34 Gef .: 72 50 7, 39 Example 53

N 2.84 Cl 7.18 2.52. "7.32

5,6-dimethoxy-2- [3 - ((2- (4-methoxypheny1) ethyl) methylamino) -propylü-indene hydrochloride

Prepared from 5,6-dimethoxy-2-C3 - ((2- (4-methoxyphenyl) ethyl) methylamino) propyl] -1-hydroxyindane and salsbic acid analogously to Example 17

Yield: 68% of theory, melting point: 188-190 ⁰ C.

Boron: C 68.96 H 7.72 N 3.35 Cl 8.48 F .: 68.36 7.72 3.25 8.68

Example 54

5,6-Dimethoxy-2- [3 - ((2- (4-methylphenyl) ethyl) methylamino) propyl] indene hydrochloride

Prepared from 5,6-dimethoxy-2- [3 - ((2- (4-methylphenyl) ethyl) methylamino) propyl] -1-hydroxyindane and hydrochloric acid analogously to Example 17

Yield: 72% of theory, Melting point: 205-207 ⁰ C.

Calc .: C 71.71 K 8.02 N 3.48 Cl 8.82 F .: 71.63 8.04 3.48 8.94

2 63 5IS

- 58 -

Example 55

7-Methyl-2- [3 - ((2- (3,5-dimethoxyphenyl) ethyl) methylamino) propyl] indene oxalate

Prepared from 4-methyl-2- [3 - ((2- (3,5-dimethoxyphenyl) -ethyl) -methyl) -propyl] -JL-hydroxy-inaan and hydrochloric acid analogously to Example 17

Yield: 37% of theory, melting point: 133-134 ⁰

Ber. : C 68.55 H 7.30 N 3.07 Vessel: 68.43 7.45 3.17

Example 56

7-methyl-2- [3 - ((2-phenylethyl) methylamino) propyl] -indenfumarat

Prepared from 4-methyl-2- [3 - ((2-phenylethyl) methylamino) · propyl] -l-hydroxy-indan and hydrochloric acid analogously to Example 17. Yield: 33% of theory, Melting point: 124-126 ⁰ C.

Calc .: C 74.08 H 7.41 N 3.32 G .: 73.83 7.38 3.52

Example 57

7-Methyl-2- [3 - ((2- (3,4,5-trimethoxyphenyl) ethyl) -methylamino) -propyl] -inden-oxalate

Prepared from 4-methyl-2- [3- ((2- (3,4,5-trimethoxyphenyl) ethyl) -methylsilyl) -propyl] -1-hydroxyindane and hydrochloric acid analogously to Example 17.

- 59 -

Exploits 28% of theory, melting point: 102-104 ⁰ C (Zers.)

Calc .: C 66.78 H 7.27 N 2.88 F .: 66.59 7.48 2.62

Example 58

5,6-Dimethoxy-2- [3 - ((2- (4-benzyloxyphenyl) -ethyl) -methylamino) -propyl-1-oxo-indane hydrochloride

Prepared from 5,6-dimethoxy-2- [3 - ((2- (4-benzyloxyphenyl) -ethyl) -methylamino) -propyl3-l-hydroxyindane and benzophenone analogously to Example 3.

Yield: 12% of theory,

Melting point: 189-191 ⁰ C

Calc .: C 70.64 H 7.11 N 2.75 Cl 6.95 F .: 70.50 7.22 2.83 7.10

Example 59

6,7-dimethoxy-3- [3 - ((2- (3-benzyloxyphenyl) ethyl) -methy1-amino) propyl] -l, 2-dihydro-naphthalene hydrochloride

Prepared from 6,7-dimethoxy-2- [3 - ((2- (3-benzyloxyphenyl) ethyl) methylamino) propyl] -1,3,3,4-tetrahydro-1-hydroxynaphthalene and hydrochloric acid analogously to Example 17.

Yield: 23% of theory,

Melting point: 133-134 ⁰ C

Calc .: C 73.28 H 7.54 N 2.76 Cl 6.98 F .: 73.12 7.46 2.89 7.07

2 * 352

- 59a ~

Example 60

6,7-Dimethoxy-2-Z3 - ((2 ~ (4-methanesulfonyloxyphenyl) -ethyl) -methylarrotino) -proxy} »7-1-oxo-1,2,3,4-t-etrahydro-naphthalene hydroo b lorid _r '

Prepared from 6,7-dimethoxy-2-methyl- (2-methanesulfonyloxyphenyl) ethyl) -methylamino) -propyl7-1-hydroxy-1,2,3,4-tetrahydronaphthalene and benzophenone analogously to Example 3. Yield: 53 % of theory, melting point: 183 ⁰ C.

Ber ·: C 58 64 H 6 69 N 2 , 63 Cl 6 , 92 S 6 26 Found .: 58 48 6 93 2 7 , 22 6 50 example 61

6,7-Dimethoxy-2-p-3 - ((2- (3-methanesulfonyloxyphenyl) -ethyl) -methylamino) -propyl-7-1-oxo-1,2,3,4-tetrahydronaphthalene- 1-chloroaurate «_________« »« --- ^ - ^

Prepared from 6,7-dimethoxy-2-Z3 - ((2- (3-methanesulfonyloxyphenyl) ethyl) -raethylamino) -propyl7-1-hydroxy-1,2,3,4-tetrahydronaphthalene and benzophenone analogously to Example 3 »Yield: 28 % of theory,

Melting point: 81 ^° C. (sintered from 66 ^° C.)

Calcd .: C, 58.64, H, 6.69, N, 2.74

Gef .: 58.56 6.83 2.69

2 A3 5 25

- 59b -

Example 62

6,7-Dimethoxy-2-Z3 - ((2- (3-benzyloxyphenyl) -ethyl) -methylamino ) -propyl7- "1" oxo "1" 2 "3" 4-tetrahydronaphthalene hydrochloride

Prepared from 6,7-dimethoxy-2-p-3 - ((2- (3-benzyloxyphenyl) -ethyl) -methylamino) -propyl7- * 1 -hydroxy-1,2,3,4-tetrahydronaphthalene and benzophenone analogously to Example 3 Yield: 27% of theory, melting point: 170 ^° C.

H 7,31 N 2,67 Cl 6,77 7,31 2,64 6,68

Calc .: C 71 , 04 Vascular: 70 20 example

6,7-Dimethoxy-2-p-3 ~ ((2- (3-hydroxyphenyl-1) -ethyl) -mine- lamino) -propyl7-1-hydroxy-1,2,314-tetrahydronaphthalene oxalate

Prepared from 6,7-dimethoxy-2- / 3 - ((2- (3-benzyloxyphenyl) -ethyl) -methylamino) -propyl-7-1-hydroxy-1,2,3,4-tetrahydronaphthalene and hydrogen in counterpart ⁴ "of palladium / carbon analogously to Example 8

Yield: 84 % of theory,

melting point : 77 ° C H 7, 21 N 2 , 86 Ber .: C 63 , 79 7, 40 2 , 68 Found .: 63 , 57

- 59ο -

Example 64

6,7-dimethoxy-2- ^ 3- ((2- (3-hydroxyphenyl) -ethyl) -methylamine)) propyl7-1,2,3,4-tetrahydronaphthalene hydrochloride

Prepared from 6,7-dimethoxy-3-Z3 - ((2- (3-benzyloxyphenyl) -ethyl) -methylamino) -propyl-7-, 2,2-dihydronaphthalene and hydrogen in the presence of palladium / carbon in ethanol as Lo-. Sungniittel similar to Example 8 «Yield: 65 % of theory, melting point: slnt. from 72 ⁰ C

H 8:, 16 N 3.34 Cl 8.44 7.95 3.02 8.84

Ber .: C 65 68 64 Vascular: 68 50 example

6 _> 7-Dimethoxy-2-Z3 - ((2- (3-benzyloxyphenyl) ethyl) methylamino ) propyl 7-1-hydroxyl, 2,3,4-tetrahydronaphthalene oxalate

Prepared from 3- (6,7-dimethoxy-1-oj: -j-1,2,3,4-tetrahydronaphthalen-2-yl) -N- (2- (3-benzyloxyphenyl) -ethyl) -N- methyl-propionamide and Lithiumalialliuraliydrid analogous example

Yield: 51 % of theory,

Melting point: 108 ⁰ C (dec.)

Calc .: C 68.37 H 7,13 N 2,42

Gef .: 68.09 7.08 2.38

- 60 Example I

Tablets to 10 mg of 6,7-dimethoxy-2- [3 - ((2- (3,4-dimethoxyphenyl) -ethyl) -methylamino) -propyl] -l-oxo-1,2,3,4-tetrahydro- naphthalene

5 composition: 10.0 mg 1 tablet contains: 57.0 mg active substance 4 8.0 mg corn starch 4.0 mg lactose 1.0 mg Q polyvinylpyrrolidone 120.0 mg magnesium stearate production method

The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed and moistened with water. The wet mixture is printed through a 1.5 mm mesh screen and dried at about 45 ° C. The dry granules are beaten through a 1.0 mm mesh screen and mixed with magnesium stearate. The finished mixture is compressed on a tablet press with punches of 7 mm diameter, which are provided with a partial notch, into tablets. Tablet weight: 120 mg

Example II

Dragees to 5 mg of 6,7-dimethoxy-2- [3 - ((2- (3,4-dimethoxyphenyl) ethyl) -methylamino) -propyl] -l-oxo-l ^^^ - tetrahydronaphthalene

1 Drageocern contains:

Active substance 5.0 mg

2 * 3525 "

- 61 -

41 5 mg 30 0 mg 3, 0 mg 0 5 mg 80 0 mg

Corn Starch Milk Sugar Polyvinylpyrrolidone Magnesi umstearat

production method

The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed well and moistened with water. The moist mass is forced through a sieve with 1 mm mesh size, dried at about 45 ⁰ C and then beat the granules through the same sieve. After admixing magnesium stearate, curved tablet cores having a diameter of 6 mm are pressed on a tableting machine. The coated dragee cores are coated in a known manner with a layer consisting essentially of sugar and talc. The finished dragees are polished with wax. Dragee weight: 130 mg

Example III

Ampoules of 5 mg of 6,7-dimethoxy-2- [3 - ((2- (3,4-dimethoxyphenyl) -ethyl) -methylamino) -propyl] -1-oxo-1,2,3,4-tetrahydro- naphthalene

1 ampoule contains:

Active substance 5.0 mg

Sorbitol 50.0 mg

Water for injections ad 2.0 ml

production method

In a suitable mixing vessel, the active ingredient is dissolved in water for injection and the solution is made isotonic with sorbitol.

- 62 -

After filtration through a membrane filter, the solution is bottled under N ₂ gassing in purified and sterilized vials and autoclaved for 20 minutes in flowing steam.

Example IV

Suppositories to 15 mg of 6,7-dimethoxy-2- [3 - ((2- (3,4-dimethoxyphenyl) ethyl) methylamino) propyl] -1-hydronaphthalene

1 suppository contains:

Active substance 0,015 g

Hard grease (eg Witepsol H 19 and W 45) 1.685 g

1,700 g

Production method:

The hard fat wire "melted. At 38 ° C the ground active substance is homogeneously dispersed in the melt. It is cooled to 35 ⁰ C and poured into slightly chilled suppository molds.

Example V

Drop solution with 10 mg of 6,7-dimethoxy-2- [3 - ((2- (3,4-dimethoxyphenyl) -ethyl) -methylamino) -propyl] -1-oxo-1,2,3,4-tetra- hydronaphthalin

100 ml solutions contain:

Active ingredient 0.2 g

Hydroxyethylcellulose 0.15 g

Tartaric acid 0.1 g

Sorbitol solution 70% dry substance 30.0 g

- 63 -

2 * 3525

Glycerol benzoic acid Dest.Wasser

ad

10.0 g 0.15 g 100 ml

Production method:

Dest.Wasser is heated to 70 ⁰ C. Herein, hydroxyethylcellulose, benzoic acid and tartaric acid are dissolved with stirring. It is cooled to room temperature and in this case the glycerol and the sorbitol solution are added with stirring. At room temperature, the active ingredient is added and stirred until complete dissolution. The mixture is then evacuated with stirring to vent the juice.

Claims (3)

claims 1 · Process for the preparation of naphthalene and Indanderivaten of formula E - N - G (D η is the number 1 or 2, A is a carbonyl group and R is a hydrogen atom or ?8th
A represents a group of the formula -OH-, in which Rq represents a nitrogen atom, a hydroxy, alkanoyloxy or alkoxycarbonyloxy group, and R 'represents a hydrogen atom or Rj and Rg together form a further bond, E is an optionally substituted by an alkyl group straight-chain alkyl group having 3 or 4 carbon atoms, G is a straight-chain alkylene group having 2 to 5 carbon atoms optionally substituted by an alkyl group, R _{1 represents} a hydrogen or halogen atom, an ilifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkenyl 2 * 3-5 kyl, hydroxy, alkoxy or phenylalkoxy group, R _{2 is} a hydrogen atom or halogen atom, a hydroxy, alkoxy, phenylalkoxy or alkyl group, or R ₁ and R ₂ together represent an alkylenedioxy group having 1 or 2 carbon atoms, Ro is a hydrogen atom, an alkyl group or an alkenyl group having 3 to 5 carbon atoms, R, a hydrogen or halogen atom, an alkyl, amino, alkylarcino, dialkylarainw, alkanoylamino, alkoxycarbonylamino, alkylsulfonylajQino, bis (alkylsulfonyl) amino, N-alkyl-alkylsulfonylamino, cyano, alkylmeroapto, , Alkylsulfinyl or alkylsulfonyl group or optionally by an alkyl, phenylalkyl, 2-hydroxyethyl, 3-hydroxyn-propyl, 2-hydroxy-n-propyl, alkylsulfonyl, cyanoalkyl, alkoxycarbonyl, hydroxycarbonyloylalkyl, alkojcycarbonylalkyl , Trifluoromethyl, difluoromethyl or trifluoromethylsulfonyl substituted hydroxy group, Rc is a hydrogen or halogenatora, an alkyl, hydroxy, alkoxy, nitro, cyano or trifluoromethyl group or R, and Rc together represent an alkylenedioxy group having 1 or 2 carbon atoms and Rg.ein hydrogen or halogen atom, an alkyl or alkoxy group, wherein all the above-mentioned alkyl or alkoxy groups each have 1 to 3 carbon atoms and the above-mentioned alkanoyl groups each 2 or 3 carbon atoms. 525 - 66 ~ , their enantiomers, their Diastereomeran and their acid addition salts, characterized in that a) for the preparation of compounds of the formula I, in which R ~ and Rq each represent a hydrogen atom or together form another bond, a compound of the formula II (ID Xj ₃ . 3 in the are, η and E as defined in claims 1 to 5 A a group of formula -CH-, in which Rg is a hydrogen atom, and R ₇ is a hydrogen atom or Ij and Rq together represent an additional bond, and X represents a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, with an amine of formula III ^R 4 (III) in the Ro to Rg are G as defined above ₉ or is reacted - 67 b) a compound of formula IV 243525 ^A / ^R 7 ¹ Vn ^N B - H (IV) in the η, A, E, R ₁ to Ro and R "are as defined above, with a compound of formula V Y-G (V) in the R until Rg and G are as defined above and Y represents a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group or c) for the preparation of compounds of the formula I in which represents a group of the formula -CH-, in which Rq represents a hydrogen atom or a hydroxy group, compound of the formula VI E · - N - G ¹ in the η and R to Rg are as defined above _t R ₅ (VI) 2 ö 3 5 2 5 - 68 a carboxyl group and Ry eia V / asseratoffatom or ?8th A _{2 represents} a group of the formula -CH-, in which R _{Q is} a hydrogen atom or a hydroxy group, and R is a hydrogen atom, E 'which for E or G ^{1 has} the meanings mentioned, but in the radicals B or G, a methylene group adjacent to the] ^ N-Ro ~ group must be replaced by a carboxyl group is reduced or d) for the preparation of compounds of the formula I in which A represents the carbonyl group, a compound of the formula e) for the preparation of compounds of the formula I in which R. an alkylaraino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, bis (alkylsulfonyl) amino, N-alkyl-alkylsulfonylamino, alkylmercapto, alkoxy , Alkoxycarbonyloxy, hydro: eyearbonylalkoxy, alkoxycarbony! Alkoxy, phenylalkoxy, trifluoromethoxy, difluoromethoxy, cyanoalkoxy, alkylsulfoxide - 69 - represents fonyloxy or trifluoromethylsulfonyloxy, a compound of formula VIII R V h f-hs ^{5 (VIII)} '--GT. in the R ₁ to Ro, R ₅ to R ~, A, E, G and η as above are defined and Rq represents a hydroxy, amino or alkylaminophen having 1 to 3 carbon atoms, with a compound of the formula (IX) ZR ₁₀ · (IX) in the Z is a nucleophilic leaving group such as a halogen atom and R ₁ Q is an alkyl, alkanoyl, alkoxycarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, alkylsulphonyl, phenylalkyl, trifluoromethyl, difluoroethyl or oyanoalkyl group, the above-mentioned alkyl and Alkoxy each 1 to 3 carbon atoms or the alkanoyl moiety may contain 2 or 3 carbon atoms, is reacted or g) for the preparation of compounds of tforrael I, in which Ry and Rg together represent another bond, a compound of formula X. 2 o3 52s - 70 - (2) in the η, E, G and R- to R ™ are as defined above, dehydrated, if necessary, a protective group used in the reactions a) to g) for contactors of reactive groups is subsequently eliminated and, if desired, subsequently a compound of the formula I in which R.sup.1 is a benzyloxy group is then converted into the corresponding hydroxy compound by means of debenzylation or the like a compound of the formula I thus obtained, if it contains at least one chiral center, is resolved into its diestereomers or into its enantiomers and / or a compound of the formula I thus obtained is converted into its acid addition salts, in particular into its physiologically tolerated acid addition salts with inorganic or organic acids, and then optionally nonchemically a compound of the formula I or of physiologically tolerated acid addition salt in one or more inert carriers and / or or diluents incorporated. 63 5 - 71 « 2. Process according to claim 1, characterized in that the reaction is carried out in a solvent, ; 3. Process according to claims 1a, 1b and 2, characterized in that the reaction is carried out in the presence of an acid-binding agent. 4 · process na claims 1a, 1b and 2, daduroh characterized in that the reaction at temperatures between 0 and 150 ⁰ C, z. B. at the boiling temperature of the solvent used is carried out. Process according to claims 1c and 2, characterized in that the reduction with a metal hydride is optionally carried out in the presence of a Lewis acid. 6. Process according to claims 1c, 2 and 5 », characterized in that the reaction at temperatures between 0 and 8O ⁰ C, but preferably at the boiling temperature of the solvent used, is carried out. 7β Process according to claims 1d and 2, characterized in that the oxidation at temperatures between 0 and 150 ⁰ C, preferably with an inorganic oxidizing agent at temperatures between 0 and 5O ⁰ C and with an organic oxidizing agent at the boiling temperature of the reaction mixture carried out becomes* 0. The method according to claims 1e and 2, characterized in that the reaction is carried out in the presence of an acid activating agent or a dehydrating agent. - 72 - Process according to claims 1e, 2 and 8, characterized in that the reaction is carried out in the presence of an inorganic base or a tertiary organic base. « 10 · Process according to claims 1e, 2, Ö and 9 »characterized in that the reaction at temperatures between - 25 and 250 ⁰ C, preferably jjedooh at temperatures between - 10 ⁰ C and the boiling temperature of the solvent used, is performed. 1 "! · Process according to claims 1g and 2, characterized gekennreichnet that the dehydration in the presence of an acid bei.Temperaturen between 0 and 5O ⁰ C, preferably at room temperature, performed. 12. The method according to claim 1, characterized in that the subsequent cleavage of a protective moiety used hydrolytically or a benzyl radical is hydrogenolysis. Process according to claims 1 to 12, characterized in that compounds of the formula I are prepared, in which η is the number 1 or 2, A is a carbonyl group and R is a hydrogen atom or ?8th A is a -CH- uruppe of formula in which R _Q is a hydrogen atom or a hydroxy group, and R _1, together represent an additional bond, a V / asserstoffatom or R ^ and R _Q, 2 * 3525 - 73 - E is the n-propylene group, 6 is the ethylene or n-propylene group, R _{1 is} a methyl or methoxy group, R _{2 is} a hydrogen atom or a methoxy group, R 1 is the methyl group, Rm is a hydrogen, chlorine or bromine atom, a hydroxy, methoxy, cyano, cyanomethoxy, hydroxycarbonylmethoxy, methoxycarbonylmethoxy, ethoxyo-carbonylmethoxy, methyl-, amino-, acetylamino-, methoxycarbonyl-amino-, methylsulfonyloxy-, Trifluoromethylsulfonyloxy, benzyloxy, methylsulfonylamino or bis (methylsulfonyl) amino group, Rc is a hydrogen, chlorine or bromination, a methoxy or nitro group and Rg is a hydrogen, chlorine or bromine atom, and their enantiomers, their diastereomers and their acid addition salts. 14 »Process according to Claims 1 to 12, characterized in that compounds of the formula I are prepared in which R ₁ to RJ, A, E, G and η are as defined in Claim 13, R is a methoxy group,
Rc is a methoxy group and 2 6 3 5 2s - 74 - Rg is a hydrogen atom "and their enantiomers, their diastereomers and their acid addition salts · Process according to claims 1 to 14, characterized in that 6,7-dimethoxy-2-p-3 - ((2- (3, 4-dimethoxyphenyl) -ethyl) -methylamino) -propyl-7-o-1-ol , 2, 3 »4-tetrahydronaphthalene and its acid addition salts are prepared« 16, method of Anepruoh 1 to 14 #, characterized in that 6,7-T) iwethoxy-2- ^ 3 - ((2- (3,4-dimethoxyphenyl) -etliyl) -methylejnir.o) -propyl7 ~ 1, 2,3,4-tetrahydro-naphthalene and its acid addition salts are prepared 17. Process according to Claims 1 to 16, characterized in that physiologically tolerated acid addition salts of the compounds of the formula I are prepared with inorganic or organic acids.