CA2033323A1 - 2-amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes, processes for their preparation and their use as medicaments - Google Patents

Abstract

Abstract The invention relates to novel 2-amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes, processes for their preparation and their use as medicaments.

Description

2 ~ 3 ~
S011119T.os The invention relates to novel 2-amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes, processes for their preparation and their use as medicaments. The 2-amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes (2-amino-7-carbamoyltetralins) correspond to the general formula 1:

H~ C ~ N / 2 ,, ~R

wherein R1 denotes Cl-C8-alkyl;
R2 denotes hydrogen, C1-Clz-alkyl, C3-C6-alkenyl, C3--C6--alkynyl, --( CH2) n~OR4 ~ ~ ( CH2) n--SR4 ~ ~ ( CH2) n--C--oR5 -(CH2) n~ X

R4 denotes hydroqen, C1-C4-alkyl, acyl, R5 denotes C1-C8-alkyl;
X denotes hydrogen, hydroxy, halogen, C1-C6-alkyl, halomethyl, C1-C6-alkoxy, n denotes a number 1, 2, 3, 4, 5 or 6;
R3 denotes hydrogen, C1-C6-alkyl.

Compounds of the general formula 1 wherein 3 2Q33~3 Rl may denote C~-C6-alkyl;
R2 may denote C~-C1O-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, (CH2) n~OR4 ~

R4 may denote hydrogen, methyl, ethyl, C~-C4-alkylcarbonyl, n may denote a number 1, 2, 3, 4 or 5;
R3 may denote hydrogen, Cl-C4-alkyl, are preferred.

Compounds of the general formula 1, wherein Rl may denote ethyl, propyl or butyl, RZ may denote C3-C7-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, -(CH2)n~OR ~
R4 may denote methyl, ethyl, acetyl, trifluoroacetyl, ethylcarbonyl, n may denote a number 1, 2, 3 or 4;
.

R3 may denote hydrogen, methyl, ethyl or propyl, are particularly preferred.

The 2-amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes (2-amino- 7-carbamoyltetralins) of the invention have at least one C atom having a centre of asymmetry, and may also have several centres of asymmetry depending on the substitution pattern and may therefore exist in various stereochemical forms.

The following isomers of substituted 2-amino-7-carbamoyltetralins of the general formula la and lb may be mentioned as examples 2Q~3~3 R 3 1N ~ R H N ` C ,1~`1 N ~ R 2 O \R O
1a lb The invention relates to the individual isomers, mixtures thereof and the corresponding physiologically suitable acid addition salts with inorganic or organic acids. Examples of preferred salts are those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, lactic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid or benzoic acid.

The general definitions are used in the following sense unless varying details are given individually:

Alkyl generally represents an unbranched or branched hydrocarbon radical having 1 to 12 carbon atoms, which may be optionally substituted by a halogen atom or several halogen atoms - preferably fluorine -, which may be the same or different, lower alkyl radicals being preferred. Lower alkyl generally represents a branched or unbranched hydrocarbon radical having 1 to about 6 carbon atoms. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl may be mentioned as examples.

Alkenyl generally represents a straight-chain or branched hydrocarbon radical having 3 to 6 carbon atoms 2~3~3~3 and having one or several, preferably with one double bond, which may be optionally substituted by a halogen atom or several halogen atoms - preferably fluorine -, which may be the same or different. A lower alkenyl radical having 3 to about 4 carbon atoms and one double bond is preferred. An alkenyl radical having 3 or 4 carbon atoms and one double boncl is particularly preferred. Allyl, but-2-enyl, but-3-enyl, isopropenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl and isooctenyl may be mentioned as examples.

Alkynyl generally represents a straight-chain or branched hydrocarbon radical having 3 to 6 carbon atoms and having one or more, preferably with one triple bond.
A lower alkynyl radical having 3 to about 4 carbon atoms and one triple bond and which may be optionally substituted by a halogen atom - preferably fluorine -or several halogen atoms which may be the same or different, is preferred. An alkynyl radical having 3 carbon atoms and one triple bond is particularly preferred. Propargyl and but-2-ynyl may be mentioned as examples.

Acyl generally represents benzoyl or alkylcarbonyl radicals - such as straight-chain or branched lower alkyl groups having 1 to about 6 carbon atoms which are bonded via a carbonyl group, wherein the alkyl radical may be substituted optionally by one or more halogen atom(s) which may be the same or different. Alkyl radicals having up to 4 carbon atoms are preferred. The following may be mentioned as examples: acetyl, trifluoroacetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.

An alkoxycarbonyl radical having 1 to 2 carbon atoms in the alkyl radical is particularly preferred. The 6 2~33~2~
following alkoxycarbonyl radicals may be mentioned as examples: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

Alkoxycarbonyl may be represented for example by the formula -C-O-Alkyl o Alkyl thus represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. A lower alkoxycarbonyl radical having 1 to 6 carbon atoms is preferred. An alkoxycarbonyl radical having 1 to 4 carbon atoms in the alkyl radical is particularly preferred. The following alkoxycarbonyl radicals may be mentioned as examples: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

Unless otherwise stated, halogen denotes fluorine, chlorine, bromine and to a lesser extent iodine.

Pharmacoloqical characteristics The novel compounds or their physiologically acceptable acid addition salts have valuable pharmacological properties and have effects on high blood pressure and heartbeat rate and on prolactin secretion, and in particular on the central nervous system. The presynaptic dopamine antagonistic effect of the compounds of the invention with simultaneous postsynaptic dopamine antagonistic effect should be emphasised in particular.

2~33~23 ~y way of example the effect on the inhibition of ~opamine synthesis was therefore determined for the compounds A: 7-carbamoyl-2-(N,N-dipropylamino)-1,2,3,4-tetrahydronaphthalene hydrochloride B: 2-(N,N-dipropylamino)-7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride C: 2-(N-allyl-N-propylamino)-7-carbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride D: 2-(N-allyl-N-propylamino)-7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride E: 2-(N-butyl-N-propylamino)-7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride F: 7-methylcarbamoyl-2-(N-phenylethyl-N-propylamino)-1,2,3,4- tetrahydronaphthalene hydrochloride G: 2-(N-butyl-N-propylamino-7-carbamoyl-1,2,3,4-tetrahydronaphthale hydrochloride Yp: 221-223C) to investigate the influence of presynaptic dopaminergic neurones. The effect on postsynaptic dopamine receptors was determined in the monkey (MPTP model).

(In the following tables, the letters assigned to the compounds are used instead of the compound names -optionally supplemented by the detail of the optical isomer (+) or (-)) Determination of the inhibition of dopamine svnthesis The methods are carried out in accordance with J.R.

2Q33~

Walters and R.H.Roth [Naunyn - Schmiedeberg's Arch.
Pharmacol. 296, (1976) 5]: For this 5 animals each received 10 mg/kg of the substance to be investigated subcutaneously. After 5 minutes, 750 mg/kg of ~-butyrolactone are administered intraperitoneally to exclude the influence of postsynaptic feedback loops on the rate of dopamine synthesis as a result of the blocking of the presynaptic pulse line. The administration of ~-butyrolactone leads to a considerable increase in the DOPA or dopa~ine synthesis.
200 mg/kg of 3-hydroxybenzylhydrazine hydrochloride are administered intraperitoneally after a further 5 minutes to inhibit decarboxylation of DOPA. 40 minutes after administration of the substance, the animals are killed and the Corpus striatum is sectioned. The DOPA content is measured with the aid of HPLC with electrochemical detection (standard: dihydroxybenzylamine).

The percentage inhibition of the accumulation of Dopa stimulated by ~-butyrolactone effected as a result of the test substance is determined compared to the control animals treated with 0.9 per cent sodium chloride solution.

The results of this experiment are compiled in the following table:

Substance Dosage Inhibition of accu~ 3f (mg/kg Dopa in % compared to controls subcutaneously) treated with sodium chloride .

(+)-A 10 go (+)-B 10 75 (+)-C 10 83 (+)-D 10 76 (+)-E 10 ~4 (+)-F 10 85 (+)-G 10 85 Determination of the ~ostsyna~tic dopaminerqic effect usinq MPTP model The pharmacological properties of the neurotoxin l-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) [J.W. Langston, P.
Bollard, J.W. Tetrud and I. Irwin, Science 219, (1983) 979]
enable it to be used in the animal model for Parkinson's disease.

The irreversible neurological clinical picture triggered by MPTP in the human and in the monkey to a large extent has similar clinical, pathological, biochemical and pharmacological expression to idiopathic Parkinson's disease [S.D. Markey, J.N. Johannessen, C.C. Chivek, R.S. Burns and M.A. Herkenham, Nature 311, (1984) 464]. The cause of this convincing agreement is the fact that MPTP selectively destroys small groups of dopaminergic nerve cells in the substantia nigra of the brain which are also destroyed by degenerative processes in naturally occurring Parkinson's disease.

There is the possibility that the cause of idiopathic Parkinson's disease is the MPTP produced in the organism or a similar chemical compound [S.H. Snyder, Nature 311 (1984) 514]. The clinical expression oE the MPTP Parkinson picture has hitherto only been detected in monkeys as well as in humans - this is possibly the result of the specific metabolism of MPTP.

The MPTP model realised in the Rhesus monkey is therefore suitable for testing the effect of postsynaptic substances having dopamine antagonistic effect.

For this purpose, Rhesus monkeys receive MPTP in total dosages up to about 6 mg/kg of body weight until the following symptoms appear: the animals become akinetic and are not in a position to take water and food. They show a typical bent stance; occasionally cataleptic conditions occur. The extremities have rigor which is interrupted during passive movement of clonic spasms.

Dopamine agonists, such as B-HT 920, Levadopa or Apomorphine lead to temporary relief of the condition picture for the period 4 to 5 hours for a single dosage of 100 g/kg intramuscularly. Then the symptoms described above appear once again.

After intramuscular administration of the compounds of the invention (0.1 - 3.0 mg/kg) there is no observable improvement or even relief of the condition picture in the monkeys treated with MPTP. It was even possible to observe antagonisation of the relief of symptoms similar to Parkinson's disease caused by B-HT 920. The animals remain bradykinetic during the administration of 0.1 - 3.0 mg/kg of the compounds of the invention together with 0.1 mg/kg of B-HT 920 and furthermore, are not in a position to take water and food. It may be concluded from this that these substances have a postsynaptic dopamine antagonistic effect.

The results are compiled in the following table:

Substance Dosage Effect A 3 mg/kg Antagonisation of B-HT 920 B 3 mg/kg Antagonisation of B-HT 920 (+)-B 1 mg/kg Antagonisation of B-HT 920 (+)-C 3 mg/kg Antagonisation of B-HT 920 (+)-D 1 mg/kg Antagonisation of B-HT 920 * 0.1 mg of B-HT 920 per kg of body weight The preparation of the compounds of the invention is achieved in accordance with the synthetic scheme below, the individual steps of which are described in detail below:

2 Q ~ .~ ~3 2 3 i H2~`.' ~ ~R
~ R 2 NC~N~R2 O ' ~ ~ R

& ~ R~
0 1i ~ R2 H2N ~C~N~Rl HN ~C J~N~R1 lia H 0 13b H2N `C~l~N~RRZ N/R2 t4b 14a 12 2 ~3 3 3 e~ 2 3 Preparation Processes The 2,7-diamino-1,2,3,4-tetrahydronaphthalene (2) used as starting material may be prepared in accordance with methods known in the literature [S. Chiavarelli and G.
Settimj, Rend. ist. super. sanita 22 (1959) 508;
Chemical Abstracts 54 (1960) 2281 g] and may be separated into the two enantiomers using the conventional methods - for example via the corresponding tartaric acid sal_s.

II
The protection of the amino function (Rs) required for further synthesis can be achieved using the methods known from the state of the art [M. Bodanszky, Principles of Peptide Synthesis, Springer-Verlag, Berlin 1984, page 84; T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York N.Y. 1981, page 218 ff.; Houben-Weyl, Methoden der organischen Chemie (Methods in organic chemistry), Volume E 4, Georg Thieme Verlag, Stuttgart 1983, page 144], wherein the protection of the amino function using an alkoxycarbonyl - or an aralkoxycarbonyl protective group - particularly using a tert.butoxycarbonyl (BOC) protective group, is preferred.

H2N NH2 H2N N,HS

13 2~3~2`~
Hence, the corresponding 7-amino-2-tert.-butoxycarbonylamido- 1,2,3,4-tetrahydronaphthalenes of the type 3 - optionally in the form of pure enantiomers - can be prepared, for example using methods known per se - using di-tert.butyl pyrocarbonate in the presence of a compound reacting as a base - preferably an organic nitrogen base, such as, for example triethylamine in inert solvents. Organic solvents which do not change under the reaction conditions used serve in general as inert solvents. These preferably include ethers, such as, for example tetrahydrofuran or glycoldimethylether (Glyme).

H N ~[~----~\ N / H N ' `" -- ` N ~
2 \ C- O RS

III
The particular protected racemic or R- or S-diamino-1,2,3,4- tetrahydronaphthalene derivative, preferably the racemic or R- or S-7-amino-2-tert.butoxycarbonylamido-1,2,3,4- tetrahydronaphthalene of the general formula 3 can be converted to the corresponding protected 7-acylamido-2-amino-1,2,3,4-tetrahydronaphthalene derivatives or 7-acylamido-2-tert.butoxycarbonylamido-1,2,3,4-tetrahydronaphthalenes, which fall under the general formula 4, using the processes known from the state of the art, and in particular processes suitable for the preparation of acyl anilides [C. Ferri, Reaktionen der organischen Synthese (Reactions in organic synthesis), Georg Thieme Verlag, Stuttgart 1978, page 222 ff.].

The reaction of the particular protected 2,7-diamino-1,2,3,4- tetrahydronaphthalene derivative or of the 332~

preferred 7-amino-2-tert.butoxycarbonylamido-1,2,3,4-tetrahydronaphthalene with a reactive carboxylic acid derivative in an inert solvent and in the presence of a base, is preferred in this case. Reactive carboxylic acid derivatives are generally understood to mean carboxylic acid halides and carboxylic acid anhydrides which may optionally be substituted by halogen atoms. Carboxylic acid derivatives of this type are known or may be prepared by known methods [Houben-Weyl, Methoden der organischen Chemie (Methods in organic chemistry), Volume VIII and Volume E 5, Georg Thieme Verlag, Stuttgart 1952 or 1985). Aliphatic carboxylic acid bromides, carboxylic acid chlorides or aliphatic carboxylic acid anhydrides are preferred in this case. Acetic acid bromide, acetic acid chloride, acetic acid anhydride and trifluoroacetic acid anhydride are particularly preferred.

All conventional basic compounds, which are suitable for a basic reaction, may be used as bases. These include, for example alkali metal or alkaline earth metal hydroxides, carbonates or alcoholates, and preferably tertiary amines, wherein triethylamine is particularly preferably used.

Organic solvents, which do not change under the reaction conditions used, such as, for example hydrocarbons -such as benzene, toluene, xylene or petroleum fractions - or halogen hydrocarbons - such as, for example methylene chloride, chloroform or carbon tetrachloride, or preferably ethers - such as diethylether, glycoldimethylether (Glyme), diglycoldimethylether (Diglyme) and particularly preferably tetrahydrofuran -are generally used as inert solvents.

2~3~3 --N ~ N / HN ~ N H2 C=O s C=O
RA

IV
The subsequent cleavage of the protective group Rs from the amino function in the 2-position of the tetrahydronaphthalene of the general formula 4 may take place using the processes known from the state of the art - depending on the type of protective group and as a function of the chemical stability of the acyl anilide partial structure [T.W. GrPene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York 1981, page 218 ff.; U. Petersen in Houben-Weyl, Methoden der organischen Chemie (Methods in organic chemistry), Volume E4, Georg Thieme Verlag, Stuttgart 1983, page 144], the acylated 1,2,3,4-tetrahydronaphthalene derivative of the general formula 5 resulting from this.

HN' \ ~ 1 NH2 HN ~ N/ HN ~ 1 N~ 2 C~O C=O R C=O
RA RA RA

S 6a 6b 16 ~ F3 2 3 Numerous processes are also known from the state of the art for the conversion of the primary amino function in the 7-acylamino-2-amino-1,2,3,4-tetrahydronaphthalene derivative of the general formula 5 to a tertiary amine - a tetrahydronaphthalene derivative of the general formula 6b resulting from this [G. Spielberger in Houben-Weyl, Methoden der organischen Chemie (Methods in organic chemistry), Volume XI/l, Georg Thieme Verlag, Stuttgart 1957, page 24; J. March, Advanced Organic Chemistry, 3rd Edition, John Wiley and Sons, New York 1985, page 1153], wherein - in the case where R1 = R2 _ the alkylation takes place in one step and - in the case where R1 is not equal to R2 _ the intermediate product of the type 6a is reacted to give the corresponding tertiary amine 6b.

The further course of the synthesis may make it necessary for a protective group (R2 = Rs) - such as, for example a benzyl protective group - to be introduced under certain circumstances in this synthetic step.

The particular protective group may be cleaved again or replaced with a further substituent in accordance with methods known from the state of the art [T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York N.Y. 1981, page 272 ff. and cited literature]. (See schematic formula page 25, 9 - 13a -14a or 12 - 13b - 14b) The alkylation is preferably carried out using alkyl or aralkyl halides or sulphates, tosylates, methane-sulphonates or trifluoromethanesulphonates - such as, for example methyl halides, ethyl halides, propyl halides, isopropyl halides, butyl halides, benzyl halides, phenethyl halides, o-methylbenzyl halides, m-methylbenzyl halides, p-methylbenzyl halides, 1-17 20~3~23 halogeno-3-phenylpropanes and 1-halogeno-4-phenylbutanes, wherein halogen or halide denotes chlorine, bromine or iodine.

Halides, sulphates, methanesulphonates, trifluoromethanesulphonates or tosylates of this type are known or may be prepared by known methods.

All inert organic solvents which do not change under the reaction conditions or are themselves unable to take part disadvantageously as reactive components in the course of the reaction, are suitable as solvents. These include alcohols - such as methanol, ethanol, propanol or isopropanol - or halogenated hydrocarbons as long as they themselves do not act as an alkylating agent -preferably halogenated hydrocarbons - such as fluorinated hydrocarbons, methylene chloride, chloroform or carbon tetrachloride - and particularly preferably ethers, such as diethyl ether, di-n-butylether, tert.butylmethylether, glycoldimethylether (~lyme), diethyleneglycoldimethylether (Diglyme), tetra-hydrofuran, dioxane and acid amides, such as, for example hexamethylphosphoric acid triamide or dimethylformamide.

It is also possible to use mixtures of the known solvents.

Furthermore, it has proved to be particularly advantageous to use dimethylformamide as the reaction medium in the second alkylation reaction of two-step alkylations for the preparation of tertiary amines which fall under the general formula 6b.

It has also proved to be advantageous to use dimethylformamide likewise as solvent in the one-step conversion of a primary amine of the type 5 into the 18 2~33~3 tertiary amine of the type 6b.

The reaction is preferably carried out in the presence of acid-binding agents - such as, for example alkali metal or alkaline earth metal carbonates or hydrogen carbonates.

VI
In addition, the primary amino function of the diamine of the general formula 5 may be converted into the corresponding secondary or tertiary amine via the route of reductive amination of a suitable aldehyde or ketone or suitable derivatives thereof as a function of the molar ratio of the carbonyl compound used to the 7-acylamino-2-amino-1,2,3,4-tetrahydronaphthalene of the general formula 5. This conversion may take place either directly or via the particular Schiff's bases as intermediate products.

The aldehydes or ketones used as educts are known or may be prepared by known methods ~Aldehydes: Houben-Weyl, Methoden der organischen Chemie (Methods in organic chemistry), Volume VII/1 and E5, Georg Thieme Verlag, Stuttgart 1954 or 1983; Ketones: Houben-Weyl, Methoden der organischen Chemie (Methods in organic chemistry), Volume VII/2a and 2b, Georg Thieme Verlag, Stuttgart 1973 or 1976].

Suitable aldehydes or ketones are embodied, for example by formaldehyde, acetaldehyde, propionaldehyde, acetone, butyraldehyde, benzaldehyde, phenylacetaldehyde, 2-phenylpropionaldehyde, 3-phenylpropionaldehyde, 4-phenylbutyraldehyde.

The Schiff's base is prepared in inert organic solvents, optionally in the presence of a catalyst and if required in the presence of a water-binding agent.

2~3~3 Inert organic solvents, which do not change under the given reaction conditions and themselves do not take part disadvantageously in the course of the reaction, are suitable in this case as inert solvents. These preferably include alcohols - such as, for example methanol, ethanol, propanol or isopropanol - or ethers, such as, for example diethylether, tert.butyl-methylether, di-n-butylether, glycoldimethylether (Glyme), diethyleneglycoldimethylether (Diglyme), tetrahydrofuran - or halogenated hydrocarbons - such as, for example dichloromethane, trichloromethane, tetrachloromethane - or hydrocarbons - such as, for example petroleum fractions, benzene, toluene, xylene -and particularly preferably amides -such as, for example dimethylformamide, acetamide, hexamethylphosphoric acid triamide - or carboxylic acids - such as, for example formic acid or acetic acid - or also mixtures of the solvents mentioned.

Protonic acids are optionally used as catalysts.These preferably include mineral acids, such as, for example hydrochloric acid or sulphuric acid or organic carboxylic acids having 1 to 6 C atoms, which may be optionally substituted by fluorine, chlorine and/or bromine. Examples of acids of this type are formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid or propionic acid. Sulphonic acids having Cl-C4-alkyl radicals or aryl radicals, which may be substituted optionally by halogen atoms - such as, for example methanesulphonic acid, trifluoromethanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid, also fall into the group of preferred acids.

The water produced in the reaction may be removed from the reaction mixture, if required by adding 2~33~3 water-binding agents - such as, for example phosphorus pentoxide - or preferably by means of a molecular sieve, or when mixed with the solvent used, may be removed from the reaction mixture during or after the reaction is completed, for example via the distillation route.

The reaction is generally carried out within a temperature range from +20C to the boiling point of the particular reaction mixture, and preferably within a temperature range from +20C to 100C.

The boiling temperature of the particular azeotrope is preferred for azeotropic distillation of the water formed during the reaction with the solvent or solvent mixture used in each case.

The reaction is generally carried out under normal pressure, but may also be carried out at elevated or reduced pressure.

The 7-acetamido-2-amino-1,2,3,4-tetrahydronaphthalene and the particular carbonyl compound are used in equimolar amounts for the preparation of the secondary amine. The particular carbonyl compound is used in excess for the preparation of the tertiary amine.

The Schiff's bases or enamines or imminium salts produced as intermediate products in the preparation of secondary or tertiary amines may be hydrogenated or reduced either by hydrogen in water or in inert organic solvents, such as alcohols, ethers or halogenated hydrocarbons, or mixtures thereof with hydrogen in the presence of suitable catalysts, or also with complex hydrides - optionally in the presence of a catalyst. The reduction may thus take place in the same reaction medium or even in a further solvent or in a further solvent mixture. In the latter case, the solvent or 2~33323 solvent mixture initially used is preferably removed by means of distillation.

Raney nickel, palladium, palladium on animal charcoal, platinum and preferably palladium on charcoal (10 % Pd content) are examples of catalysts used in the catalytic reduction with hydrogen.

Complex hydrides of boron are preferably used in the reduction using hydrides. Sodium borohydride is particularly preferably used.

All inert organic solvents, which remain unchanged under the reaction conditions selected, or at least largely unchanged, and which do not take part disadvantageously in the course of the reaction, are suitable as solvents.
These include amides - such as, for example dimethylformamide or hexamethylphosphoric acid triamide - or ethers - such as, for example diethylether, tert.butylmethylether, di-n-butylether, glycoldimethylether (Glyme), diglycoldimethylether (Diglyme), tetrahydrofuran and dioxane - and particularly preferably alcohols - for example methanol, ethanol, propanol or isopropanol.
.
In the case of the reduction using hydrogen, the reaction i5 carried out under the reaction conditions known for catalytic hydrogenation as a function of the particular catalysts, solvents and reactants used [K.
Harada in Patai, "The Chemistry of the Carbon- Nitrogen Double Bond", Interscience Publishers, London 1970, page 276 and cited literature; P.N. Rylander, Catalytic Hydrogenation over Platinum Metals, Academic Press, New York 1967, page 123; F. M~ller and R. Schr~ter in Houben-Weyl, Methoden der organischen Chemie (Methods in organic chemistry), Volume XI/l, Georg Thieme Verlag, Stuttgart 1957, page 602; W.S. Emerson, organic 22 2~ ?~2~
Reactions 4 (1949) 174; E.M. Hancock and A.C. Cope, Org.
Synth., Coll. Vol. III (1955) 501; J.C. Robinson and H.R. Snyder, Org. Synth., Coll, Volume III (1955) 717;
D.M. Malcolm and C.R. Noller, Org. Synth., Coll. Volume IV (1963) 603].

The hydrogenation is preferably carried out using palladium on charcoal (10 % Pd content) in methanol within a temperature range from 20 to 50C - particularly preferably within a temperature interval from 25C to 35C - under a hydrogen pressure of preferably 0.1 to 0.O
MPa - particularly preferably under a hydrogen pressure of 0.4 to 0.6 MPa.

When carrying out the process of the invention using complex hydrides, it has proved to be advantageous to react the amine with the corresponding aldehyde or ketone in a one-pot reaction using an inert solvent, preferably a carboxylic acid amide, and particularly preferably using dimethylformamide within a temperature range between 50C and 100C, to distill the solvent off after the reaction is complete under reduced pressure, to dissolve or to disperse the remaining residue in an organic solvent - preferably an alcohol - and to react the mixture with an at least equimolar amount of a reducing agent - preferably a complex hydride and particularly preferably sodium borohydride, to work up the mixture hydrolytically when the reduction is complete, to remove the reaction product from the reaction mixture via an extractive route and to optionally purify it chromatographically or to subject it to a purification step via another route and to isolate it.

VII
The preparation of the compounds of the invention within the framework of reductive amination can be carried out 2~33~23 in a further synthetic variant via the route of a Leukart-Wallach reaction, which is particularly suitable for the preparation of tertiary amides. The reaction conditions for reductive aminations of this type are known tAutorenkollektiv, Organikum, VEB Deutscher Verlag der Wissenschaften, Berlin 1986 (16th Edition) page 491;
C. Ferri, Reactionen der organischen Synthese (Reactions in organic synthesis), Georg Thieme Verlag, Stuttgart 1978, page 133 and cited literature; F. M~ller and R.
SchrUter in Houben-Weyl, Methoden der organischen Chemie (Methods in organic chemistry), Volume XI/l, Georg Thieme Verlag, Stuttgart 1957, page 648].

The tertiary amines of the invention of the general formula 6b may also be obtained by a combination of the preparation methods mentioned.

HN'J~`~`~N/H NJ~X l ~R1 -c=o ~ R22 ~ R2 R/A

6b: R'lH ,R2t H 7 Rl~H, R TH

VIII
The acyl group is cleaved to form a further derivative of the aniline amino function, the diamines of the general formula 7 resulting from this.

The saponification of arylamides of this type is known and may be achieved, for example by reacting a carboxylic acid amide of the general formula 6b with aqueous solutions of alkali metal hydroxides or acids [F. M~ller in Houben-Weyl, Methoden der organischen Chemie (Methods in organic chemistry), Volume XI/l, Georg Thieme Verlag, Stuttgart 1957, page 927 ff. and 24 20~3~23 934 ff.; R.M. Herbst and D. Shemin, Org. Synth., Coll.
Volume II (1943) 491; P.E. Fanta and D.S. Tarbell, Org.
Synth., Coll. Volume III (1955) 661~. The reaction with dilute mineral acids under reflux conditions, wherein the saponification using 2N hydrochloric acid is particularly preferred, which produces the corresponding hydrochlorides immediately in a one-pot reaction, which hydrochlorides may be removed after distilling off the reaction medium and the volatile components of the reaction mixture - preferably under reduced pressure -and after forming a slurry in an organic solvent -preferably an alcohol, wherein ethanol is particularly preferred - and after filtering and drying, is preferred.
IX

~2N)~)~ ~R NC 8 N/R2 The preparation of 2-amino-2-eyano-tetralin derivative 8 is possible - in a manner known per se [Organikum, Deutscher Verlag der Wissenschaften, 17th Edition, Berlin 1988, page 547; Vogel's Textbook of Practical Organic Chemistry, 4th Edition, Longman, London 1978, page 703] - via the route of a so-called Sandmeyer reaetion, by reacting the optionally protected 2,7-diamino- 1,2,3,4-tetrahydronaphthalene derivative of the type 7, for example using potassium cyanide in the presence of copper (I) cyanide.

When earrying out the process of the invention, diazonium salts are generally produeed as intermediate products which may be removed. However, it has proved to be advantageous to carry out the process without removing the intermediate products.

2Q~2~

Water or alcohols - such as methanol, ethanol, propanol or isopropanol - or amides - such as formamide or dimethylformamide, are suitable in this case as inert solvents - water being the preferred solvent.

Mineral acids - such as sulphuric acid or phosphoric acid - are generally used as acids, sulphuric acid being preferred. ~owever, it is also possible to use mixtures of the acids mentioned.

Alkali metal cyanide, such as sodium or potassium cyanide are generally used as nitriles. Potassium cyanide is preferably used.

The reaction is generally carried out within a temperature range from -10C to +150C, preferably from -5C to +50C.

The reaction is generally carried out at normal pressure. It is also possible to carry out the reaction at elevated or reduced pressure (for example from 0.5 to 5 bar).

The process of the invention is generally carried out such that a solution of nitrite in water is initially added to 2-aminotetralin in aqueous sulphuric acid and the reaction solution is then treated with the alkali metal cyanide - preferably potassium cyanide and copper (I) cyanide, optionally dissolved in water. The diazonium salt is generally not removed.

Working up is generally carried out by neutralising the reaction mixture using aqueous ammonia solution or using alkali metal hydroxides or carbonates, and extracting the free bases thus obtained, from which salts thereof may be obtained by reacting with corresponding acids.

26 2~33~3 2 ~ C- ~ ~N ~ Rl __ I'\R2 N C -~ N / R

R2 = HOC ', R
~ ,~,2 O r~

X

On the one hand, the corresponding amides of the type 9 may be obtained by further reacting the 2-amino-7-cyano-1,2,3,4-tetrahydronaphthalene derivative 8, in the presence of methanesulphonic acid and a small amount of water, whereas the saponification of the cyano compound 8 using concentrated hydrochloric acid makes it possible to obtain the corresponding tetraline carboxylic acid derivatives of the type 10. However, it is also possible to use other strong mineral acids which are suitable for the hydrolysis of nitrile groups to give amino carbonyl groups. Saponification reactions of nitriles - per se -are known from the state of the art [P.L. Compagnon and i~ M. Mioque, Ann. Chim. (Paris) [14] 5 (1970) 11-22; P.L.
Compagnon and M. Mioque, ibid. 23-37; E.N. Zil'berman, Russ. Chem. Rev. 31 (1962) 615]. Water is preferably used as reaction medium. The reaction is carried out within a temperature range from 0C to the boiling point of the reaction mixture and under normal pressure. A
temperature in the range from 20~C to 120C is preferred.

0 1 ~ N /Rl 27 2~3~ 3 ¦ H 2N R3 --C ~i~ ~ N /

~R
~,N R3 XI
The tetralin carboxylic acid derivative 10 can be converted to the corresponding acid halide or acid chloride 11 with the aid of methods known in the literature [J. March, Advanced Organic Chemistry, 3rd Edition, New York N.Y. 1985, page 388 and cited literature] advantageously using thionyl chloride [C.
Ferri, Reaktionen der organischen Synthese (Reactions in organic synthesis), Georg Thieme Verlag, Stuttgart 1978, page 192 and cited literature; Organikum, Deutscher Verlag der Wissenschaften, 17th Edition, Berlin 1988, page 422, J.S. Pizey, Synthetic Reagents, Volume 1, 321, Wiley, New York N.Y. 1974]

Subsequent reaction of the resulting acid halide or acid chloride with a primary amine produces the corresponding acid amide 12 - in a manner known per se [C. Ferri, Reaktionen der organischen Synthese (Reactions in organic synthesis), Georg Thieme Verlag, Stuttgart 1978, page 223 and cited literature). The reaction is advantageously carried out in inert solvents.

In this case, inert solvents are generally solvents which do not change under the reaction conditions. These preferably include ethers, such as diethylether, tetrahydrofuran, dioxane or glycoldimethylether, or hydrocarbons, such as benzene, toluene, xylene or 2~33~ ~,3 petroleum fractions, or halogenated hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride. It is also possible to use mixtures of the solvents mentioned.

Amination of the acid halide or chloride of the type 11 is generally carried out within a temperature range from -20C to 100C, preferably -20C to 50C under normal pressure.

O ,f~ ~ ~R ~C,~ l NHR
~ Rs NH2 13a ~CJ~ 1 - O ~`NHR
H NR --Rs HNR3 12 13b XII
Subsequent cleavage of the protective group Rs (R2 = Rs) from the amino function in the 2 position of the tetrahydronaphthalene of the general formula 9 or 12 may take place using the processes known from the state of the art - depending on the type of protective group and as a function of the chemical stability of the carbamoyl partial structure [T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York 1981, page 218 ff.; U. Petersen in Houben-Weyl, Methoden der organischen Chemie (Methods in organic chemistry), Volume E4, Georg Thieme Verlag, Stuttgart 1983, page 144], the 1,2,3,4- tetrahydronaphthalene derivative of the general formula 13a or 13b resulting from this. For 29 2~3~?
example, cleavage of the protective group from compounds of the type 9 and 12 which carry a benzyl radical as protective group at the amino function, is made possible by catalytic hydrogenation over a palladium catalyst, the tetrahydronaphthalene of the type 13a resulting from this.

`~ C ~ N / ~ C ~ i~ N /
\H I \R
HN~R3 HN R3 13a 14 a C~'\~ 1 N / ~C = N /

14b 13b XIII

Numerous processes are also known from the state of the art, as described under V and VI, for the conversion of the secondary amino function in the 2-amino-1,2,3,4-tetrahydronaphthalene derivative of the general formula 14a or 14b to a tertiary amine - a tetrahydronaphthalene derivative of the general formula 14a or 14b resulting from this [G. Spielberger in Houben-Weyl, Methoden der organischen Chemie (Methods in organic chemistry), Volume XI/1, Georg Thieme Verlag, Stuttgart 1957, page 24; J. March, Advanced Organic Chemistry, 3rd Edition, John Wiley and Sons, New York 1985, page 1153], wherein 3 o 2 ~3 u ~
the reducing agent for reductive aminations must be selected so that the carboxylic acid amide function is not attacked. [J. March, Advanced Organic Chemistry, 3rd Edition, John Wiley and Sons, New York N.Y. 1985, page 1095].

On the one hand, alkylation is preferably carried out using optionally derived alkyl or aralkyl halides or sulphates, tosylates, methanesulphonates or trifluoromethanesulphonates - such as, for example methyl, ethyl, propyl, isopropyl, butyl, allyl, propargyl, benzyl, phenethyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, o-methoxybenzyl, m-methoxybenzyl or p-methoxybenzyl halides, l-halogen-3-phenylpropanes, 1-halogen-3-phenyl-prop-2-enes, 1-halogen-4-phenylbutanes, 1-halogen-3-(p- chlorophenyl)-propanes, (2-hal¢ethyl)-methylethers, 1-halogen-3-methoxypropanes, (2-haloethyl)-methylsulphides, (2-haloethyl)- phenylsulphides, (3-halo-propyl)-methylsulphides, methyl-halopropionates, p-(2-haloethyl)-methoxybenzenes, p-(2-haloethyl)-toluenes, p-(2-haloethyl)-methoxybenzenes, (2-haloethyl)-3,4-dimethoxybenzenes, (2-haloethyl)-3-chlorobenzenes, (2-haloethyl)-2,4-dichlorobenzenes, (2-haloethyl)-3,5- dichlorobenzenes or (2-halogen-1-methylethyl)-benzenes, wherein halogen or halide denotes chlorine, bromine or iodine.

Halides, sulphates, trifluoromethylsulphonates or tosylates of this type are known or may be prepared by known methods, wherein when incorporating polyfunctional substituents, which have, for example free phenolic hydroxyl or (carboxylic) acid functions, or correspondingly protected derivatives thereof - such as, 31 2~3~323 for example ethers or esters, which are converted to the required derivatives in a further step in conventional manner - for example by means of ether or ester cleavage or by means of saponification, are initially introduced.
Derivatives of this type include, for example 1-bromo-2-(4-methoxyphenyl -)ethane, ethyl bromoacetate, and ethyl 3-bromopropionate.

Suitable aldehydes or ketones for reductive amination are embodied, for example by formaldehyde, acetaldehyde, propionaldehyde, acetone, butyraldehyde, acrolein, propargylaldehyde, benzaldehyde, phenylacetaldehyde, 2-phenylpropionaldehyde, 3-phenylpropionaldehyde, 3-phenylacrolein, (cinnamic aldehyde), 4-phenylbutyraldehyde, methoxyacetaldehyde, phenoxyacetaldehyde, benzyloxyacetaldehyde, 3-methoxypropionaldehyde, methylmercaptoacetaldehyde, 3-methylmercaptopropionaldehyde, methylmercapto-acetaldehyde, (3,4-dichlorophenyl)-acetaldehyde, 4-methoxyphenylacetaldehyde, (3,4-dimethoxyphenyl)-acetaldehyde and (3,5-dimethoxyphenyl)-acetaldehyde.

Furthermore, the compounds of the invention may be prepared by any other reaction which starts from secondary amines as the amine component - for example via the Michael reaction route. Suitable reactants for these preparation variants embody, for example derivatives of acrylic acid, methacrylic acid or crotonic acid [C. Ferri, Reaktionen der organischen Synthese (Reactions in organic synthesis), G. Thieme Verlag, Stuttgart 1978, page 173 and cited literature;
M.B. Gasc, A. Lattes and J.J. Perie, Tetrahedron 39, (1983) 703; H. Pines and W.M. Stalick in "Base-catalysed Reactions of Hydrocarbons and Related Compounds", Academic Press, New York N.Y. 1977, page, 423; M.S. Gibson in Patai "The Chemistry of the Amino Group", Interscience, New York N.Y. 1968, page 61 ff.].

32 2~33~?3 The tertiary amines of the general formula 14a or 14b according to the invention may also be obtained by combining the preparation methods mentioned.

The following examples should explain the invention without limiting it:

The prefix (+)/(-) given in the preparation examples before the substance terms mean that these syntheses can be carried out both with the laevorotatory as well zs the dextrorotatory optical isomer or with a mixture thereof or the corresponding racemate.

Example 1 Separation of the enantiomeric 2,7-diamino-1,2,3,4-tetrahydronaphthalenes 81.0 g (0.5 mole) of 2,7-diamino-1,2,3,4-tetra-hydronaphthalene are dissolved in 1 litre of a methanol/water mixture (95:5) and heated to 50C. A
solution of 37.5 g (0.25 mole) of L-(+)- tartaric acid in 200 ml of methanol is added at this temperature. The crystals precipitated after a short time are filtered off under suction, boiled off three times with 300 ml of methanol/water mixture (95:5) in each case and recrystallised once from water. The tartrate is then suspended in 70 ml of water, treated with 33 g (0.6 mole) of potassium hydroxide and extracted twice using 70 ml of tetrahydrofuran in each case. After drying the organic phase using magnesium sulphate and filtering off the drying agent, the solvent is removed in vacuo and the residue is distilled under a reduced pressure of 0.08 hPa.

The (+)-2,7-diamino-1,2,3,4-tetrahydronaphthalene is 2~33323 removed as colourless crystals.
Yield: 9.7 g (12 %) Melting polnt: 33 - 34C
Boiling point: 108 - 110C

The (-)-enantiomer is obtained via an analogous route using R-(-)-tartaric acid.
Yield: 9.8 g (12 %) Melting point: 33 - 34C
Boiling point: 108 - 110C

In the following examples the preparation of the pure enantiomer compounds starts in each case from (+)-2,7-diamino-1,2,3,4-tetrahydronaphthalene or from (-)-2,7-diamino-1,2,3,4-tetrahydronaphthalene.

Exam~le 2 (+)/(-)-7-Amino-2-tert.butoxycarbonylamido-1,2,3,4-tetrahydronaphthalene A solution of 28.7 ml (0.12 mole) of di-tert.butyl pyrocarbonate in 140 ml of anhydrous tetrahydrofuran is added dropwise at -10C to a solution of 20 g (0.12 mole) of (+)/(-)-2,7-diamino-1,2,3,4-tetrahydronaphthalene and 17.1 ml (0.12 mole) of triethylamine in 250 ml of anhydrous tetrahydrofuran. The mixture is stirred for 30 minutes at -10C and the reaction solution is then allowed to rise to room temperature. The solvent is distilled off in vacuo and the residue is treated with 500 ml of ethyl acetate and washed twice using 100 ml of water each time. The organic phase is then dried using magnesium sulphate, the solvent is removed in vacuo and the residue is recrystallised from diethylether.
Yield: 25 g (80 %) Melting point: 119 - 121C

34 ~3~Ji3 Example 3 (+)/(-)-7-Acetamido-2-tert.butoxycarbonylamido-1,2,3,4-tetrahydronaphthalene 25 g (95 mmoles) of 7-amino-2-tert.butoxy-carbonylamido-1,2,3,4-tetrahydronaphthalene and 14.5 ml (100 mmoles) of triethylamine are dissolved in 120 ml of anhydrous tetrahydrofuran and the solution is treated with 9.9 ml (105 mmoles) of acetic acid anhydride at room temperature. The mixture is stirred for 1 hour at room temperature and then 450 ml of iced water are added. The precipitated crystals are filtered off under suction and washed using 200 ml of water, 35 ml of acetone and 60 ml of diethylether and dried in a drying oven with circulating air until the weight is constant.
Yield: 25.9 g (93 %) Melting point: 193 - 195C

Exam~le 4 (+)/(-)-7-Acetamido-2-amino-1,2,3,4-tetrahydro-naphthalene hydrochloride 50 g (0.16 mole) of 7-acetamido-2-tert.butoxy-carbonylamido-1,2,3,4-tetrahydronaphthalene are suspended in 300 ml of ethanol. A vigorous HCl gas stream is passed through the suspension for about 10 minutes, the temperature being allowed to rise to 70C.
The suspension is allowed to cool to room temperature, the precipitated crystals are filtered off under suction, washed once using 100 ml of acetone and once using 100 ml of diethylether and dried in a drying oven with circulating air initially at room temperature, then at 80C under normal pressure until the weight is constant.

Yield: 36 g (91 %) Melting point: 260C

Example 5 (+)/(-)-7-Acetamido-2-propylamino-1,2,3,4-tetrahydro-naphthalene hydrochloride (Alkylation) 83.8 g (0.41 mole) of (+)/(-)-7-acetamido-2-amino-1,2,3,4-tetrahydronaphthalene and 75.6 g (0.61 mole) of propyl bromide are dissolved in 900 ml of tetrahydrofuran, treated with 84 g (0.84 mole) of potassium hydrogen carbonate and heated for 7 hours at reflux temperature. A further 75.6 g (0.61 mole) of propyl bromide are then added and the mixture is heated to boiling once again for 7 hours. It is allowed to cool to room temperature,filtered, and the filtrate is concentrated in vacuo, treated with 500 ml of ethyl acetate and extracted using 500 ml of water. The organic phase is dried using magnesium sulphate, concentrated in vacuo after filtering off the drying agent and the remaining residue is chromatographed over silica gel (grain size 0.063 to 0.2 mm) using a mixture of methylene chloride and methanol (80:20). After removal by chromatography, concentrating the eluate in vacuo and reacting the residue with a solution of hydrogen chloride in diethylether, the title compound is precipitated as hydrochloride, filtered off and dried in a drying oven with circulating air until the weight is constant.
Yield: 43.4 g (38 %) Melting point: 171C

ExamPle 6 (+)/(-)-7-Acetamido-2-(N-butylpropylamino)-1,2,3,4-tetrahydronaphthalene hydrochloride 36 2Q3~

7 g (24.8 mmoles) of (+)/(-)-7-acetamido-2-propylamino-1,2,3,4-tetrahydronaphthalene hydrochloride and 12.8 g (93 mmoles) of butyl bromide are dissolved in 80 ml of dimethylformamide, the solution is treated with 10 g (100 mmoles) of potassium hydrogen carbonate and stirred for 9 hours at 80C. The solution is allowed to cool to room temperature, filtered and the filtrate is concentrated in vacuo, treated with 250 ml of water and extracted twice using 200 ml of ethyl acetate in each case. The combined organic extracts are dried using magnesium sulphate and concentrated in vacuo after filtering off the drying agent. The remaining residue is chromatographed over silica gel (grain size 0.063 to 0.2 mm) using a mixture of methylene chloride and methanol (80:20).

After removal by chromatography, concentrating the eluate in vacuo and reacting the residue with a solution of hydrogen chloride in diethylether, the title compound is precipitated as hydrochloride, filtered off and dried until the weight is constant.
Yield: 5.5 g (67 %) Melting point: 208-210C

Example 7 (+)/(-)-7-Acetamido-2-N,N-diethylamino-1,2,3,4-tetrahydronaphthalene hydrochloride (reductive amination using hydrogen) 6.5 g (32 mmoles) of 7-acetamido-2-amino-1,2,3,4-tetrahydronaphthalene and 22 g (500 mmoles) of acetaldehyde are dissolved in 110 ml of methanol and treated with 2.2 g of palladium/charcoal (10 ~ Pd). The solution is hydrogenated for 18 hours in an autoclave at 30C and a hydrogen pressure of 500 kPa. The product is 37 2Q333~3 then filtered off under suction over silica gel and the solvent is distilled off in vacuo. The-residue is then treated with 150 ml of diethyl,ether and washed twice using 60 ml of water in each case. The organic phase is dried using magnesium sulphate, the solvent is removed in vacuo after filtering off the drying agent and the remaining residue is chromatographed (mobile phase:
ethyl acetate/methanol; 80:20) over silica gel (grain size 0.063 - 0.2 mm). After removal by chromatography, the eluate is concentrated and the (+)/(-)-acetamido-2-N,N-diethylamino-1,2,3,4-tetrahydronaphthalene is converted to the hydrochloride using ethereal hydrochloric acid. The crystals are filtered off under suction and dried in a drying oven with circulating air until the weight is constant.
Yield: 1.7 g (18 %) Melting point: > 265C

Exam~le 8 (+)/(-)-7-Amino-2-(N-butyl-N-propylamino)-1,2,3,4-tetrahydronaphthalene dihydrochloride 1.5 g (4.4 mmoles) of (+)/(-)-7-acetamido-2-(N-butyl-N-propylamino-1,2,3,4-tetrahydronaphthalene hydrochloride are heated with 30 ml of 2N HCl for 2 hours at reflux temperature. The solution is then concentrated in vacuo, the residue is treated with 20 ml of ethanol, the crystals are filtered off under suction, washed with ethanol and dried in a drying oven with circulating air until the weight is constant.
Yield: 1.1 g (75 %) Melting point: > 167C

- ~33~3 Exam~le 9 (+)/(-)-7-Cyano-2-(N,N-dipropylamino)-1,2,3,4-tetrahydronaphthalene A solution of 8.5 g (0.12 mole) of sodium nitrite in 50 ml of water is allowed to flow into a solution of 24.6 g (0.1 mole) of 7-amino-2-(N,N-dipropylamino)-1,2,3,4-tetrahydronaphthalene in 50 ml of water and 12.5 ml of concentrated sulphuric acid within a temperature range of -5C to 0C. The mixture is allowed to react for 30 minutes at -5C.

The reaction mixture is then treated with a solution of 40 g (0.6 mole) of potassium cyanide and 20 g (0.2 mole) of copper (I) cyanide in 200 ml of water cooled to -5C, the mixture foaming strongly. After the evolution of gas has receded, the mixture is stirred at room temperature for a further 30 minutes. The reaction solution is rendered alkaline using 400 ml of concentrated ammonia solution. The solution is extracted three times using 400 ml of ethyl acetate each time, the combined organic extracts are washed using 500 ml of water, dried and concentrated in vacuo after removing the drying agent. The residue is distilled in a high vacuum.
Yield: 20.2 g (79 %) Boiling point: 132-135C (0.06 Torr).

The following is prepared in analogous manner to Example 9:

(+)/(-)-2-(N-benzyl-N-propylamino)-7-cyano-1,2,3,4-tetrahydronaphthalene Yield: 58 %
Boiling point: 180-185 (10 3 mbar) 2~33~2' Example 10 (+)/(-)-7-Carbamoyl-2-(N,N-dipropylamino)-1,2,3,4-tetrahydronaphthalene hydrochloride 3.0 g (12 mmoles) of 7-cyano-2-(N,N-dipropylamino)-1,2,3,4-tetrahydronaphthalene are dissolved in a mixture of 18 ml of methanesulphonic acid and 2 ml of water and the reaction mixture is heated for 1 hour at 110C. It is then allowed to cool, the reaction mixture is poured onto ice and rendered alkaline using about 60 ml of concentrated ammonia solution. The solution is extracted twice using 100 ml of ethyl acetate each time, the combined organic extracts are washed using 100 ml of water, dried and concentrated in vacuo. The remaining base is dissolved in acetone and the hydrochloride is precipitated using ethereal hydrochloric acid.
Yield: 3.0 g (81 %) Melting point: 251-253C.

The following are prepared in analogous manner to Example 10:

(2R)-7-carbamoyl-2-(N,N-dipropylamino)-1,2,3,4-tetrahydronaphthalene hydrochloride Yield: 78 %
Melting point: 255C
t~r]D2O = (+) 76.7 (C = l; methanol) (2S)-7-carbamoyl-2-(N,N-dipropylamino)-1,2,3,4-tetrahydronaphthalene hydrochloride Yield: 79 %
Melting point: 252-254C
[~]D20 = -71.9 (C = l; methanol) (+)/(-)-2-(N-benzyl-N-propylamino)-7-carbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride 2~333,~i~
Yield: 65 %
Melting point: 142-144C

Exam~le 11 (+)/(-)-7-~ydroxycarbonyl-2-(N,N-dipropylamino)-1,2,3,4-tetrahydronaphthalene hydrochloride 8.1 g (31.5 mmoles) of 7-cyano-2-(N,N-dipropylamino)-1,2,3,4-tetrahydronaphthalene are treated with 150 ml of concentrated hydrochloric acid and heated for 8 hours under reflux. The reaction mixture is then concentrated in vacuo, the residue is treated with 100 ml of acetone and the crystals thus precipitated are filtered off under suction. The crystals are washed once using 30 ml of cold water and once using 50 ml of acetone and diethylether and then dried in a drying oven at 50DC.
Yield: 6.2 g (63 %) Melting point: 223-226C

Exam~le 12 2-(N,N-Dipropylamino)-7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride 5 g (16 mmoles) of 7-hydroxycarbonyl-2-(N,N-dipropylamino)-1,2,3,4-tetrahydronaphthalene hydrochloride are heated with 1.8 ml (24 mmoles) of thionyl chloride for 30 minutes under reflux and with exclusion of moisture. The excess thionyl chloride is then distilled off in vacuo and 100 ml of dichloroethane is added to the residue. The solution is cooled to 0C
and a solution of 36 g (1.1 moles) of methylamine in 300 ml of absolute tetrahydrofuran is allowed to run in such that the reaction mixture is not heated to a temperature above 10C. The mixture is allowed to react for a further 30 minutes at room temperature, the solvent is removed 41 2033~23 in vacuo and the residue is treated with 150 ml of potassium carbonate solution (20 g of K2CO3 in 150 ml of water). The mixture is extracted three times using 150 ml of ethyl acetate each time, the combined organic extracts are washed using 150 ml of water, dried and concentrated in vacuo after removing the drying agent.
The remaining base is dissolved in acetone and is treated with ethereal hydrochloric acid to precipitate the hydrochloride.
Yield: 4.6 g (88 %) Melting point: 222-224C

The following are prepared in analogous manner to Example 12:

7-ethylcarbamoyl-2-(N,N-dipropylamino)-1,2,3,4-tetrahydronaphthalene hydrochloride Yield: 92 %
Melting point: l9S-196C

(+)-2-(N,N-dipropylamino)-7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride Yield: 75 %
Melting point: 233- 2 35C
t~]D20 = +73.5 (c=l; methanol) (-)-2-(N,N-dipropylamino)-7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride Yield: 71 %
Melting point: 233-235C
[~]D20 = -73.6 (c=l; methanol) 42 2Q333~3 Example 13 (2R)-7-Carbamoyl-2-propylamino-1,2,3,4-tetrahydronaphtha lene hydrochloride 28.5 g (85 mmoles) of (2R)-7-carbamoyl-2-(N-benzyl-N-propylamino)-1,2,3,4-tetrahydronaphthalene are dissolved in 500 ml of methanol and treated with 4 g of palladium/charcoal (10 %). The solution is hydrated for 5 hours in an autoclave at 20C and a hydrogen pressure of 5 bar. The uptake of hydrogen is completed when the calculated amount is consumed. The catalyst is removed under suction over silica gel and the filtrate is concentrated in vacuo. The remaining base is dissolved in ethanol and the hydrochloride is precipitated using ethereal hydrochloric acid.
Yield: 15.4 g (68 %) Melting point: 242-244C
[~]D20 = (+) 70.7 (C = l; methanol) The following are prepared in analogous manner to Example 13:

(2S)-7-carbamoyl-2-propylamino-1,2,3,4-tetrahydro-naphthalene hydrochloride Yield: 73 %
Melting point: 244-246C
[~]D20 = -68.9 (C = l; methanol) (+)/(-)-7-carbamoyl-2-propylamino-1,2,3,4-tetrahydro-naphthalene hydrochloride Yield: 97 %
Melting point: 255-257C

(+)-7-methylcarbamoyl-2-propylamino-1,2,3,4-tetrahydro-naphthalene hydrochloride Yield: 91 %

2 ~

Melting point: 245-247C
[~]D20 = +60.5 (c=l; methanol) ExamPle 14 (2R)-2-(N-Allyl-N-propylamino)-7-carbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride 7.3 g (27 mmoles) of (2R)-7-carbamoyl-2-propylamino-1,2,3,4-tetrahydronaphthalene hydrochloride, 6.4 ml (74 mmoles) of allyl bromide and 5.6 g (41 mmoles) of potassium carbonate are stirred in 73 ml of dimethylformamide for 4 hours at 35C. The reaction mixture is then concentrated in vacuo, the residue is treated with 200 ml of water and extracted twice using 150 ml of ethyl acetate each time. The combined organic extracts are washed using 100 ml of water, dried and concentrated in vacuo after removing the drying agent.
The residue is recrystallised once from ether. The purified base is then dissolved in methanol and the hydrochloride is precipitated using ethereal hydrochloric acid.
Yield: 67 %
Melting point: 233-235C
[~]D20 = -81.1 (C = l; methanol) The following are prepared in analogous manner to Example 14:

(-)-2-(N-allyl-N-propylamino)-7-carbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride Yield: 62 %
Melting point: 228-233C
[~]D20 = -80.1 (c=l; methanol) (+)/(-)-7-carbamoyl-2-(N-ethyl-N-propylamino)-1,2,3,4-tetrahydronaphthalene hydrochloride 44 2~?f ~2~
Yield: 72 %
Melting point: 168-170C

(+)-2-(N-allyl-N-propylamino)-7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride Yield: 72 ~
Melting point: 223-225C
t~]D20 = +83.9 (c=1; methanol) (+)-2-(N-butyl-N-propylamino)-7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride Yield: 84 %
Melting point: > 100C decomposition [~]D20 = +70.9 (c=l; methanol) (+)-7-methylcarbamoyl-2-(N-phenylethyl-N-propylamino)-l, 2,3,4-tetrahydronaphthalene hydrochloride Yield: 69 %
Melting point: >80C decomposition [~]D20 = +50.5 (c=l; methanol) ExamPle 15 (+)-2-(N-Methoxycarbonylethyl-N-propylamino)-7-methylcar bamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride 1.5 g (S.3 mmoles) of (2R)-2-propylamino-7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride and 1.4 g of potassium carbonate are dissolved in 15 ml of methanol, treated with 2 ml of methyl acrylate and heated at 50C. The mixture is heated for a total of 36 hours, a further 2 ml of acrylate being added every 9 hours. The reaction mixture is then concentrated in vacuo, the residue is treated with 5p ml of water and extracted twice using 50 ml of ether each time. The combined organic extracts are dried, concentrated and the residue is filtered over 2~3~ 3 a short silica gel column (about 5 g of silica gel and 200 ml of ethyl acetate). The appropriate fractions are concentrated and the hydrochlorlde is precipitated using ethereal hydrochloric acid.
Yield: 1.4 g = 71 %
Melting point: > 65C decomposition [ ~ ] D2 0 = + 66.8 (c=1; methanol) Pharmaceutical formulations which contain one or more compounds of the invention, in addition to non-toxic, inert pharmaceutically suitable excipients, or which consist of one or more active ingredients of the invention, are part of the present invention, as well as processes for the preparation of these formulations.

Pharmaceutical formulations in dosage units are also part of the present invention. This means that the formulations are present in the form of individual components, for example tablets, dragees, capsules, pills, suppositories and ampoules, the active ingredient content of which corresponds to a fraction or a multiple of a single dosage. The dosage units may contain, for example 1, 2, 3 or 4 single dosages or 1/2, 1/3 or 1/4 of a single dosage. A single dosage preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dosage.

Non-toxic, inert pharmaceutically suitable excipients are understood as meaning solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of every type.

Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions may be mentioned as preferred pharmaceutical formulations.

2~33~

Tablets, dragees, capsules, pills and granules may contain the active ingredient or ingredients in addition to the conventional excipients; such as ta) fillers and extenders, for example starches, lactose, sucrose, glucose, mannitol and silicic ac:Ld, (b) binding agents, for example carboxymethylcellulose, alginates, gelatines, polyvinylpyrrolidone, (c) moisture retention agents, for example glycerol; (d) activating agents, for example agar-agar, calcium carbonate and sodium carbonate, (e) solution retarders, for example paraffin and (f) resorption accelerators, for example quaternary ammonium compounds, (g) wetting agents, for example cetyl alcohol, glycerol monostearate, (h) adsorption agents, for example kaolin and bentonite and (i) lubricants, for example talcum, calcium stearate and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules may be provided with the conventional coatings and shells, optionally containing opaqueing agents, and may also be composed such that they release the active ingredient or ingredients optionally in a delayed manner only or preferably in a certain part of the intestinal tract, it being possible for polymer substances and waxes to be used as examples of embedding compositions.

The active ingredient or ingredients may also be present in microencapsulated form optionally with one or more of the excipients given above.

Suppositories may contain the conventional water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example Cl~-alcohol with C~5-fatty acid) or mixtures of these substances, in addition to the active ingredient or ingredients.

2 ~ ;, 3 Solutions and emulsions may cont:ain the conventional excipients, such as solvents, solution promoters and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cotton seed oil, peanut oil, corn seed oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, in addition to the active ingredient or ingredients.

The solutions and emulsions may also be present in sterile and blood isotonic forms for parenteral application.

Suspensions may contain the conventional excipients, such as licluid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and sorbitan esters, microcrystalline cellulose, aluminium methahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances, in addition to the active ingredient or ingredients.

The formulation forms mentioned may also contain colourants, preservatives and smell and taste-improving additives, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.

The therapeutically active compounds should be present in the pharmaceutical formulations listed above, preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95 weight % of the total mixture.

48 2~323 The pharmaceutical formulations listed above may also contain further pharmaceutically active ingredients in addition to the compounds of the invention.

The preparation of the pharmaceutical formulations listed above is carried out in a conventional manner by known methods, for example by mixing the active ingredient or ingredients with the excipient or excipients.

The formulations mentioned may be administered orally, rectally, or parenterally (intravenously, intramuscularly, subcutaneously). Examples of suitable formulations for therapy are injection solutions, solutions and suspensions.

In general it has proved to be advantageous in human medicine to administer the active ingredient or ingredients of the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, optionally in the form of several single dosages, to achieve the required results. A
single dosage contains the active ingredient or ingredients of the invention preferably in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight. However, it may be necessary to deviate from the dosages mentioned, and to do so as a function of the type and the body weight of the object to be treated, of the type and the severity of the disease, of the type of formulation and the application of the medicament, as well as the period or interval within which administration is carried out.

In some cases it may thus be sufficient to manage with less than the amount of active ingredient mentioned above, whereas in other cases the amount of active 203~?~2~

ingredient listed above must be exceeded. Any expert may easily determine the optimum dosage required in each case and type of application of the active ingredients on the basis of his expert knowledge.

The following preparation examples should explain the invention without limiting it:

Tablets 1. The tablet contains the following components:
Active ingredient according to formula 1 0.020 parts Stearic acid 0.010 "
Dextrose 1.890 "

Total 1.920 parts Pre~aration:
The substances are mixed together in known manner and the mixture is pressed to form tablets, each of which weighs 1.92 g and contains 20 mg of active ingredient.

2. Ointment The ointment is composed of the following components:

Active ingredient according to formula 1 50 mg Neribas ointment (commercial product Scherax) ad 10 g Preparation:

The active ingredient is ground with 0.5 g of ointment base and the remaining base is mixed in intimately to form an ointment gradually in small amounts of 1.0 g. A
0.5 % strength ointment is obtained. The distribution of the active ingredient in the base is monitored optically under the microscope.

2~3~3 3. Cream Composition:
Active ingredient according to formula 1 50 mg Neribas ointment (commercial product Scherax) ad 10 g Preparation The active ingredient is ground with 0.5 g of cream base and the remaining base is gradually worked in using a pestle in small amounts of 1.0 g. A 0.5 % strength cream is obtained. The distribution of the active ingredient in the base is monitored optically under the microscope.

4. AmPoule solution Composition:
Active ingredient according to formula 1 1.0 mg Sodium chloride 45.0 mg Water per injection ad 5.0 ml Preparation:

The active ingredient is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added as isotonic agent. The solution obtained is filtered until free of pyrogen and the filtrate is filled under aseptic conditions into ampoules which are then sterilised and fused. The ampoules contain 1 mg, 5 mg and 10 mg of active ingredient.

51 ~3~.3 5. Suppositories Each suppository contains:
Active ingredient according to formula 1 1.0 parts Cocoa butter (melting point: 36-37C) 1,200.0 parts Carnuba wax 5.0 parts Preparation Cocoa butter and carnuba wax are melted together. The active ingredient is added at 45C and the mixture is stirred until a complete dispersion is produced.
The mixture is poured into moulds of appropriate size and the suppositories are suitably packed.

Claims (10)

Patent claims

1. 2-Amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes (2-amino-7-carbamoyltetralins) of the general formula 1 wherein R1 may denote C1-C8-alkyl;
R2 may denote hydrogen, C1-C12-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, -(CH2)n-OR4, -( CH2) n-SR4, -(CH2)n R4 may denote hydrogen, C1-C4-alkyl, acyl, R5 may denote C1-C8-alkyl;
X may denote hydrogen, hydroxy, halogen, C1-C6-alkyl, halomethyl, C1-C6-alkoxy, n may denote a number 1, 2, 3, 4, 5 or 6;
R3 may denote hydrogen, C1-C6-alkyl, enantiomers thereof, mixtures of the enantiomers, the racemate and acid addition salts thereof.

2. 2-Amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes (2-amino-7-carbamoyltetralins) of the general formula 1 wherein R1 may denote C1-C6-alkyl;
R2 may denote C1-C10-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, (CH2)n-OR4, R4 may denote hydrogen, methyl, ethyl, C1-C4-alkylcarbonyl, n may denote a number 1, 2, 3, 4 or 5;
R3 may denote hydrogen, C1-C4-alkyl, enantiomers thereof, mixtures of the enantiomers, the racemate and acid addition salts thereof.

3. 2-Amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes (2-amino-7-carbamoyltetralins) of the general formula 1 wherein R1 may denote ethyl, propyl, butyl, R2 may denote C3-C7-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, -(CH2)n-OR4, R4 may denote methyl, ethyl, acetyl, trifluoroacetyl, ethylcarbonyl, n may denote a number 1, 2, 3 or 4;
R3 may denote hydrogen, methyl, ethyl or propyl, enantiomers thereof, mixtures of the enantiomers, the racemate and acid addition salts thereof.

4. (+)/(-)-7-Carbamoyl-2-(N,N-dipropylamino)-1,2,3,4-tetrahydronaphthalene, enantiomers thereof, mixtures of the enantiomers, racemates and acid addition salts thereof.

5. (+)/(-)-2-(N,N-Dipropylamino)-7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene, enantiomers thereof, mixtures of the enantiomers, racemates and acid addition salts thereof.

6. 2-Amino-7-cyano-1,2,3,4-tetrahydronaphthalenes of the general formula 8 as intermediate compounds, wherein R1 and R2 have the meanings mentioned in claim 1.

(8)

7. Pharmaceutical formulations characterised by containing a compound according to one of claims 1 to 5.

8. Use of compounds according to one of claims 1 to 5 as medicaments.

9. Use of compounds according to one of claims 1 to 5 in the preparation of pharmaceutical formulations for the treatment of diseases which are based on a disorder of the dopaminergic systems.

10. Processes for the preparation of 2-amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes of the general formula 1 characterised in that in the case a) R1 and R2 have the meaning given in claim 1 and R3 denotes hydrogen - (+)- or (-)-2,7-diamino-1,2,3,4-tetrahydronaphthalenes of the general formula 7 (7) wherein R1 and R2 have the meaning given in claim 1 with the exception of hydrogen, wherein R2 may also represent a protective group, is reacted with an alkali metal cyanide in the presence of copper (I) cyanide in a manner known per se, the resulting 2-amino-7-cyano-1,2,3,4-tetrahydronaphthalene derivative of the general formula 8 (8) is reacted with an acid in the presence of water under reaction conditions known per se, methanesulphonic acid being preferred as acid, an optionally present protective group (R2 = Rs) from the resulting 2-amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalene derivative of the general formula 9 (9) is cleaved and the resulting tetralin derivatives of the general formula 13a (13a) are optionally reacted with an alkylating agent of the general formula 15 R2-Y (15) wherein Y denotes a halogen, a sulphate, a tosylate, a methanesulphonate, a halomethanesulphonate radical or a further group which can be substituted by an amino function, and R2 has the meaning given in claim 1 with the exception of hydrogen, under reaction conditions known per se either in an inert solvent or solvent mixture - optionally in the presence of a base, and optionally previously protected functional groups are converted to the unprotected groups, and in the case of the preparation of the different acid addition salts, are reacted with the corresponding acids and converted to their acid addition salts, or the tetrahydronaphthalene derivatives of the general formula 13a are reacted with a carbonyl compound of the general formula 16 (16) wherein R denotes hydrogen or an alkyl group and -CHR'R'' = R2, and R2 has the meaning given in claim 1, under reducing conditions - optionally in the presence of a catalyst - in an inert solvent, and optionally previously protected functional groups are converted to the unprotected groups, and in the case of the preparation of the different acid addition salts, are reacted with the corresponding acids and the end product is removed;

b) R1 and R2 have the meaning given in claim 1 and R3 has the meaning given in claim 1 with the exception of hydrogen - (+)- or (-)-2,7-diamino-1,2,3,4-tetra-hydronaphthalenes of the general formula 7 (7) are reacted with an alkali metal cyanide in the presence of copper (I) cyanide in a manner known per se, the resulting 2-amino-7-cyano-1,2,3,4-tetrahydronaphthalene derivative of the general formula 8 (8) is saponified to the carboxylic acid derivative of the general formula 10 (10) under reaction conditions known per se in the presence of an acid, the resulting tetralin carboxylic acid derivative is converted to an acid halide, particularly preferably to the acid chloride of the qeneral formula 11 using methods known per se, and then reacted with an amine of the general formula 17 H2NR3 (17) wherein R3 has the meaning given in claim 1 with the exception of hydrogen, under reaction conditions known per se to give the corresponding acid amide of the general formula 12, an optionally present protective group (R2 = R3) from the resulting 2-amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalene derivative of the general formula 12 (12) is cleaved and the resulting tetralin derivative of the general formula 13b (13b) is optionally reacted with an alkylating agent of the general formula 15 R2-y (15) wherein Y denotes a halogen, a sulphate, a tosylate, a methanesulphonate, a halomethanesulphonate radical or a further group which can be substituted by an amino function, and R2 has the meaning given in claim 1 with the exception of hydrogen, under reaction conditions known per se either in an inert solvent or solvent mixture - optionally in the presence of a base, and optionally previously protected functional groups are converted to the unprotected groups, and in the case of the preparation of the different acid addition salts, is reacted with the corresponding acids and converted to their acid addition salts or the tetrahydronaphthalene derivatives of the general formula 13a are reacted with a carbonyl compound of the general formula 16 (16) wherein R denotes hydrogen or an alkyl group and -CHR'R'' = R2 and R2 has the meaning given in claim 1, under reducing conditions - optionally in the presence of a catalyst - in an inert solvent, and optionally previously protected functional groups are converted to the unprotected groups, and in the case of the preparation of the different acid addition salts, is reacted with the corresponding acids, and the end product is removed.