WO1991001297A1 - 2-amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes, process for preparing them and their use as drugs - Google Patents

Abstract

The invention relates to new 2-amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes, a process for preparing them and their use as drugs.

Description

 2-Amino-7-carbamoγl-1,2,3,4-tetrahydronaphthalenes, process for their preparation and their

 Use as a medicine

The invention relates to new 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-carbamoyltetraline)

 correspond to the general formula 1:

worin

wherein

R ¹ C ₁ -C ₈ alkyl;

R ^{2 is} hydrogen, C ₁ -C ₁₂ alkyl,

C ₃ -C ₆ alkene ₄ yl, C ₃ -C ₆ alkynyl,

- (CH ₂ ) _n -OR ⁴ , - (CH ₂ ) _n -SR ⁴ ,

R ^{4 is} hydrogen, C ₁ -C ₄ alkyl, acyl,

R ^{5 is} C ₁ -C ₈ alkyl;

 X is hydrogen, hydroxy, halogen,

C ₁ -C ₆ alkyl, halomethyl,

C ₁ -C ₆ alkoxy,

n is a number 1, 2, 3, 4, 5 or 6; R ^{3 is} hydrogen, C ₁ -C ₆ alkyl Compounds of the general formula 1 are preferred

R ¹ C ₁ -C ₆ alkyl;

R ² C _i -C ₁₈ alkyl, C ₃ -C ₄ alkenyl,

C ₃ -C ₄ alkynyl, (CH ₂ ) _n -OR ⁴ ,

R ^{4 is} hydrogen, methyl, ethyl,

C ₁ -C ₄ alkylcarbonyl,

 n is a number 1, 2, 3, 4 or 5;

R ^{3 can be} hydrogen, C ₁ -C ₁ alkyl.

Compounds of are particularly preferred

general formula 1, wherein

R ^{1 is} ethyl, propyl, butyl,

R ² C ₃ -C ₇ alkyl, C ₃ -C ₄ alkenyl,

C ₃ -C ₄ alkynyl, - (CH ₂ ) _n -OR ₄ ,

 R is methyl, ethyl, acetyl,

 Trifluoroacetyl, ethylcarbonyl,

 n is a number 1, 2, 3 or 4;

R ³ can denote hydrogen, methyl, ethyl, propyl.

The 2-amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes (2-amino-7-carbamoyltetraline) according to the invention have at least one carbon atom with one

Center of asymmetry and depending on

Substitution patterns also have several centers of asymmetry and therefore in different

stereochemical forms exist.

The following isomers are examples of

Substituted 2-amino-7-carbamoyltetralines of the general formula la and lb called

The invention relates to the individual

 Isomers, their mixtures and the corresponding physiologically suitable acid addition salts with inorganic or organic acids. For example, salts with are preferred

 Hydrochloric acid, hydrobromic acid,

 Sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid,

 Benzenesulfonic acid, lactic acid, malonic acid,

 Succinic acid, maleic acid, fumaric acid,

 Malic acid, tartaric acid, citric acid or

 Benzoic acid.

Unless otherwise specified, the general definitions are used in the following sense:

Alkyl generally represents an unbranched or branched hydrocarbon radical having 1 to 12 carbon atoms, which may optionally be substituted by one or more halogen atoms, preferably fluorine, which can be identical or different from one another, lower alkyl radicals being preferred. Lower alkyl generally represents a branched or unbranched hydrocarbon radical having 1 to about 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.

Alkenyl generally represents one

straight chain or branched

 Hydrocarbon radical with 3 to 6 carbon atoms and with one or more, preferably with a double bond, which may be with a

Halogen atom or several halogen atoms - preferably fluorine - which may be the same or different from one another. A lower alkenyl radical having 3 to about 4 carbon atoms and a double bond is preferred.

An alkenyl radical having 3 or 4 carbon atoms and a double bond is particularly preferred. Examples include allyl, 2-butenyl, 3-butenyl,

Isopropenyl, pentenyl, isopentenyl, hexenyl,

Called isohexenyl, heptenyl, isoheptenyl, octenyl and isooctenyl.

Alkynyl generally represents one

straight chain or branched

Hydrocarbon radical with 3 to 6 carbon atoms and with one or more, preferably with a triple bond. A lower alkynyl radical having 3 to about 4 carbon atoms and a triple bond, which can optionally be substituted by one halogen atom - preferably fluorine - or more halogen atoms, which are the same as or

 can be different. An alkynyl radical with 3 carbon atoms and a triple bond is particularly preferred. Examples include propargyl and butynyl (2).

Acyl generally represents benzoyl or alkylcarbonyl radicals - such as straight-chain or

 branched lower alkyl with 1 to about 6

 Carbon atoms which are bonded via a carbonyl group, where the alkyl radical can optionally be substituted by one or more halogen atoms, which may be the same or different from one another. Alkyl radicals having up to 4 carbon atoms are preferred. Examples include: acetyl, trifluoroacetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.

An alkoxycarbonyl radical having 1 to 2 carbon atoms in the alkyl radical is particularly preferred. As

Examples include the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl,

Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

dargestellt werden. Alkyl steht hierbei für einen geradkettigen oder verzweigten Kohlenwasserstoffrest mit 1 bis 12 Kohlenstoffatomen. Bevorzugt wird ein Alkoxycarbonyl can, for example, by the formula

being represented. Alkyl stands for a straight-chain or branched hydrocarbon radical with 1 to 12 carbon atoms. A is preferred

Niederalkoxycarbonylrest with 1 to 6

Carbon atoms. An alkoxycarbonyl radical having 1 to 4 carbon atoms in the alkyl radical is particularly preferred. The following are examples

Alkoxycarbonyl radicals called: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,

Isopropoxycarbonyl, butoxycarbonyl or

Isobutoxycarbonyl.

Unless otherwise stated, halogen means fluorine, chlorine, bromine and secondly iodine.

Pharmacological characterization

The new compounds or their physiologically acceptable acid addition salts

valuable pharmacological properties and have effects on high blood pressure and

Heart rate as well as on prolactin secretion and especially on the central nervous system. Of particular note are the presynaptic

Dopamine-agonistic activity of the compounds according to the invention with simultaneous postsynaptic dopamine-antagonistic activity.

For example, the connections

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-tetrahydronaphthalene hydrochloride

 (Mp: 221-223ºC)

(In the tables below, instead of

Compound names the letters assigned to these - possibly supplemented by the indication of the optical isomer (+) or (-) - used to investigate the influence of presynaptic dopaminergic neurons determines the effect on the inhibition of dopamine synthesis. The effect on

 Postsynaptic dopamine receptors were determined in the monkey (MPTP model).

Determination of inhibition of dopamine synthesis

The methodology is according to J.R. Walters and R.H. Roth [Naunyn - Schmiedeberg's Aren. Pharmacol. 296, (1976) 5]: 5 animals each received 10 mg / kg s.c. the substance to be examined. After 5 minutes, 750 mg / kg i.p.

 γ-butyrolactone to block the

 presynaptic impulse line the influence

postsynaptic feedback loops on the Exclude dopamine synthesis rate. The administration of γ-butyrolactone leads to a considerable

Increase in DOPA or dopamine synthesis. To inhibit the decarboxylation of DOPA, 200 mg / kg i.p.

3-Hydroxybenzyl hydrazine hydrochloride applied. The animals are sacrificed 40 minutes after administration of the substance and the corpus striatum is prepared. The DOPA content is measured using HPLC with electrochemical detection (standard:

Dihydroxybenzylamine).

The percentage inhibition by γ-butyrolactone caused by the test substance is determined

stimulated dopa accumulation compared to the 0.9 percent. Control animals treated with saline.

The results of this experiment are in

the following table:

Substance dose inhibition of

 Dopaaccumulation (mg / kg s, c.) Compared to%

 saline controls

A 10 86

(+) - A 10 90

 B 10 73

(+) - B 10 75

(+) - C 10 83

(+) - D 10 76

(+) - E 10 84

(+) - F 10 85

(+) - G 10 85 Determination of the postsynaptic dopaminergic

 Effect using the MPTP model

The pharmacological properties of the neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydro-pyridine (MPTP) [J.W. Langston, P. Bollard, J.W. Tetrud and I.

 Irwin, Science 219, (1983) 979] enable its use in animal models for Parkinson's

 Illness.

MPTP in humans and monkeys

 triggered, irreversible, neurological

 Clinical picture resembles in its clinical,

 pathological, biochemical and pharmacological expression largely of the 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 reason for this convincing agreement is the fact that MPTP selectively small groups of dopaminergic

 Nerve cells in the substantia nigra of the brain are destroyed, which also occurs naturally

 occurring Parkinson's disease can be destroyed by degenerative processes.

There is a possibility that the cause of the idiopathic Parkinson's disease in the

MPTP or a similar chemical compound produced by the organism [S.H. Snyder, Nature 311 (1984) 514]. The clinical expression of the

MPTP-Parkinson's picture is - possibly due to the specific metabolism of the MPTP - except in humans only in monkeys

detectable. The MPTP model implemented in rhesus monkeys is therefore suitable for testing the effects of substances with a postsynaptic, dopamine agonistic effect.

In addition, rhesus monkeys receive MPTP in total doses up to about 6 mg / kg body weight until the following symptoms occur: the animals become akinetic and are unable to absorb water and food. They show a typical, stooped posture;

cataleptic states occasionally occur. The extremities have a rigor, which with passive movement of clonic cramps

is broken.

Dopamine agonists such as B-HT 920, Levadopa or Apomorphin lead to a temporary one

Removal of this condition for 4 to 5 hours with a single dose of 100 μg / kg intramuscularly. Then the symptoms described above appear again.

After intramuscular administration of the compounds according to the invention (0.1-3.0 mg / kg) none can

Improvement or even elimination of the condition of the monkeys treated with MPTP can be observed. It could even antagonize the B-HT 920 elimination of Parkinson's

Similar symptoms are observed. The animals remain bradykinetic when given 1.0-3.0 mg / kg of the compounds according to the invention together with 0.1 mg / kg of B-HT 920 and are still unable to absorb water and feed. Out of it is postsynaptic

dopamine antagonistic effects of these substances. The results are summarized in the following table:

Substance dose effect

A 3 mg / kg antagonization of

B-HT 920 ^*

 B 3 mg / kg antagonization of

B-HT 920 ^*

 (+) - B 1 mg / kg antagonization of

B-HT 920 ^*

 (+) - c 3 mg / kg antagonization of

B-HT 920 ^*

 (+) - D 1 mg / kg antagonization of

B-HT 920 ^*

* 0.1 mg B-HT 920 per kg body weight

The compounds according to the invention are prepared in accordance with the synthesis scheme below, the individual stages of which are described in detail below:

Herstellungsverfahren

production method

I.

 The one used as the starting material

 2,7-diamino-1,2,3,4-tetrahydronaphthalene (2) can follow

 methods known from the literature [p.

 Chiavarelli and G. Settimj, Rend. is. super, sanitary 22 (1959) 508; CA. M (1960) 2281 g] and with the usual methods - for example via the corresponding tartaric acid salts - into the two

Enantiomers are separated.

II

The necessary for further synthesis protect the amino (R _S) may be using the methods known from the prior art achieve [M. Bodanszky, Principles of

Peptide Synthesis, Springer-Verlag, Berlin 1984, p. 84; T.W. Greene, Protective Groups in Organic

Synthesis, John Wiley and Sons, New York N.Y. 1981, pp. 218 ff; Houben-Weyl, Methods of Organic Chemistry, Volume E 4, Georg Thieme Verlag, Stuttgart 1983, p. 144], the protection of the amino function with an alkoxycarbonyl or a

Araloxycarbonyl protective group - especially with a tert-butoxycarbonyl (BOC) protective group

is preferred.

For example, using methods known per se - with

 Pyrocarbonate di-tert-butyl ester in the presence of a basic reacting compound - preferably an organic nitrogen base such as e.g. Triethylamine in inert solvents - the corresponding - optionally enantiomerically pure 7-amino-2-tert-butoxycarbonylamido-1,2,3,4-tetrahydronaphthalenes of type 3. In general serve as inert solvents

organic solvents that do not change under the reaction conditions used. These preferably include ethers such as tetrahydrofuran or glycol dimethyl ether (Glyme).

III

III

 The respective 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 prepared using the methods known from the prior art and particularly suitable for the preparation of acylanilides

 protected 7-acylamido-2-amino-1,2,3,4-tetrahydronaphthalene derivatives or

 Convert 7-acylamido-2-tert-butoxy-carbonylamido-1,2,3,4-tetrahydronaphthalenes, which fall under the general formula 4 [C. Ferri, Reactions in Organic Synthesis, Georg Thieme Verlag, Stuttgart 1978, pp. 222 ff].

Here, the implementation of each

 protected

 2, 7-diamino-l, 2,3,4-tetrahydronaphthalene derivative or the 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. Reactive carboxylic acid derivatives are generally understood to mean carboxylic acid halides and carboxylic acid anhydrides, which can optionally be substituted by halogen atoms. such

Carboxylic acid derivatives are known or can be prepared by known methods [Houben-Weyl, Methods of Organic Chemistry, Volume VIII and Volume E 5, Georg Thieme Verlag, Stuttgart 1952 and 1985, respectively]. Aliphatic are preferred here

 Carboxylic acid bromides, carboxylic acid chlorides or aliphatic carboxylic acid anhydrides. Acetic acid bromide, acetic acid chloride, acetic anhydride and trifluoroacetic anhydride are particularly preferred.

All common basic ones can be used as bases

 Compounds that are basic

 Reaction control are suitable to be used. These include, for example, alkali or

 Alkaline earth metal hydroxides, carbonates or alcoholates and preferably tertiary amines, triethylamine being particularly preferably used.

Organic solvents which are not used under the reaction conditions used are generally used as inert solvents

 change such as hydrocarbons - such as benzene, toluene, xylene or petroleum fractions - or halogenated hydrocarbons - such as

 Methylene chloride, chloroform or

 Carbon tetrachloride or preferably ether - such as diethyl ether, glycol dimethyl ether (glyme),

 Diglycol dimethyl ether (diglyme) and particularly preferably tetrahydrofuran.

IV

IV

The subsequent splitting off of the protective group R _S from the amino function in the 2-position in

 Tetrahydronaphthalene of the general formula 4 can - depending on the type of protective group and depending on the chemical stability of the

 Partial acylanilide structure - using the methods known from the prior art [T.W. Greene, Protective Groups in Organic

 Synthesis, John Wiley and Sons, New York 1981, pp. 218 ff; U. Petersen in Houben-Weyl, Methods of Organic Chemistry, Volume E4, Georg Thieme Verlag, Stuttgart 1983, p. 144], from which the acylated 1,2,3,4-tetrahydronaphthalene derivative of

 general formula 5 results.

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 into a tertiary amine - which results in a tetrahydronaphthalene derivative of the general formula 6b - are known from the prior art numerous processes are also known in the art [G. Spielberger in Houben-Weyl, Methods of Organic Chemistry, Volume XI / 1, Georg Thieme Verlag, Stuttgart 1957, p. 24; J. March, Advanced Organic Chemistry, 3 Ed., John Wiley and Sons, New York 1985, p. 1153], wherein - in the case of R ¹ = R ² - the alkylation takes place in one step and - in the case

R 1 not equal to R2 - the intermediate of type 6a is converted to the corresponding tertiary amine 6b.

The further course of the synthesis can be based on this

 Synthesis level may introduce a

Protecting group (R ² = R _s ) - such as one

 Benzyl protective group - make it necessary.

The respective protective group can be split off again according to the methods known from the prior art or replaced with another substituent [T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York N.Y. 1981, pp. 272 ff and cit. Lit.]. (see formula on page 25, 9 - 13a - 14a or 12 - 13b - 14b)

Alkylation with alkyl or

Aralkyl halides or sulfates,

-tosylates, -methanesulfonates or

-trifluoromethanesulfonates - such as

Methyl, ethyl, propyl, isopropyl, butyl, benzyl, phenethyl, o-, m-, p-methylbenzyl halides,

l-halo-3-phenylpropane

l-Halogen-4-phenylbutanes, where halogen or halide means chlorine, bromine or iodine.

Such halides, sulfates, methanesulfonates,

Trifluoromethanesulfonates or tosylates are known or can be prepared by known methods. All inert solvents are suitable

 organic solvents, which are among the

 Do not change the reaction conditions or cannot intervene disadvantageously as reactive components in the course of the reaction. These include alcohols - such as methanol, ethanol, propanol or isopropanol - or halogenated hydrocarbons if they do not themselves act as an alkylating agent - preferably halogenated hydrocarbons - such as fluorocarbons, methylene chloride,

 Chloroform or carbon tetrachloride - and

 particularly preferably ethers such as diethyl ether,

 Di-n-butyl ether, tert-butyl methyl ether,

 Glycol dimethyl ether (Glyme),

 Diethylene glycol dimethyl ether (diglyme),

 Tetrahydrofuran, dioxane and acid amides such as hexamethylphosphoric triamide or

 Dimethylformamide.

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

Furthermore, it has been shown in the preparation of tertiary amines, which is under the general

 Formula 6b are, in two-stage alkylations in the second alkylation reaction proven to be particularly advantageous, dimethylformamide as

Use reaction medium.

It also proves to be advantageous to also use dimethylformamide as the solvent in the single-stage conversion of a primary amine of type 5 to the tertiary amine of type 6b.

The reaction is preferably carried out in the presence of acid binding agents such as e.g. Alkali or alkaline earth carbonates or bicarbonates

carried out. VI

 On the other hand, the primary amino function of the diamine of the general formula 5 can be reductively aminated by means of a suitable aldehyde or ketone or of their suitable derivatives - depending on the molar ratio of the carbonyl compound used to

 7-acylamino-2-amino-1,2,3,4-tetrahydronaphthalene derivative of the general formula 5 - in the

corresponding secondary or tertiary amine

be transferred. This transfer can take place either directly or via the respective ship bases as intermediate products.

The aldehydes or ketones used as starting materials are known or can be prepared by known methods [Aldehydes: Houben-Weyl, Methods of Organic Chemistry, Volume VII / 1 and E5, Georg Thieme Verlag, Stuttgart 1954 and 1983; Ketones: Houben Weyl, Methods of Organic Chemistry, Vol. VII / 2a and 2b, Georg Thieme Verlag, Stuttgart 1973 and 1976, respectively].

Suitable aldehydes or ketones are e.g. represented by formaldehyde, acetaldehyde, propionaldehyde, acetone, butyraldehyde, benzaldehyde, phenylacetaldehyde, 2-phenylpropionaldehyde, 3-phenylpropionaldehyde, 4-phenylbutyraldehyde.

The Schiff base is produced in inert organic solvents, optionally in the presence of a catalyst and

if necessary in the presence of a

water-binding agent. Inert organic solvents are suitable as inert solvents which do not change under the given reaction conditions and do not themselves adversely affect the course of the reaction. These preferably include alcohols - such as methanol, ethanol, propanol or isopropanol - or ethers such as

 Diethyl ether, tert-butyl methyl ether,

 Di-n-butyl ether, glycol dimethyl ether (Glyme), diethylene glycol dimethyl ether (Diglyme),

 Tetrahydrofuran - or halogenated hydrocarbons - such as dichloromethane, trichloromethane, carbon tetrachloride - or hydrocarbons - such as petroleum fractions, benzene, toluene, xylene

- and particularly preferably amides - such as dimethylformamide, acetamide,

 Hexamethylphosphoric triamide or carboxylic acids

- Such as formic acid or acetic acid - or mixtures of the solvents mentioned.

Optionally, as catalysts

Protonic acids used. This includes

preferably mineral acids such as hydrochloric acid or sulfuric acid or organic carboxylic acids with 1 to 6 carbon atoms, which may optionally be substituted by fluorine, chlorine and / or bromine.

Examples of such acids are formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid or propionic acid. The group of preferred acids also includes sulfonic acids

C ₁ -C ₄ alkyl radicals or aryl radicals, the

can optionally be substituted by halogen atoms - such as methanesulfonic acid,

Trifluoromethanesulfonic acid, ethanesulfonic acid,

Benzenesulfonic acid, toluenesulfonic acid. The water formed in the reaction can, if necessary, by adding

water-binding agents - such as

Phosphorus pentoxide - or preferably using a molecular sieve or in a mixture with the

solvents used are withdrawn from the reaction mixture during or after the end of the reaction, for example by distillation.

The reaction is generally carried out in one

Temperature interval from + 20 ° C to the boiling point of the respective reaction mixture and preferably in a temperature range from + 20 ° C to 100 ° C

carried out.

When the water formed in the reaction is distilled off azeotropically with the solvent or solvent mixture used in each case, the boiling temperature of the respective azeotrope is preferred.

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

To produce the secondary amine, the 7-acetamido-2-amino-1,2,3,4-tetrahydronaphthalene and the respective carbonyl compound are used in equimolar amounts. The respective carbonyl compound is used in excess to prepare the tertiary amine.

The in the manufacture of secondary or

Bases or enamines or immonium salts can be obtained either as hydrogen by means of hydrogen in water or in tertiary amines as intermediates inert organic solvents such as alcohols, ethers or halogenated hydrocarbons, or their mixtures with hydrogen in the presence of suitable catalysts or with complex hydrides - optionally in the presence of a catalyst - are hydrogenated or reduced. The reduction can take place in the same reaction medium or else in a different solvent or in a different solvent mixture. in the

 the latter case is the one used first

 Solvent or solvent mixture preferably removed by distillation.

Catalysts used for example in the catalytic reduction with hydrogen

 Raney nickel, palladium, palladium on animal charcoal, platinum and preferably palladium on charcoal (10% Pd content) use.

Complex hydrides of boron are preferably used for the reduction with hydrides. Sodium borohydride is particularly preferably used.

All inert solvents are suitable

 organic solvents which remain unchanged or at least largely unchanged under the selected reaction conditions and which do not adversely affect the course of the reaction. These include amides - such as dimethylformamide or hexamethylphosphoric triamide - or ethers - such as diethyl ether, tert-butyl methyl ether, di-n-butyl ether,

Glycol dimethyl ether (Glyme), diglycol dimethyl ether (Diglyme), tetrahydrofuran and dioxane - and

particularly preferred alcohols - for example

Methanol, ethanol, propanol or isopropanol. In the reduction with hydrogen, the reaction is among those for the catalytic hydrogenation in

Dependence on the one used

Catalysts, solvents and reactants known reaction conditions carried out [K. Harada in Patai, "The Chemistry of the

Carbon-Nitrogen Double-Bond ", Interscience

Publishers, London 1970, pp. 276 u. quot. Lit .; P.N. Rylander, Catalytic Hydrogenation over Platinum Metals, Academic Press, New York 1967, p. 123; F. Möller and R. Schröter in Houben-Weyl, Methods of Organic Chemistry, Volume XI / 1, Georg Thieme Verlag, Stuttgart 1957, p. 602; W.S. Emerson, Org.

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, Vol. III (1955) 717; DM. Malcolm and C.R. Noller, Org. Synth., Coll. Vol. IV (1963) 603].

The hydrogenation with palladium on carbon (10% Pd content) in methanol is preferred in one

Temperature range from 20 to 50 ° C - particularly preferably in a temperature interval from 25 ° C to 35 ° C - under a hydrogen pressure of

preferably 0.1 to 0.8 MPa - particularly preferably under a hydrogen pressure of 0.4 to 0.6 MPa.

When performing the invention

Process using complex hydrides, it has proven to be advantageous to 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

 To implement dimethylformamide in a temperature range between 50 ° C and 100 ° C, the

 After the reaction has ended, the solvent is distilled off under reduced pressure

 remaining residue in an organic

 Solving or dispersing solvents - preferably an alcohol - and reacting them with an at least equimolar amount of a reducing agent - preferably a complex hydride and particularly preferably sodium borohydride - after the reduction has been carried out, the reaction product has to be processed by extraction from the extract

 Isolate reaction mixture and if necessary

 to be cleaned chromatographically or to subject and isolate a cleaning step in another way.

VII

 The preparation of the compounds according to the invention in the context of a reductive amination is in a further synthesis variant by way of a

Leukart-Wallach reaction can be carried out, which is particularly suitable for the preparation of tertiary amides. The reaction conditions for such reductive aminations are known [collective of authors,

Organikum, VEB German Publishing House of Sciences, Berlin 1986 (16th edition) p. 491; C. Ferri,

Reactions of organic synthesis, Georg Thieme Verlag, Stuttgart 1978, p. 133 and cit. Lit .; F. Möller and R. Schröter in Houben-Weyl, Methods of Organic Chemistry, Volume XI / 1, Georg Thieme Verlag, Stuttgart 1957, p. 648]. The tertiary amines of the invention

 general formula 6b can also by

 Combination of the production methods mentioned can be obtained.

VIII

 The acyl group is split off for further derivatization of the aniline amino function, from which the diamines of the general formula 7 result.

The saponification of such arylamides is known and can be achieved, for example, by the implementation of a

 Carboxamides of the general formula 6b with aqueous solutions of alkali metal hydroxides or

Acids are obtained [F. Möller in Houben-Weyl, Methods of Organic Chemistry, Volume XI / 1, Georg Thieme Verlag Stuttgart 1957, pp. 927 ff and 934 ff; RM Herbst and D. Shemin, Org. Synth., Coll. Vol. II (1943) 491; PE Fanta and DS Tarbell, Org. Synth., Coll. Vol. III (1955) 661]. The reaction with dilute mineral acids under reflux conditions is preferred, saponification with 2N hydrochloric acid, which is carried out in a One-pot reaction immediately the appropriate

 Hydrochloride supplies which after the

 Distilling off the reaction medium and the

 volatile constituents of the reaction mixture - preferably under reduced pressure - and slurrying in an organic solvent - preferably an alcohol, with ethanol being particularly preferred - and after filtering and drying can be isolated.

 IX

The preparation of the 2-amino-2-cyano-tetralin derivative 8 succeeds - in a manner known per se [Organikum, German Publishing House of Sciences, 17th edition, Berlin 1988, p. 547; Vogel's Textbook of Practical Organic Chemistry, 4th Edition,

 Longman, London 1978, p. 703] - on the way of a so-called Sandmeyer reaction by implementing the

 optionally protected 2,7-diamino-1,2,3,4-tetrahydronaphthalene derivative of type 7 e.g. with potassium cyanide in the presence of copper (I) cyanide.

When performing the invention

Process generally produce dazonium salts as intermediates that can be isolated. However, it has proven advantageous to carry out the process without isolating the intermediates. Suitable inert solvents here are water or alcohols - such as methanol, ethanol, propanol or isopropanol - or amides - such as formamide or dimethylformamide - water being the preferred solvent.

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

to use.

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

The implementation is generally in one

Temperature range from -10 ° C to + 150 ° C, preferably from -5 ° C to + 50 ° C.

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

The process according to the invention is generally carried out by first adding a solution of nitrite in water to the 2-aminotetralin in aqueous sulfuric acid and then reacting the reaction solution with the alkali metal cyanide - preferably potassium cyanide and copper (I) cyanide, optionally dissolved in water, treated. The diazonium salt is generally not isolated. Working up is generally carried out by neutralizing the reaction mixture with aqueous ammonia solution or with

 Alkali hydroxides or carbonates, and extraction of the free bases thus obtained, from which the salts thereof can be obtained by reaction with appropriate acids.

 X

 By further reaction of the 2-amino-7-cyano-1,2,3,4-tetrahydronaphthalene derivative 8, in the presence of methanesulfonic acid and a little water, on the one hand the corresponding amides of type 9 are accessible, while the saponification of the cyano compound 8 with concentrated hydrochloric acid the corresponding

Tetralin carboxylic acid derivatives of the type 10 accessible. However, it is also possible to use other strong mineral acids which are suitable for the hydrolysis of nitrile groups to aminocarbonyl groups. Saponification reactions of nitriles - per se - are known from the prior art [PL Compagnon and M. Mioque, Ann. Chim. (Paris) [14] yy (1970) 11-22; PL Compagnon and M. Mioque, ibid. 23-37; EN Zil'berman, Russ. Chem. Rev. 31 (1962) 615]. Water is preferably used as the reaction medium. The reaction is carried out in a temperature range from 0 ° C. to the boiling point of the reaction mixture and under normal pressure. A temperature in the range of 20 ° C to 120 ° C is preferred.

 XI

 The tetralin carboxylic acid derivative 10 can be found under

Using methods known from the literature [J. March,

Advanced Organic Chemistry, 3 Edition, New York N.Y. 1985, p. 388 and cit. Lit.] conveniently using thionyl chloride in the

corresponding acid halide or acid chloride 11 convict [C. Ferri, reactions of organic synthesis, Georg Thieme Verlag, Stuttgart 1978, p. 192 and cit. Lit .; Organikum, German Publishing House of Sciences, 17th edition, Berlin 1988, p. 422, JS Pizey, Synthetic Reagents, Vol. 1, 321, Wiley, New York NY 1974]

The subsequent implementation of the resulting

 Acid halide or acid chloride with a primary amine provides - in a manner known per se [C. Ferri, reactions of organic synthesis, Georg Thieme Verlag, Stuttgart 1978, p. 223 and cit. Lit.] the corresponding acid amide 12. The reaction is conveniently carried out in inert

 Solvents.

Inert solvents are generally solvents which are among the

 Do not change reaction conditions. These preferably include ethers such as diethyl ether,

Tetrahydrofuran, dioxane or glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene or petroleum fractions, or

 Halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride. It is also possible to use mixtures of the solvents mentioned.

The amination of the type 11 acid halide or chloride is generally carried out in one

Temperature range from -20 ° C to 100 ° C, preferably from -20 ° C to 50 ° C at normal pressure.

 XII

The subsequent splitting off of the protective group R _S (R ² = R _S ) from the amino function in the 2-position in the tetrahydronaphthalene of the general formula 9 or 12 can - depending on the type of protective group and depending on the chemical stability of the carbamoyl substructure The methods known from the prior art are used [TW Greene, Protective Groups in Organic

 Synthesis, John Wiley and Sons, New York 1981, pp. 218 ff; U. Petersen in Houben-Weyl, Methods of Organic Chemistry, Volume E4, Georg Thieme Verlag, Stuttgart 1983, p. 144], from which the

 1,2,3,4-tetrahydronaphthalene derivative of the general formula 13a or 13b results.

 For example, compounds of types 9 and 12 which carry a benzyl radical as a protective group on the amino function enable the protective group to be split off by catalytic hydrogenation on a palladium catalyst, from which the

Type 13a tetrahydronaphthalene results.

XIII

For the conversion of the secondary amino function in the 2-amino-l, 2,3,4-tetrahydronaphthalene derivative of the general formula 14a or 14b into a tertiary amine - which results in a tetrahydronaphthalene derivative of the general formula 14a or 14b - as described under V and VI - numerous processes are also known from the prior art [G. Spielberger in Houben-Weyl, Methods of Organic Chemistry, Volume XI / 1, Georg Thieme Verlag, Stuttgart 1957, p. 24; J. March, Advanced Organic Chemistry, ^3rd Ed., John Wiley and Sons, New York 1985, p 1153], wherein the reducing agent must be selected in reductive amination that the carboxylic acid amide function is not attacked. [J. March, Advanced Organic Chemistry, ^3rd Ed. John Wiley and Sons, New York NY 1985, p.

1095]. On the one hand, preference is given to alkylation with optionally derivatized alkyl or

 Aralkyl halides or sulfates,

 -tosylates, -methanesulfonates or

 -trifluoromethanesulfonates - such as

Methyl, ethyl, propyl, isopropyl, butyl,

Allyl, propargyl, benzyl, phenethyl, o, m, p-methylbenzyl, o, m, p-methoxybenzyl

halides,

 1-halo-3-phenylpropane,

 1-halo-3-phenyl-prop-2-enes,

 1-halo-4-phenylbutanes,

 1-halo-3- (p-chlorophenyl) propane,

 (2-haloethyl) methyl ethers,

 1-halogen-3-methoxypropanes,

 (2-haloethyl) methyl sulfides,

 (2-haloethyl) phenyl sulfides,

 (3-halopropyl) methyl sulfides,

ß-halogenopropionic acid methyl esters,

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,

 (2-Halogen-l-methylethyl) -benzenes, where halogen or halide means chlorine, bromine or iodine.

Such halides, sulfates,

Trifluoromethyl sulfonates or tosylates are known or can be prepared by known methods, with the incorporation of polyfunctional substituents, for example free phenolic hydroxyl or (carbon) acid functions, first of all their correspondingly protected derivatives - such as ethers or esters - are introduced, which in a further step are carried out in a conventional manner - for example by ether or ester cleavage or by

 Saponification - can be converted into the desired derivatives. Such derivatives include, for example, 1-bromo-2- (4-methoxyphenyl) ethane,

 Ethyl bromoacetate, and

 3-Bromopropionic acid ethyl ester.

Suitable aldehydes or ketones for the reductive amination are e.g. through formaldehyde,

 Acetaldehyde, propionaldehyde, acetone, butyraldehyde, acrolein, propargylaldehyde, benzaldehyde,

 Phenylacetaldehyde, 2-phenylpropionaldehyde,

 3-phenylpropionaldehyde, 3-phenylacrolein

 (Cinnamaldehyde), 4-phenylbutyraldehyde,

Methoxyacetaldehyde, phenoxyacetaldehyde,

Benzyloxyacetaldehyde, 3-methoxypropionaldehyde, methylmercaptoacetaldehyde,

 3-methylmercaptopropionaldehyde,

Methyl mercaptoacetaldehyde,

 (3, 4-dichlorophenyl) acetaldehyde,

4-methoxyphenylacetaldehyde,

 (3,4-dimethoxyphenyl) acetaldehyde,

(3,5-Dimethoxyphenyl) acetaldehyde.

Furthermore, the invention

Compounds by any other reaction that starts from secondary amines as an amine component - for example, by a Michael reaction. Suitable reaction partners for this representation variant embody, for example, derivatives of acrylic acid, methacrylic acid or crotonic acid [C. Ferri, reactions of organic synthesis, G. Thieme Verlag, Stuttgart 1978, p. 173 and cit.

 Lit .; M.B. Gase, A. Lattes and J.J. Perie,

 Tetrahedron 39, (1983) 703; H. Pines and W.M.

 Stalick in "Base-Catalized Reactions of

 Hydrocarbons and Realed Compounds ", Academic

 Press, New York N.Y. 1977, p. 423; M.S. Gibson in Patai "The Chemistry of the Amino Group",

 Interscience, New York N.Y. 1968, p. 61 ff].

The tertiary amines of the invention

 General formulas 14a and 14b can also be obtained by combining the production methods mentioned.

The following examples are intended to illustrate the invention without restricting it:

That in the manufacturing examples before

 Prefix (+) / (-) specified for substance names is intended to mean that these syntheses can be carried out both with the left-handed and with the right-handed optical isomers or with their mixture or the corresponding racemate.

example 1

Separation of the enantiomeric 2,7-diamino-1,2,3,4-tetrahydronaphthalenes 81.0 g (0.5 mol) of 2,7-diamino-1,2,3,4-tetrahydronaphthalene are dissolved in 1 liter of a methanol / water mixture (95: 5) and heated to 50.degree. At this temperature, a solution of 37.5 g (0.25 mol) of L - (+) - tartaric acid in 200 ml of methanol is added. The crystals that fail after a short time become

 aspirated, three times with 300 ml each

 Boiled methanol / water mixture (95: 5) and recrystallized once from water. The tartrate is then suspended in 70 ml of water, 33 g (0.6 mol) of potassium hydroxide are added and the mixture is extracted twice with 70 ml of tetrahydrofuran. After drying the organic phase with magnesium sulfate and the

Filtering off the desiccant i. Vac. removed and the residue under one

reduced pressure of 0.08 hPa distilled.

The (+) - 2,7-diamino-1,2,3,4-tetrahydronaphthalene is isolated as colorless crystals.

Yield 9.7 g (12%)

Mp 33-34 ° C

Bp 108-110 ° C

The (-) - enantiomer is converted in an analogous manner under

Obtained using R - (-) - tartaric acid.

Yield 9.8 g (12%)

Mp 33-34 ° C

Bp 108-110 ° C

In the following examples, each of

(+) - 2,7-diamino-1,2,3,4-tetrahydronaphthalene or of (-) - 2,7-diamino-1,2,3,4-tetrahydronaphthalene

went out. Example 2

(+) / (-) - 7-Amino-2-tert-butoxycarbonylamido-1,2,3,4-tetrahydronaphthalene

To a solution of 20 g (0.12 mol) (+) / (-) - 2,7-diamino-1,2,3,4-tetrahydronaphthalene and 17.1 ml (0.12 mol) triethylamine in 250 ml anhydrous tetrahydrofuran is a solution of 28.7 ml (0.12 mol) at -10 ° C

Pyrocarbonate di-tert-butyl ester in 140 ml

anhydrous tetrahydrofuran added dropwise. You stir

30 minutes at -10 ° C and then allows the reaction solution to warm to room temperature. The

Solvent is i. Vac. distilled off and the

The residue is mixed with 500 ml of ethyl acetate and washed twice with 100 ml of water each time. Then the organic phase is dried with magnesium sulfate, the solvent i. Vac. removed and the residue recrystallized from diethyl ether.

Yield: 25 g (80%)

Mp: 119 - 121 ° C

Example 3

(+) / (-) - 7-Acetamido-2-tert-butoxycarbonylamido-1,2,3,4-tetrahydronaρhthaline

25 g (95 mmol) 7-amino-2-tert-butoxycarbonylamido-1,2,3,4-tetrahydronaphthalene and 14.5 ml (100 mmol) triethylamine are anhydrous in 120 ml

Dissolved tetrahydrofuran and at room temperature with

9.9 ml (105 mmol) of acetic anhydride were added. The mixture is stirred for 1 hour at room temperature and added

then add 450 ml of ice water. The fancy Crystals are suctioned off and washed with 200 ml of water, with 35 ml of acetone and with 60 ml of diethyl ether and in a forced-air drying cabinet to constant weight

 dried.

Yield: 25.9 g (93%)

 Mp: 193-195 ° C

Example 4

(+) / (-) - 7-acetamido-2-amino-1,2,3,4-tetrahydronaphthalene hydrochloride

50 g (0.16 mol) of 7-acetamido-2-tert-butoxycarbonylamido-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, during which the

 Temperature can rise to 70 ° C. You let go

Cool down to room temperature, sucks the failed ones

Crystals, washed once with 100 ml of acetone and 100 ml of diethyl ether and dried in

 Circulating air drying cabinet first at room temperature, then at 80 ° C under normal pressure to constant weight.

Yield: 36 g (91%)

Mp: 260 ° C

Example 5

(+) / (-) - 7-acetamido-2-propylamino-1,2,3,4-tetrahydronaphthalene hydrochloride

(Alkylation) 83.8 g (0.41 mol) of (+) / (-) - 7-acetamido-2-amino-1,2,3,4-tetrahydronaphthalene and 75.6 g (0.61 mol) of propyl bromide are added in 900 ml of tetrahydrofuran dissolved, mixed with 84 g (0.84 mol) of potassium hydrogen carbonate and heated to reflux temperature for 7 hours. A further 75.6 g (0.61 mol) of propyl bromide are then added and the mixture is boiled again for 7 hours. You let go

Cool to room temperature, filter and concentrate the filtrate i. Vac. one, mixed with 500 ml of ethyl acetate and extracted with 500 ml of water. The organic phase is dried with magnesium sulfate, after which

Filter off the desiccant i. Vac. concentrated and the remaining residue of silica gel (grain size 0.063 to 0.2 mm) with a mixture of

Chromatograph methylene chloride and methanol (80:20). After the chromatographic isolation, the concentration of the eluate i. Vac. and reaction of the residue with a solution of hydrogen chloride in diethyl ether, the title compound is precipitated as the hydrochloride,

filtered and in a convection oven up to

Weight constant dried.

Yield: 43.4 g (38%)

Mp: 171 ° C

Example 6

(+) / (-) - 7-Acetamido-2- (N-butyl-propylamino) -1,2,3,4-tetrahydronaphthalene hydrochloride

7 g (24.8 mmol) (+) / (-) - 7-acetamido-2-propylamino-1,2,3,4-tetrahydronaphthalene hydrochloride and 12.8 g (93 mmol) butyl bromide are dissolved in 80 ml dimethylformamide dissolved, mixed with 10 g (100 mmol) of potassium hydrogen carbonate and stirred at 80 ° C for 9 hours. You let go Cool to room temperature, filter and concentrate the filtrate i. Vac. a, mixed with 250 ml of water and extracted 2 times with 200 ml of ethyl acetate. The combined organic extracts are with

 Magnesium sulfate dried and after filtering off the desiccant i. Vac. constricted. The remaining residue is chromatographed on silica gel (particle size 0.063 to 0.2 mm) with a mixture on methylene chloride and methanol (80:20).

After chromatographic isolation, the concentration of the eluate i. Vac. and reaction of the residue with a solution of hydrogen chloride in diethyl ether, the title compound is precipitated as the hydrochloride,

 filtered off and dried to constant weight.

Yield: 5.5 g (67%)

 Mp: 208-210 ° C

Example 7

(+) / (-) - 7-acetamido-2-N, N-diethylamino-1,2,3,4-tetrahydronaphthalene hydrochloride

 (reductive amination with hydrogen)

6.5 g (32 mmol) of 7-acetamido-2-amino-1,2,3,4-tetrahydronaphthalene and 22 g (500 mmol) of acetaldehyde are dissolved in 110 ml of methanol and mixed with 2.2 g of palladium / carbon (10 % Pd). It is hydrogenated for 18 hours

Autoclaves at 30 ° C and a hydrogen pressure of 500 kPa. It is then suction filtered through silica gel and the solvent i. Vac. distilled off. The residue is then mixed with 150 ml of diethyl ether and washed twice with 60 ml of water each. The organic phase is dried with magnesium sulfate, the solvent after filtering off the

Desiccant i. Vac. removed and the remaining residue on silica gel (particle size 0.063-0.2 mm) was chromatographed (eluent: ethyl acetate / methanol; 80:20). After the chromatographic isolation, the eluate is concentrated and the

(+) / (-) - Acetamido-2-N, N-diethylamino¬

-1,2,3,4-tetrahydronaphthalene converted into the hydrochloride using ethereal hydrochloric acid. The crystals are suctioned off and in the circulating air drying cabinet

Weight constant dried.

Yield: 1.7 g (18%)

Mp:> 265 ° C

Example 8

(+) / (-) - 7-Amino-2- (N-butyl-N-propylamino) -1,2,3,4-tetrahydronaphthalene dihydrochloride

1.5 g (4.4 mmol)

 (+) / (-) - 7-Acetamido-2- (N-butyl-N-propylamino-1,2,3,4-tetrahydronaphthalene hydrochloride are heated to reflux temperature for 2 hours with 30 ml of 2N HCl, then the solution is i.Vac. concentrated, 20 ml of ethanol are added to the residue, the crystals are filtered off, washed with ethanol and in

Circulating air drying cabinet to constant weight

dried.

Yield: 1.1 g (75%)

Mp:> 167 ° C Example 9

(+) / (-) - 7-Cyano-2- (N, N-dipropylamino) -l, 2,3,4-tetrahydronaphthalene

To a solution of 24.6 g (0.1 mol)

 7-Amino-2- (N, N-dipropylamino) -1,2,3,4-tetrahydronaphthalene in 50 ml water and 12.5 ml conc.

 One leaves sulfuric acid within one

 Temperature interval from -5 ° C to 0 ° C a solution of 8.5 g (0.12 mol) of sodium nitrite in 50 ml of water

 flow to. It is left for 30 min. React at -5 ° C.

A solution of 40 g (0.6 mol) of potassium cyanide and 20 g (0.2 mol) of copper (I) cyanide in 200 ml of water, cooled to -5 ° C., is then added to the reaction mixture, the mixture foaming strongly. After the evolution of gas has subsided, another 30 min. at

 Room temperature stirred. The reaction solution is concentrated with 400 ml. Alkaline ammonia solution. It is extracted three times with 400 ml of ethyl acetate each time, the combined organic extracts are washed with 500 ml of water, dried and, after removing the drying agent, i. Vac. constricted. The residue is distilled in a high vacuum.

Yield: 20.2 g (79%)

Bp: 132-135 ° C (0.06 torr).

The following is prepared analogously to Example 9:

(+) / (-) - 2- (N-Benzyl-N-propylamino) -7-cyano-1,2,3,4-tetrahydronaphthalene

Yield: 58%

Sdp: 180-185 (10 ^-3 mbar) Example 10

(+) / (-) - 7-carbamoyl-2- (N, N-dipropylamino) -1,2,3,4-tetrahydronaphthalene hydrochloride

3.0 g (12 mmol) of 7-cyano-2- (N, N-dipropylamino) -1,2,3,4-tetrahydronaphthalene are dissolved in a mixture of 18 ml of methanesulfonic acid and 2 ml of water and the reaction mixture is heated for 1 hour to 110 ° C. Then allowed to cool, the reaction mixture is poured onto ice and concentrated with about 60 ml. Ammonia solution

alkaline. It is twice with 100 ml

Extracted ethyl acetate, the combined

organic extracts washed with 100 ml of water, dried and i. Vac. constricted. The remaining base is dissolved in acetone and the hydrochloride is precipitated with ethereal hydrochloric acid.

Yield: 3.0 g (81%)

Mp: 251-253 ° C.

Analogously to example 10, the following is shown:

(2R) -7-Carbamoyl-2- (N, N-dipropylamino) -1,2,3,4-tetrahydronaphthalene hydrochloride

Yield: 78%

 Mp: 255 ° C

[α] _D 20 = (+) 76.7 ° (C = 1; methanol)

(2S) -7-Carbamoyl-2- (N, N-dipropylamino) -1,2,3,4-tetrahydronaphthalene hydrochloride

Yield: 79%

 Mp: 252-254 ° C

[α] _D 20 = -71.9 ° (C = 1; methanol) (+) / (-) - 2- (N-Benzyl-N-propylamino) -7-carbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride

 Yield: 65%

 Mp: 142-144 ° C

Example 11 (+) / (-) - 7-Hydroxycarbonyl-2- (N, N-dipropylamino) -1,2,3,4-tetrahydronaphthalene hydrochloride

8.1 g (31.5 mmol) of 7-cyano-2- (N, N-dipropylamino) - 1,2,3,4-tetrahydronaphthalene are concentrated with 150 ml. Hydrochloric acid and refluxed for 8 hours

 heated. Then the reaction mixture i.

 Vac. concentrated, the residue with 100 ml of acetone

 and the crystals that precipitated

 aspirated. The crystals are washed once with 30 ml of cold water and once each with 50 ml of acetone and

 Washed diethyl ether and then in

 Drying cabinet dried at 50 ° C.

Yield 6.2 g (63%)

Mp: 223-226 ° C

Example 12

2- (N, N-Dipropylamino) -7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride

5 g (16 mmol) of 7-hydroxycarbonyl-2- (N, N-dipropylamino) -1,2,3,4-tetrahydronaphthalene hydrochloride are mixed with 1.8 ml (24 mmol) of thionyl chloride for 30 min. under

Reflux and exclusion of moisture heated. Then the excess is distilled

Thionyl chloride i. Vac. and the residue is mixed with 100 ml of diehlorethane. The solution was cooled to 0 ° C. and a solution of 36 g (1.1 mol) of methylamine in 300 ml of abs. Tetrahydrofuran run so that the reaction mixture does not heat up to a temperature above 10 ° C. It is left for 30 min. React at room temperature, the solvent is removed i. Vac. and the residue is mixed with 150 ml of potassium arbonate solution (20 g of K ₂ CO ₃ in 150 ml of water). The mixture is extracted three times with 150 ml of ethyl acetate, the combined organic extracts washed with 150 ml of water, dried and after removing the

Desiccant i. Vac. constricted. The remaining base is dissolved in acetone and to precipitate the

Hydrochloride mixed with ethereal hydrochloric acid.

Yield: 4.6 g (88%)

Mp: 222-224 ° C

The following is prepared analogously to Example 12:

7-ethylcarbamoyl-2- (N, N-dipropylamino) -1,2,3,4-tetrahydronaphthalene hydrochloride

Yield 92%

Mp: 195-196 ° C.

(+) - 2- (N, N-Dipropylamino) -7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride

Yield: 75%

 Mp: 233-235 ° C

[α] _D 20 = +73.5 ° (c = 1; methanol)

(-) - 2- (N, N-Dipropylamino) -7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride Yield: 71%

 Mp: 233-235 ° C

[α] _D 20 = -73.6 ° (c = 1; methanol)

Example 13

(2R) -7-Carbamoyl-2-propylamino-1,2,3,4-tetrahydronaphthalene hydrochloride

28.5 g (85 mmol) (2R) -7-carbamoyl-2- (N-benzyl-N-propylamino) -1,2,3,4-tetrahydronaphthalene are dissolved in 500 ml of methanol and with 4 g of palladium / carbon (10%) offset. It is hydrogenated for 5 hours in an autoclave at 20 ° C and a hydrogen pressure of 5 bar. The

 Hydrogen uptake ends after the calculated amount has been used up. The catalyst is suctioned off through silica gel and the filtrate is evaporated down i. Vac. on. The

 remaining base is dissolved in ethanol and the hydrochloride is precipitated with ethereal hydrochloric acid.

Yield: 15.4 g (68%)

 Mp: 242-244 ° C

[α] _D 20 = (+) 70.7 ° (C = 1; methanol)

Analogously to example 13, the following is shown:

(2S) -7-Carbamoyl-2-propylamino-1,2,3,4-tetrahydronaphthalene hydrochloride

Yield 73%

 Mp: 244-246 ° C

[α] _D 20 = -68.9 ° (C = 1; methanol)

(+) / (-) - 7-carbamoyl-2-propylamino-1,2,3,4-tetrahydronaphthalene hydrochloride Yield: 97%

Mp: 255-257 ° C

(+) - 7-Methylcarbamoyl-2-propylamino-1,2,3,4-tetrahydronaphthalene hydrochloride

Yield; 91%

 Mp: 245-247 ° C

[α] _D 20 = + 60.5 ° (c = 1; methanol)

Example 14

(2R) -2- (N-Allyl-N-propylamino) -7-carbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride

7.3 g (27 mmol) (2R) -7-carbamoyl-2-propylamino-1,2,3,4-tetrahydronaphthalene hydrochloride, 6.4 ml (74 mmol) allyl bromide and 5.6 g (41 mmol) Potassium arbonate is stirred for 4 hours at 35 ° C in 73 ml of dimethylformamide. Then the reaction mixture i. Vac.

concentrated, the residue mixed with 200 ml of water and extracted twice with 150 ml of ethyl acetate. The combined organic extracts are washed with 100 ml of water, dried and, after removing the drying agent, i. Vac. constricted. The residue is recrystallized once from ether. Then the cleaned base is dissolved in methanol and the

Hydrochloride precipitated with ethereal hydrochloric acid.

Yield: 67%

 Mp: 233-235 ° C

[α] _D 20 = -81.1 ° (C = 1; methanol)

The following is prepared analogously to Example 14: (-) - 2- (N-Allyl-N-propylamino) -7-carbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride

Yield: 62%

 Mp: 228-233 ° C

[α] _D 20 = -80.1 ° (c-1; methanol)

(+) / (-) - 7-carbamoyl-2- (N-ethyl-N-propylamino) -1,2,3,4-tetrahydronaphthalene hydrochloride

Yield: 72%

 Mp: 168-170 ° C

(+) - 2- (N-Allyl-N-propylamino) -7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride

Yield: 72%

 Mp: 223-225 ° C

[α] _D 20 = + 83.9 ° (c-1; methanol)

(+) - 2- (N-Butyl-N-propylamino) -7-methylcarbomoyl-1,2,3,4-tetrahydronaphthalene hydrochloride

Yield: 84%

 Mp:> 100 ° C dec.

[α] _D 20 = + 70.9 ° (c-1; methanol)

(+) - 7-Methylcarbamoyl-2- (N-phenylethyl-N-propylamino) -1,2,3,4-tetrahydronaphthalene hydrochloride

Yield: 69%

 Mp:> 80 ° C dec.

[α] _D 20 = + 50.5 ° (c-1; methanol) Example 15

(+) - 2- (N-Methoxycarbonylethyl-N-propylaraino) -7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride

1.5 g (5.3 mmol) (2R) -2-propylamino-7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride and 1.4 g of potassium arbonate are dissolved in 15 ml of methanol, 2 ml of methyl acrylate are added and heated to 50 ° C. The mixture is heated for a total of 36 h, with a further 2 ml of acrylic ester being added every 9 h. Then the reaction mixture i. Vac. concentrated, the residue mixed with 50 ml of water and extracted twice with 50 ml of ether. The combined organic extracts are dried and concentrated, and the residue is filtered through a short column of silica gel (about 5 g of silica gel and 200 ml of ethyl acetate). The appropriate fractions are concentrated and the hydrochloride is precipitated with ethereal hydrochloric acid.

Yield: 1.4 g = 71%

 Mp:> 65 ° C dec.

[α] _D 20 = + 66.8 ° (c-1; methanol)

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds according to the invention or which consist of one or more according to the invention

Active ingredients exist, as well as processes for the preparation of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, for example Tablets, coated tablets, capsules, pills, suppositories and ampoules are available, the active ingredient content of which

 Fraction or a multiple of a single dose. The dosage units can e.g. 1, 2, 3 or 4 single cans or 1/2, 1/3 or 1/4 one

 Single dose included. Contains a single dose

 preferably the amount of active ingredient in a

 Application is administered and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

Taking non-toxic, inert pharmaceutically

 Suitable carriers are solid, semi-solid or liquid diluents, fillers and

 Understand all types of formulation aids.

Preferred pharmaceutical preparations are tablets, dragees, capsules, pills, granules,

 Called suppositories, solutions, suspensions and emulsions.

Tablets, coated tablets, capsules, pills and granules can contain the active ingredient or ingredients in addition to the usual ones

Contain carriers, such as (a) filling and

Extenders, e.g. Starches, milk sugar, cane sugar, glucose mannitol and silica, (b) binders, e.g. Carboxymethyl cellulose, alginates, gelatin,

Polyvinyl pyrrolidone, (c) humectant, e.g.

Glycerin, (d) disintegrant, e.g. Agar Agar,

Calcium carbonate and sodium carbonate, (e)

Solution delay, e.g. Paraffin and (f)

Resorption accelerators, eg quaternary Ammonium compounds, (g) wetting agents, e.g.

Cetyl alcohol, glycerol monostearate, (h)

Adsorbents, e.g. Kaolin and bentonite and (i) lubricants e.g. Talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules can with the usual, if necessary

Be provided with opacifying agents, coatings and casings and also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, possibly with a delay, with the embedding compositions e.g. Polymer substances and waxes can be used.

The active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned carriers.

In addition to the active ingredient (s), suppositories can be the usual water-soluble or water-insoluble ones

Contain carriers, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C ₁₄ alcohol with C ₁₅ fatty acid) or mixtures of these substances.

Solutions and emulsions can be added to the one or more

Active substances the usual carriers like

Solvents, solubilizers and emulsifiers, e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,

Propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin,

Formal glycerin, tetrahydrofuryl alcohol,

Contain polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances. For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can contain the usual carriers such as liquid diluents, e.g. Water, ethyl alcohol, propylene glycol,

 Suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,

 microcrystalline cellulose, aluminum methoxide, bentonite. Agar and tragacanth or mixtures of these substances contain.

The formulation forms mentioned can also

 Colorants, preservatives as well as odor and taste-improving additives, e.g. Peppermint oil and eucalyptus oil and sweeteners, e.g. Saccharin.

The therapeutically active compounds in the pharmaceutical preparations listed above are preferably in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight of the

Total mixture must be present.

In addition to the compounds according to the invention, the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.

The pharmaceutical preparations listed above are prepared in a customary manner by known methods, e.g. by mixing the active ingredient (s) with the excipient (s).

The preparations mentioned can be administered orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously) be applied. Injection solutions, solutions and suspensions for therapy are suitable as preparations.

In general, it has proven advantageous in human medicine to add the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg body weight per 24

Hours, if necessary in the form of several single doses, to achieve the desired results

administer. A single dose contains the active ingredient (s) according to the invention preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg body weight. However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and the severity of the

Disease, the type of preparation and application of the drug and the period or interval within which the administration takes place.

So in some cases it may be sufficient with less than the above amount of active ingredient

get along while in other cases the above

specified amount of active ingredient must be exceeded. The determination of the optimum required in each case

Dosage and type of application of the active ingredients can easily be carried out by any specialist on the basis of his specialist knowledge.

The following production examples are intended to explain the invention without restricting 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 "

 a total of 1,920 parts

Manufacturing;

 The fabrics are made in a known manner

 mixed together and the mixture pressed into tablets, each weighing 1.92 g and containing 20 mg of active ingredient.

2. Ointment

The ointment consists of the following ingredients:

Active ingredient according to formula 1 50 mg

Neribas ointment (trade goods Scherax) ad 10 g

Manufacturing;

The active ingredient is triturated with 0.5 g of ointment base and the remaining base in portions of 1.0 g gradually becomes an ointment

mixed. A 0.5% ointment is obtained. The distribution of the active ingredient in the base is checked optically under the microscope.

3. Cream

Composition:

 Active ingredient according to formula 1 50 mg

Neribas ointment (trade goods Scherax) ad 10 g Manufacturing

The active ingredient is triturated with 0.5 g of cream base and the rest of the base is gradually incorporated in 1.0 g portions with the pestle. A 0.5% cream is obtained. The distribution of the active ingredient in the base is visualized under the microscope

controlled.

4. Ampoule solution

Composition:

 Active ingredient according to formula 1 1.0 mg

Sodium chloride 45.0 mg

 Aqua per inj. ad 5.0 ml

Manufacturing:

The active ingredient is dissolved in water at its own pH or, if appropriate, at pH 5.5 to 6.5, and sodium chloride is added as an isotonance. The solution obtained is filtered pyrogen-free and the filtrate under

 filled aseptic conditions in ampoules, which are then sterilized and sealed. The ampoules contain 1 mg, 5 mg and 10 mg of active ingredient.

5. Suppositories

Each suppository contains:

 Active ingredient according to Formula 1 1.0 parts

 Cocoa butter (mp: 36-37 ° C) 1200.0 parts

Carnauba wax 5.0 parts Manufacturing

Cocoa butter and carnauba wax

melted together. The active ingredient is added at 45 ° C. and the mixture is stirred until a complete dispersion has formed.

 The mixture is poured into molds of the appropriate size and the suppositories are appropriately packaged.

Claims

Claims 1) 2-Amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes  (2-Amino-7-carbamoyltetraline) of the general formula 1

wherein R ¹ C ₁ -C ₈ alkyl; R ^{2 is} hydrogen, C ₁ -C ₁₂ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, - (CH ₂ ) _n -OR ⁴ , - (CH ₂ ) _n -SR ⁴ ,

R ^{4 is} hydrogen, C ₁ -C ₄ alkyl, acyl, R ^{5 is} C ₁ -C ₈ alkyl;  X is hydrogen, hydroxy, halogen, C ₁ -C ₆ alkyl, halomethyl, C ₁ -C ₆ alkoxy,  n is a number 1, 2, 3, 4, 5 or 6; R ^{3 can be} hydrogen, C ₁ -C ₆ alkyl, their enantiomers, mixtures of the enantiomers, the racemate and their Acid addition salts. 2) 2-Amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes (2-Amino-7-carbamoyltetraline) of the general formula wherein R ¹ C ₁ -C ₆ alkyl; R ² C ₁ -C ₁₀ alkyl, C ₃ -C ₄ alkenyl, C ₃ -C ₄ alkynyl, (CH ₂ ) _n -OR ⁴ , R ^{4 is} hydrogen, methyl, ethyl, C ₁ -C ₄ alkylcarbonyl,  n is a number 1, 2, 3, 4 or 5; R ^{3 can be} hydrogen, C ₁ -C ₄ alkyl, their enantiomers, mixtures of the enantiomers, the racemate and their  Acid addition salts. 3) 2-Amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes  (2-Amino-7-carbamoyltetraline) of the general formula wherein R ^{1 is} ethyl, propyl, butyl, R ² C ₃ -C ₇ alkyl, C ₃ -C ₄ alkenyl, C ₃ -C ₄ alkynyl, - (CH ₂ ) _n -OR ⁴ , R ^{4 is} methyl, ethyl, acetyl, trifluoroacetyl,  Ethyl carbonyl,  n is a number 1, 2, 3 or 4; R ³ can denote hydrogen, methyl, ethyl, propyl, their enantiomers, mixtures of the enantiomers, the racemate and their Acid addition salts. 4) (+) / (-) - 7-carbamoyl-2- (N, N-dipropylamino) -1,2,3,4-tetrahydronaphthalene, its enantiomers, mixtures of the enantiomers, racemates and their  Acid addition salts. 5) (+) / (-) - 2- (N, N-Dipropylamino) -7-methylcarbamoyl-1,2,3,4-tetrahydronaphthalene, its enantiomers, mixtures of the enantiomers, racemates and their  Acid addition salts. 6) 2-Amino-7-cyano-1,2,3,4-tetrahydronaphthalenes of  general formula 8 as intermediates, wherein R ¹ and R ^{2 have} the meanings mentioned in claim 1.

7) Pharmaceutical preparations characterized by  a content of a compound according to one of the  Claims 1 to 5. 8) Use of compounds according to one of claims 1 to 5 as a medicament. 9) Use of compounds according to one of claims 1 to 5 in the manufacture of pharmaceutical Preparations for the treatment of diseases based on a disorder of dopaminergic systems. 10) Process for the preparation of 2-amino-7-carbamoyl1,2,3,4-tetrahydronaphthalenes of the general formula

characterized in that - in the case of a) R ¹ and R ² the one specified in claim 1 Have meaning and R ^{3 is} hydrogen (+) - or (-) - 2,7-diamino-1,2,3,4-tetrahydronaphthalenes of the general formula 7

wherein R ¹ and R ^2, with the exception of hydrogen, have the meaning given in claim 1, where R ^{2 can} also represent a protective group, reacted in a manner known per se with an alkali metal cyanide in the presence of copper (I) cyanide, the resulting 2-amino -7-cyano-1,2,3,4-tetrahydronaphthalene derivative of the general formula 8

under reaction conditions known per se with an acid in the presence of water, methane sulfonic acid being preferred as the acid, an optionally present protective group (R = R _s ) from the resulting  2-Amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalene derivative of the general formula 9

split off and optionally the resulting tetralin derivatives of the general formula 13a

under known reaction conditions either in an inert solvent or  Solvent mixture - optionally in  Presence of a base - with a  Alkylating agents of the general formula 15 R ² -Y (15), wherein Y is a halogen, a sulfate, a Tosylate, one methanesulfonate, one Halogen methanesulfonate or another group which can be substituted by an amino function and R ^2, with the exception of hydrogen, means the in Claim 1 has meaning and optionally previously protected functional parts Groups transferred to the unprotected groups and in the case of the preparation of the different Reacting acid addition salts with the corresponding acids and converting them into their acid addition salts or the tetrahydronaphthalene derivatives of the general formula 13a under reductive conditions - optionally in the presence of a catalyst - in an inert solvent with a Carbonyl compound of the general formula 16

where R is hydrogen or an alkyl group and -CHR'R '' = R ² and R ^{2 is} the in  Claim 1 has the meaning given and  if necessary, previously protected functional parts  Groups transferred 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 isolated; b) R ¹ and R ^{2 are} those specified in claim 1 and R ³  with the exception of hydrogen have the meaning given in claim 1 - (+) - or (-) - 2,7-diamino-1,2,3,4-tetrahydronaphthalenes of the general formula 7

 in a manner known per se with an alkali metal cyanide in the presence of copper (I) cyanide, the resulting 2-amino-7-cyano-1,2,3,4-tetrahydronaphthalene derivative of the general formula 8

under known reaction conditions in the presence of an acid to give the carboxylic acid derivative of the general formula 10

saponified, the resulting tetralin carboxylic acid derivative is converted into an acid halide, particularly preferably into the acid chloride of the general formula 11 and then with an amine of the general formula 17 using methods known per se H ₂ NR ³ (17) wherein R ³ with the exception of hydrogen, which in Claim 1 has the meaning given under known reaction conditions to the corresponding acid amide of the general formula 12, an optionally present Protecting group (R ² = R _s ) from the resulting 2-Amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalene derivative of the general formula 12

is split off and, if appropriate, the resulting tetralin derivative of the general formula 13b

under known reaction conditions either in an inert solvent or Solvent mixture - optionally in Presence of a base - with a Alkylating agents of the general formula 15 R ² -Y (15), wherein Y is a halogen, a sulfate, a Tosylate, one methanesulfonate, one Halogen methanesulfonate or another group which can be substituted by an amino function and R ^2, with the exception of hydrogen, means the in  Claim 1 has meaning and optionally previously protected functional parts Groups transferred 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 into their acid addition salts or the tetrahydronaphthalene derivatives of the general formula 13a under reductive conditions - optionally in the presence of a catalyst - in an inert solvent with a  Carbonyl compound of the general formula 16

where R is hydrogen or an alkyl group and -CHR'R * '= R ² and R ^{2 is} the in  Claim 1 has the meaning given and if necessary, previously protected functional Groups transferred 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 isolated.