DD297401A5 - 2-AMINO-7-CARBAMOYL-1,2,3,4-TETRAHYDRONAPTHALINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICAMENT - Google Patents

Abstract

The invention relates to new processes for their preparation and their use as medicaments. {Processes for the preparation and use thereof}

Description

characterized in that - in the case

a) R ¹ and R ^{2 have} the meaning given in claim 1 and R ^{3 is} hydrogen (+) - or. (-) - 2,7-Diamino-1,2,3,4-tetrahydronaphthalenes of general formula 7

(7)

in which R ¹ and R ^2, with the exception of hydrogen, have the meaning given in claim 1, where R ^{2 can} also be a protective group, in a manner known per se with an alkali metal cyanide 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

(8th)

reacting with an acid in the presence of water under known reaction conditions, with preference being given to methanesulfonic acid, an optionally present protective group (R ² = R _s ) from the resulting 2-amino-7-carbamoyl-1,2, 3,4-tetrahydronaphthalene derivative of general formula 9

(9)

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

(13a)

under known reaction conditions either in an inert solvent or solvent mixture - optionally in the presence of a base with an alkylating agent of general formula 15

R ² -Y (15)

in which Y is a halogen, a sulphate, a tosylate, a methanesulphonate, a halomethanesulphonate radical or another amino-substitutable group, and R ^2, with the exception of hydrogen, has the meaning given in claim 1 and optionally previously protected functional groups converted into the unprotected groups and in the case of preparation of the various acid addition salts with the corresponding acids and converted into their acid addition salts

transferred

or

the tetrahydronaphthalene derivatives of the general formula 13a under reductive conditions-if appropriate in the presence of a catalyst in an inert solvent with a carbonyl compound of the general formula 16

CR "(16)

wherein R is hydrogen or an AIRylgruppe and -CHR'R "= R ² and R ^{2 has} the meaning given in claim 1 and optionally converted previously protected functional groups in the unprotected groups and in the case of preparing the various acid addition salts with the reacting corresponding acids and the final product isolated;

b) R ¹ and R ^{2 have} the meaning given 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 general formula 7

(7)

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

(8th)

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

(10)

hydrolyzed, the resulting tetralin carboxylic acid derivative using conventional methods in an acid halide, more preferably converted into the acid chloride of the general formula 11 and then with an amine of general formula 17

H ₂ NR ³

(17)

wherein R ^3, with the exception of hydrogen, which has the meaning given in claim 1, reacting under known reaction conditions to the corresponding acid amide of the general formula 12, an optionally present protective group (R ² = R ₈ ) from the resulting 2-amino-7 -carbamoyl-1,2,3,4-tetrahydronaphthalene derivative of general formula 12

(12)

cleaves off and optionally the resulting tetralin derivative of the general formula 13b »3

(13b)

under known reaction conditions either in an inert solvent or solvent mixture-optionally in the presence of a base-with an alkylating agent of general formula 15

R ² -Y

(15)

in which Y is a halogen, a sulfate, a tosylate, a methanesulfonate, a halomethanesulfonate or another substitutable by an amino group group and R ² except hydrogen has the meaning given in claim 1 and optionally previously protected functional groups converted into the unprotected groups and in the case of production of the various acid addition salts with the corresponding acids and converted into their Säureadditionssaize or

the tetrahydronaphthalene derivatives of the general formula 13a under reductive conditions - if appropriate in the presence of a catalyst in an inert solvent with a carbonyl compound of the general formula

NS-R "(16)

in which R is hydrogen or an alkyl group and -CHR'R "= R ² and R ^{2 has} the meaning given in claim 1 and optionally converted previously protected functional groups in the unprotected groups and in the case of preparing the various acid addition salts with the corresponding acids reacted and isolated the final product.

The invention relates to novel 2-amino-7-carb3moyl-1 _l 2 _l 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-carbamoyltetralines) correspond to the general formula 1:

R 'is C, -C _e alkyl;

R ^{2 is} hydrogen, C 1 -C ₂ -alkyl, C 1 -C 6 alkenyl, C ₁ -C 6 alkynyl, - (CH ₂ I _n -OR ⁴ , - (CH ₂ I _n -SR ⁴ , - (CH ₂ I _n -C-OR ⁶ ,

R ^{4 is} hydrogen, C 1 -C ₄ alkyl, acyl, R ⁵ C 1 -C ₄ alkyl;

X is hydrogen, hydroxy, halogen, Ci-C _s alkyl, halomethyl, Ct-C ₆ -alkoxy, n is a number 1,2,3,4,5 or 6; R ^{3 is} hydrogen, C, -C "alkyl

means.

Preference is given to compounds of the general formula 1 embedded image in which

R ¹ is C, -C _e alkyl; R ^J C, -C ₁₀ alkyl, Ca - ^ - alkenyl, Cj-C <alkynyl, - (CH ₂ J _n -OR ^4, R ⁴ is hydrogen, methyl, ethyl, C _l -C ₄ alkylcarbonyl,

n is 1,2,3,4 or 5; R ^{3 is} hydrogen, C ¹ -C ₈ alkyl

can mean.

Particular preference is given to compounds of the general formula 1 in which

R ^{1 is} ethyl, propyl, butyl, R ² C ₃ -C ₇ -alkyl, C ₁ -C -alkenyl, C ₁ -C -alkynyl, - (CH ₂ I _n -OR ⁴ , R ^{4 is} methyl, ethyl, acetyl, trifluoroacetyl, ethylcarbonyl,

n is a number 1,2,3 or 4; R ^{3 is} hydrogen, methyl, ethyl, propyl

can mean.

The 2-amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes (2-amino-7-carbamoyl-tetralines) according to the invention have at least one carbon atom with an asymmetric center and, depending on the substitution pattern, can also have a plurality of asymmetric centers and can therefore be present in different stereochemical forms exist.

As examples, the following isomers of substituted 2-amino-7-carbamoyltetraline of the general formula 1 a and 1 b may be mentioned

1α ^1b

The invention relates to the individual isomers, their mixtures and the corresponding physiologically suitable acid addition salts with inorganic or organic acids. For example, preferred are salts with hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, lactic, malonic, succinic, maleic, fumaric, malic, tartaric, citric or benzoic acids.

Unless different details are given, the general definitions are used in the following sense:

Alkyl is in general an unbranched or branched hydrocarbon radical having 1 to 12 carbon atoms, which may be preferably fluorine-substituted with one or more halogen atoms, which may be identical or different, with lower alkyl radicals being preferred. Lower alkyl is generally a branched or unbranched hydrocarbon radical having 1 to about 6 carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.

Alkenyl is generally a straight-chain or branched hydrocarbon radical having 3 to 8 carbon atoms and having one or more, preferably one, double bond, which may optionally be fluorine-substituted with one or more halogen atoms, which may be the same or different , Preferred is a lower alkenyl group having 3 to about 4 carbon atoms and a double bond. Particularly preferred is an alkylene radical having 3 or 4 carbon atoms and a double bond. Examples which may be mentioned are allyl, 2-butenyl, 3-butenyl, isopropenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl and isooctenyl.

Alkynyl is generally a straight-chain or branched hydrocarbon radical having 3 to 5 carbon atoms and having one or more, preferably one, triple bonds.

Preferred is a lower alkynyl radical having 3 to about 4 carbon atoms and a Drsifachbindung which is optionally substituted with a halogen atom, preferably fluorine or more halogen atoms, -; can be the same or different from each other. Particularly preferred is an alkynyl group having 3 carbon atoms and a triple bond. Examples include propargyl and butynyl (2).

Acyl is in general benzoyl or Alkylcarbonylreste- such as straight or branched lower alkyl having 1 to about 6 carbon atoms which are bonded via a carbonyl group, wherein the alkyl radical optionally with one or more halogen atom (s) which may be identical or different, may be substituted. Preference is given to alkyl radicals having up to 4 carbon atoms. Examples which may be mentioned are: acetyl, trifluoroacetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.

Particularly preferred is an alkoxycarbonyl radical having 1 to 2 carbon atoms in the alkyl radical. Examples which may be mentioned are the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

Alkoxycarbonyl, for example, by the formula

-C-O-alkyl

being represented.

Alkyl here stands for a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Preference is given to a lower alkoxycarbonyl radical having 1 to 6 carbon atoms. Particularly preferred is an alkoxycarbonyl radical having 1 to 4 carbon atoms in the alkyl radical. Examples which may be mentioned are the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

Halogen, unless otherwise stated, means fluorine, chlorine, bromine and, secondarily, iodine.

Pharmacological characterization

The novel compounds or their physiologically tolerated acid additions have valuable pharmacological properties and have effects on hypertension and heart rate as well as on prolactin secretion and in particular on the central nervous system. Particularly noteworthy the presynaptic dopamine agonistic action of the compounds of the invention with simultaneous postsynaptic dopamine antagonist effect.

For example, therefore, in the compounds

A: 7-Carbarnoyl-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

(In the following tables, instead of the compound names, the letters assigned to them-optionally supplemented by the indication of the optical isomer [+] or [-] -) determine the effect on the inhibition of dopamine synthesis in order to investigate the influence of presynaptic dopaminergic neurons. The effect on postsynaptic dopamine receptors was determined in the monkey (MPTP model).

Determination of dopamine synthesis inhibition

The methodology is carried out according to J. R. Walter and R.H. Roth (Naunyn - Schmiedeberg's Arch. Pharmacol. 296, [1976] 5):

5 animals each receive 10 mg / kg s.c. the substance to be examined. After 5 minutes the dose of 750 mg / kg i.p. γ-Butyiolactone, to exclude the influence of postsynaptic feedback loops on the Dopaminsyntheserate on the blockade of the presynaptic impulse line. The administration of γ-butyrolactone leads to a considerable increase in DOPA or dopamine synthesis. To inhibit the decarboxylation of DOPA after another 5 minutes 200mg / kg i. p.

3-Hydroxybenzyl-hydrazine hydrochloride applied. 40 minutes after substance administration, the animals are killed and the corpus striatum prepared. The measurement of the DOPA content is carried out with the aid of HPLC with electrochemical detection (standard:

Dihydroxybenzylamine).

The percentage inhibition of γ-butyrolactone-stimulated dopa accumulation caused by the test substance is determined in comparison with the control animals treated with 0.9% saline.

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

substance dose Inhibition of Dopaakkumulierung (mg / kg s, c.) in% compared saline-treated controls A 10 86 (+) - A 10 90 B 10 73 (+) - B 10 75 (+) - c 10 83 (+ K> 10 76 (+) - E 10 84 (+) - F 10 85

Determination of Post-Synaptic Dopaminergic Activity by MPTP Model The Pharmacological Properties of the Neurotoxin 1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) (J.W. Langston,

P. Bollard, J.W.Tetrud and I. Irwin, Science 219, [1983] 979) allow its use in the animal model of Parkinson's disease.

The irreversible neurological condition caused by MPTP in humans and monkeys is largely similar to idiopathic Parkinson's disease in its clinical, pathological, biochemical and pharmacological characteristics (SD Markey, JN Johannessen, CCChivek, RSBurns and MAHerkenham, Nature, 311, 1984 ] 464). The cause of this convincing agreement is the fact that MPTP selectively destroys small groups of dopaminergic neurons in the substantia nigra of the brain, which are also destroyed in the naturally occurring Parkinson's disease by degenerative processes.

There is the possibility that the cause of idiopathic Parkinson's disease in the organism is MPTP or a similar chemical compound (S.H. Snyder, Nature 311 [1984] 514). Due to the specific metabolism of MPTP, the clinical manifestation of MPTP-Parkinson's disease has been detectable only in monkeys except in humans.

The MPTP model realized in rhesus monkeys is therefore suitable for testing the effect of postsynaptic dopamine agonist-acting substances.

In addition, rhesus monkeys receive MPTP in total doses of 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; occasionally cataleptic states occur. The extremities have a rigor, which is broken by passive movements of clonic convulsions.

Dopamine agonists, such as B-HT 920, levadopa or apomorphine, result in a temporary abrogation of this conditional pattern for 4 to 5 hours at a single dose of 100 μg / kg intramuscularly. Thereafter, the symptoms described above occur again.

After the intramuscular administration of the compounds according to the invention (0.1-3.0 mg / kg), no improvement or even cancellation of the condition picture of the MPTP-treated monkeys can be observed. It was even an antagonization of the caused by B-HT 920 Aufheb Parkinson symptoms similar to be observed. The animals stay with the

Administration of 1.0-3.0 mg / kg of the compound of the invention together with 0.1 mg / kg B-HT 920 bradykinetisch and are still not able to absorb water and food. This suggests a postsynapisrh dopaminantagonistische effect 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 · (+) · Β 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 preparation of the compounds according to the invention succeeds according to the synthesis scheme below, the individual stages of which are described in detail below:

H ₂ N

NH ₁

H ₂ N

13a

NC

*H

, R ¹

^ R ²

R "HN-

XXX _n - '

^ H

13b

.R ¹

14a

14b

production method

The starting material used 2,7-diamino-1,2,3,4-tetrahydronaphthalene (2) can be prepared by literature methods (S.Chiavarelli and G. Szimimj, Rend.ist.super.sanitä 22 [1959] 508; CA 54 [1960] 2281 g) and the usual methods - for example, the corresponding tartaric acid salts - are separated into the two enantiomers.

The protection of the amino function (R ₅ ) necessary for the further synthesis can be achieved using the methods known from the prior art (M.Bodanszky, Principles of Peptide Synthesis, Springer-Verlag, Berlin 1984, p.84, TW Greene Protective Groups in Organic Synthesis, John Wiley and Sons, New York NY 1981, p.218ff .; Houben-Weyl, Methods of Organic Chemistry, Volume E4, Georg Thieme Verlag, Stuttgart 1983, p. 144), the protection of the Amino function with an alkoxycarbonyl or an araloxycarbonyl protecting group - especially with a tert-butoxycarbonyl (BOC) protecting group being preferred.

Thus, for example, using methods known per se-with pyrocarbonic di-tert-butyl ester in the presence of a base-reacting compound - preferably an organic nitrogen base such. B. triethylamine in inert solvents-the corresponding-optionally enantiomerenreirien 7-amino-2-tert-butoxycarbonylamido-1,2,3,4-tetrahydronaphthalene type 3 represent. The inert solvents are generally organic solvents which do not change under the reaction conditions used. These include preferably ethers such as tetrahydrofuran or glycol dimethyl ether (glyme).

The respective protected racemic or R- or S-diamino-1,2,3,4-tetrahydronaphthalene derivative, preferably the racemic or R- or S ^ -Amino ^ -tert.-butoxycarbonylamido-I ^ .S ^ - tetrahydronaphthalene of the general formula 3 can be prepared by the processes known from the prior art and, in particular, for the preparation of acylanilides, in the correspondingly protected 7-acylamido-2-amino-1,2,3,4-tetrahydronaphthalene derivatives or Acylamido-2-tert-butoxycarbonylamido-1,2,3,4-tetrahydronaphthalenes, which fold under the general formula 4 (C. Fern, reactions of organic synthesis, Georg Thieme Verlag, Stuttgart 1978, p 222 et seq.) ,

Here, the reaction of the respective protected 2,7-diamino-1,2,3,4-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. Reactive carboxylic acid derivatives are generally to be understood as meaning carboxylic acid halides and also carboxylic acid anhydrides, which may 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).

Aliphatic carboxylic acid bromides, carboxylic acid chlorides or aliphatic carboxylic acid anhydrides are preferred here. Particularly preferred are acetic acid bromide, acetic acid chloride, acetic anhydride and trifluoroacetic anhydride. Bases which can be used are all customary basic compounds which are suitable for a basic reaction. These include, for example, alkali metal or alkaline earth metal hydroxides, carbonates or alcoholates and preferably tertiary amines, triethylamine being particularly preferably used.

Inert solvents generally employ organic solvents which do not change under the reaction conditions used, for example hydrocarbons, such as benzene, toluene, xylene or petroleum fractions, or halohydrocarbons, e.g. For example, methylene chloride, chloroform or carbon tetrachloride, or preferably ether such as diethyl ether, glycol dimethyl ether (glyme), diglycol dimethyl ether (diglyme) and more preferably tetrahydrofuran.

The subsequent cleavage of the protecting group R _s from the amino function in the 2-position in the tetrahydronaphthalene of the general formula 4 can be carried out according to the type of protective group and depending on the chemical stability of the acylanilide partial structure using the methods known from the prior art (TW Groane, Protective Groups in Organic Synthesis, John Wiley End Sons, New York 1981, p.218ff; U. Petersen in Houben-Weyl, Methods of Organic Chemistry, Volume E4, Georg Thieme Vorlag, Stuttgart 1983, p. 144) from which the acylated 1,2,3,4-tetrahydronaphthalene derivative of the general formula 5 results.

NH,

C = O

C = O

6a

6b

For the conversion of the primary amino function in the T-acylamino-Z-amino-i ^^^ - tetrahydronaphthalene derivative of the general formula 5 into a tertiary Arnin -for which a tetrahydronaphthalene derivative of the general formula 6b results- are also known from the prior art Numerous methods are known (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 ^rd Ed., John Wiley and Sons , New York 1985, p 1153), wherein - in the case of R '= R * - the alkylation takes place in one step and - in the case of R' is not R ² - the intermediate product of type 6a to the corresponding tertiary amine 6b is reacted.

The further course of the synthesis may at this stage of the synthesis possibly the introduction of a protective group (R ² = R ₁ ) -wie

For example, a Benzylschutzgruppe-required. '

The respective protective group can be cleaved off again according to the methods known from the prior art or replaced by another substituent (TW Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, NY New York 1981, p.272ff. Lit.), (s.Formelschema page 25,9-13a-14a and 12-13b-14b) Preferably, the alkylation is carried out 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,

1-halo-3-phenylpropanes

1-halo-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.

Suitable solvents are all inert organic solvents which do not change under the reaction conditions or which themselves can not disadvantageously intervene 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 see as Alkylierungsdgenzwirken preferably halogenated hydrocarbons wi.i fluorohydrocarbons, methylene chloride, chloroform or carbon tetrachloride and more 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 win for example Hexamethylphosphorsäuretriamid or dimethylformamide.

In addition, it is possible to use mixtures of said solvents.

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

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

The reaction is preferably carried out in the presence of acid-binding agents - such as. As alkali or alkaline earth carbonates or bicarbonates carried out.

On the other hand, the primary amino function of the diamine of the general formula 5 can be achieved by the reductive amination of a suitable aldehyde or ketone or its suitable derivatives, depending on the molar ratio of the carbonyl compound used to the 7-acylamino-2-amino-1,2, 3,4-tetrahydronaphthalene derivative of the general formula 5-

be converted into the corresponding secondary or tertiary amine. This transfer can take place either directly or via the respective Schiff's bases as intermediates.

The aldehydes or ketones used as starting materials are known or can be prepared by known methods who egg. (Aldehydes: Houben-Weyl, Methods of Organic Chemistry, Volume VII / 1 and E 5, Georg Thieme Verlag, Stuttgart 1954 and 1983; Ketones: Houben-Weyl, Methods of Organic Chemistry, Volume Vil / 2 a and 2 b, Georg Thieme Verlag, Stuttgart 1973 and 1976).

Suitable aldehydes or ketones are z. B. embodied by formaldehyde, acetaldehyde, propionaldehyde, acetone, butyraldehyde, benzaldehyde, phenylacetaldehyde, 2-phenylpropionaldehyde, 3-phenylpropionaldehyde, 4-ph3nylbutyraldehyde.

The Schiff base is prepared in inert organic solvents, if appropriate in the presence of a catalyst and if necessary in the presence of a water-binding agent.

Suitable inert solvents here are inert organic 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, for example, 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 Example Dichlormethan.Trichlormethan.Tetrachlormethan- or hydrocarbons such as petroleum fractions, benzene, toluene, xyiol and particularly preferably amides- such as dimethylformamide, acetamide, hexamethylphosphoric triamide - or carboxylic acids - such as formic acid or acetic acid - or mixtures of said solvents.

If necessary, protic acids are used as catalysts. Preferred among these fall mineral acids such as hydrochloric acid or sulfuric acid or organic carboxylic acids having 1 to 6 carbon atoms, which is optionally substituted by fluorine, chlorine and / or B ^r om may be substituted. 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 having C 1 -C ₄ -alkyl radicals or aryl radicals which may be substituted by halogen atoms, for example methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid.

The water formed in the reaction may, if necessary, be removed from the reaction mixture by addition of water-binding agents such as phosphorus pentoxide or by molecular sieve or in admixture with the solvent used during or after the end of the reaction, for example by distillation.

The reaction is generally carried out in a temperature range of + 2O ⁰ C to the boiling point of the respective reaction mixture and preferably in a temperature range from + 2O ⁰ C to 100 ⁰ C.

When azeotropically distilling off the water formed in the reaction with the respectively used solvent or solvent mixture, the boiling point of the respective azeotrope is preferred.

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

For the preparation of the secondary amine, the 7-acetamido-2-amino-1,2,3,4-tetrahydronaphthalene and the respective carbonyl compound are used equimolar. To prepare the tertiary amine, the respective carbonyl compound is used in excess.

The resulting in the production of secondary or tertiary amines as intermediates Schiff bases or

Enamines or immonium salts can be hydrogenated or reduced either by hydrogen in water or in inert organic solvents such as alcohols, ethers or halocarbon, or mixtures thereof with hydrogen in the presence of suitable catalysts or with complex hydrides - optionally in the presence of a catalyst. The reduction may be carried out in the same reaction medium or else in another solvent or in another solvent mixture. In the latter case, the solvent or solvent mixture used first is preferably removed by distillation.

The catalysts used in the catalytic reduction with hydrogen, for example, Raney nickel, palladium, palladium on animal charcoal, platinum and preferably palladium on carbon (10% Pd content) use.

In the reduction with hydrides complex hydrides of boron are preferably used. Particular preference is given to using sodium borohydride.

Suitable solvents are all inert organic solvents which remain unchanged or at least largely unchanged under the chosen reaction conditions and which do not adversely interfere with the course of the reaction. These include amides such as dimethylformamide or hexamethylphosphoric triamide or ether such as diethyl ether, tert-butyl methyl ether, di-n-butyl ether, glycol dimethyl ether (glyme), diglycol dimethyl ether (diglyme), tetrahydrofuran and dioxane - and more preferably alcohols - for example methanol , Ethanol, propanol or isopropanol.

In the reduction with hydrogen, the reaction is carried out under the reaction conditions known for the catalytic hydrogenation, depending on the particular catalysts, solvents and reactants used (K. Harada in Patai, "The Chemistry of the Carbon-Nitrogen Double-Bend", lnterscience Publishers , London 1970, p.276 and cit. 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. Ill (1955) 501; J.C. Robinson and H.R. Snyder, Org. Synth., Coll, Vol. Ill (1955) 717; D.M. Malcolm and CR Noller, Org. Synth., Coll. Vol. IV11963] 603).

Preferably, the hydrogenation with palladium on carbon (10% Pd content) in methanol in a temperature range of 20 to 50 ° C - particularly preferably in a temperature range of 25 ° C to 35 ⁰ C - under a hydrogen pressure of preferably 0.1 to 0.8MPa - more preferably under a hydrogen pressure of 0.4 to 0.6 MPa - carried out.

In carrying out the process according to 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 more preferably using dimethylformamide in a temperature range between 50 ° C and 100 ⁰ C to implement, to distil off the solvent after completion of the reaction under reduced pressure, the remaining residue in an organic solvent, preferably an alcohol - to dissolve or to disperse and with an at least equimolar amount of a reducing agent - preferably

a complex hydride and particularly preferably sodium borohydride - to implement after the reduction, hydrolytically work up, the reaction product by extractive from the Reaktionsgemlrch isolie ^r en and optionally chromatographically clean or otherwise subject to a purification step and to isolate.

The preparation of the compounds of the invention in the context of a reductive amination is feasible in a further synthesis variant by way of a Leukart-Wallach reaction, which is particularly suitable for the preparation of tertiary amides. The reaction conditions for such reductive aminations are known (Autorenkollektiv, Organikum, VEB Deutscher Verlag der Wissenschaften, Berlin 1986 (16th edition) page 491; C. Ferri, reactions of organic synthesis, Georg Thieme Verlag, Stuttgart 1978, p. 133 and cited Ref. 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 general formula 6b according to the invention can also be obtained by the combination of the stated preparation methods.

C = O

^R A

6b:

⁷ ' ^: R ¹ 4H, R ² * -H

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

The saponification of such arylamides is known and can be achieved, for example, by reacting a carboxylic acid amide of general formula 6b with aqueous solutions of alkali metal hydroxides or acids (F.Möller in Houben-Weyl.

Methods of Organic Chemistry, Volume XI / 1, Georg Thieme Verlag Stuttgart 1957, S.927ff. and 934ff .; R.M.He.-bst and

D. Shemin, Org. Synth., Coll. Vol. Il [1943] 491; P.E. Fanta and D.S.Tarbell, Org. Synth., Coll. Vol. Ill [1955] 661). Preference is given to the reaction with dilute mineral acid under reflux conditions, particular preference being given to saponification with 2N hydrochloric acid which immediately gives the corresponding hydrochlorides in a one-pot reaction, which after distilling off the reaction medium and the volatile constituents of the reaction mixture are preferably under reduced pressure and slurrying in an organic solvent - preferably an alcohol, with ethanol being particularly preferred

will - be isolated after filtration and drying.

The preparation of the 2-amino-2-cyano-tetralin derivative 8 succeeds in a manner known per se (Organikum, Deutscher Verlag der Wissenschaften, 17th edition, Berlin 1988, p 547, Vogels Textbook of Practical Organic Chemistry, 4. Edition, Longman, London 1978, p.703) -on the way of a so-called Sandmeyer reaction by reacting the optionally protected 2,7-diamino-1,2,3,4-tetrahydronaphthalene derivative of type 7 z. With potassium cyanide in the presence of copper (I) cyanide.

In carrying out the process according to the invention, in general, dazonium salts are formed as intermediates which can be isolated. However, it has proved expedient to carry out the process without isolation of the intermediates.

Suitable inert solvents here are water or alcohols - such as methanol, ethanol, propanol or isopropanol - or amides - such as formamide or dimethylformamide - with water being the preferred solvent.

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

As nitriles, alkali metal cyanide such as sodium or potassium cyanide are generally used. Preferably, potassium cyanide is used.

The reaction is carried out more generally, in a temperature range from -1O ⁰ C to + 15O ⁰ C, preferably from -5 ⁰ C to + 5O ⁰ C.

The reaction is generally carried out at atmospheric 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 according to the invention is generally carried out by initially adding a solution of nitrite in water to the 2-amino-tetraun in aqueous sulfuric acid and then dissolving the reaction solution with the alkali metal cyanide, preferably potassium cyanide and copper (I) cyanide, optionally in water , treated. The diazonium salt is generally not isolated.

The workup is generally carried out by neutralization of the reaction mixture with aqueous ammonia solution or with alkali metal hydroxides or carbonates, and extraction of the resulting free bases from which their salts can be obtained by reaction with appropriate acids.

10 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, the corresponding amides of type 9 are accessible, while the saponification of the cyano compound 8 with concentrated hydrochloric acid makes the corresponding type 10 tetralin carboxylic acid derivatives 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 nitrites, per se, are known in the art (PL Compagnon and M. Mioque, Ann. Chim. [Paris] [14] 5 [1970] 11-22; PL Compagnon and M. Mioque, ibid -37; ENZil'berman, Russ. Chem. Rev. 31 [1962] 615). The reaction medium used is preferably water. The reaction is carried out in a temperature range from 0 ° C to the boiling point of the reaction mixture and under atmospheric pressure. A temperature in the range of 20 ⁰ C to 12O ⁰ C. is preferred

R ¹

10

11

H ₂ NR ""

12

The Tetralincarbonsäure derivative 10 can be processed by using literature known methods (J. March, Advanced Organic Chemistry, ^3rd Edition, New York NY 1985, p 388 and references therein. Lit.) conveniently using thionyl chloride into the corresponding acid halide or acid chloride 11, C. Ferri, Reactions of Organic Synthesis, Georg Thieme Verlag, Stuttgart 1978, p. 192, and citation, Organikum, Deutscher Verlag der Wissenschaften, 17th Edition, Berlin 1988, p.

J. S. Pizey, Synthetic Reagents, Vol. 1,321, Wiley, New York N.Y. 1974).

The subsequent reaction of the resulting acid halide or acid chloride with a primary amine yields the corresponding acid amide 12 in a manner known per se (C. Ferri, Reactions in Organic Synthesis, Georg Thieme Verlag, Stuttgart 1978, page 223 and cited The reaction is conveniently carried out in inert solvents.

Inert solvents are generally solvents which do not change under the reaction conditions. These include preferably 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 said solvents.

The amination of the acid halide or -chloride of type 11 is generally carried out in a temperature range from -20 ° C to 100 "C, preferably from -2O ⁰ C to 50 ° C at atmospheric pressure.

NHR

13a

HNR

12

HNR

NHR

13b

The subsequent separation of the protective group Rs (R ² = Rs) 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 partial structure- using the methods known in the art (TW Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York 1981, pp. 218ff; 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 13 b results.

For example, compounds of the type 9 and 12 which carry on the amino function of a benzyl radical as a protective group, which enables the cleavage of the protecting group by catalytic hydrogenation on a palladium catalyst, resulting in the tetramihydronaphthalene type 13a.

13a

14 a

13 b

14b

For the conversion of the secondary amino function in the 2-amino-1,2,3,4-tetra.iydronaphthalene derivative of the general formula 14a or 14b into a tertiary amine from which a tetrahydronaphthalene derivative of the general formula 14a or 14b Numerous methods are known from the state of the art (G. Spielberger in Houben-Weyl, Methods of Organic Chemistry, Volume XI / 1, Georg Thieme Verlag, Stuttgart 1957, p.24; March, Advanced

Organic Chemistry, 3 ^rd Ed., John Wiley and Sons, New York, p. 1153), where in reductive aminations the reducing agent must be selected so that the carboxylic acid amide function is not attacked. (March, Advanced Organic Chemistry,

3 '"Ed John Wiley and Sons, NY New York 1985, p.

Preferably, on the one hand, the alkylation is carried out with optionally derivatized alkyl or aralkyl halides or sulfates, tosylates, methanesulfonates or trifluoromethanesulfonates-such as e.g. Methyl, ethyl, propyl, isopropyl, butyl, allyl, propargyl, benzyl, phenethyl, o, m, p-methylbenzyl, o, m, p-methoxybenzyl halides, 1-halo-3-phenylpropanoids,

1-halo-3-phenyl-prop-2-enes,

1-halo-4-phenylbutanes,

1-halo-3- (p-chlorophenyl) propanes,

(2-haloethyl) -methylethern,

1-halo-3-methoxypropanes,

(2-haloethyl) -methylsulfiden,

(2-haloethyl) -phenylsulfiden,

(3-halopropyl) -methylsulfiden,

ß-Halogenpropionsäuremethylestern,

p- (2-haloethyl) methoxybenzenes, »

-toluolen p- (2-haloethyl)

-methoxybenzolen p- (2-haloethyl)

(2-haloethyl) -3,4-dimethoxybenzenes,

(2-haloethyl) -3-chloro benzenes,

(2-haloethyl) -2,4-dichlorobenzene,

(2-haloethyl) -3,5-dichlorobenzene,

(2-halo-1-methylethyl) benzenes,

where halogen or halide means chlorine, bromine or iodine.

Such halides, sulfates, trifluoromethylsulfonates or tosylates are known or can be prepared by known methods, wherein the incorporation of polyfunctional substituents, the z. B. have free phenolic hydroxyl or (carbon) acid functions, first their corresponding protected derivatives, such as. As ethers or esters can be introduced in a further step in a conventional manner -z. B. by ether or ester cleavage or by saponification - be converted into the desired derivatives. Such derivatives include, for example, 1-bromo-2- (4-methoxybenzene) ethane, ethyl bromoacetate, and ethyl 3-bromopropionate.

Suitable aldehydes or ketones for the reductive amination z. By formaldehyde, acetaldehyde, propionaldehyde, acetone, butyraldehyde, acrolein, propargyl aldehyde, benzyl aldehyde, phenyl acetaldehyde, 2-phenylpropionaldehyde, 3-phenylpropionaldehyde, 3-phenylacrolein (cinnamaldehyde), 4-phenylbutyl raldehyde, 3-phenylpropionaldehyde, 3-phononacrolein (cinnamaldehyde). , 4-phenylbutyraldehyde, methoxyacetalehyde, phenoxyacetaldehyde, benzyloxyacetaldehyde, 3-methoxypropionaldehyde,

Methylmercaptoacetaldehyd,

3-.Methylmercaptopropionaldehyd,

Methylmercaptoacetaldehyd,

(3,4-DichlorpnenyO-acetaldehyde,

4-methoxyphenylacetaldehyde,

(3,4-DimethoxyphenyO-acetaldehyde,

(3,5-dimethoxyphenyl) acetaldehyde.

Furthermore, the compounds according to the invention can be prepared by any other reaction starting from secondary amines as the amino component - for example by way of a Michael reaction. Suitable reactants for this representation variant embody z. As derivatives of acrylic acid, methacrylic acid or crotonic acid

(C. Ferri, Reactions of Organic Synthesis, G. Thieme Verlag, Stuttgart 1978, p 173 and cited L> * ..; M. B. Gases, A. Lattes and J. J.

Porio, Tetrahedron 39, (1083) 703; H. Pines and WM Stalick in "Base-Catalisied Reactions of Hydrocarbons and Realted Compounds", Academic Press, New York NY 1977, p.423, MS Gibson in Patai "The Chemistry of the Amino Group", lntercience, New York NY 1968 , P. 61 ff.).

The tertiary amines of the general formula 14a or 14b according to the invention can likewise be obtained by combining the stated preparation methods.

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

The prefix (+) / (-) given in the preparation examples before the names of substances is intended to mean that these syntheses can be carried out both with the levorotatory and with the dextrorotatory optical isomers or with the mixture or

the corresponding racemate are feasible.

example 1

Separation of 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 11 of a methanol / water mixture (95: 5) and heated to 50 ° C. At this temperature, a solution of 37.5 g (0.25 mol) of L - (+) - tartaric acid in 200 ml of methanol is added. The precipitated after a short time crystals are filtered off with suction, boiled three times with 300 ml of methanol / water mixture (95: 5) and recrystallized once from water. The tartrate is then suspended in 70 ml of water, mixed with 33 g (0.6 mol) of potassium hydroxide and extracted twice each with 70 ml of tetrahydrofuran. After drying the organic phase with magnesium sulfate and filtering off the desiccant, the solvent i. Vak. removed and the residue distilled under a reduced pressure of 0.08 hPa.

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

Yield: 9.7 g (12%) Mixture: 33-34 ° C bp. 108-110 ° C

The (-) enantiomer is obtained by analogy using R - (-) - tartaric acid.

Yield: 9.8 g (12%) Schmpf .: 33-34 ⁰ C b.p .: 108-110 ⁰ C.

In the following examples, in each case (+) - 2,7-diamino-1,2,3,4-tetrahydronaphthalene or (-) - 2,7-diamino-1, '<:, ? 4-tetrahydronaphthalene.

Example 2

(+ J / J ^ -Amino-i ^ -tert-butoxycarbonylamide-I ^ .S ^ tetrahydronaphthalen

To a solution of 20 g (0.12 mol) of (+) / (-) - 2,7-diamino-1,2,3,4-tetrahydronaphthalene and 17.1 ml (0.12 mol) of triethylamine in 250 ml of anhydrous tetrahydrofuran is added - 10 ° C is added dropwise a solution of 28.7 ml (0.12 mol) of pyrocarbonic acid di-tert-butyl ester in 140 ml of anhydrous tetrahydrofuran. The mixture is stirred for 30 minutes at -10 ° C and then the reaction solution is allowed to warm to room temperature. The solvent is i. Vak. distilled off and the residue is mixed with 500 ml of ethyl acetate and washed twice with jo 100 ml of water. Subsequently, the organic phase is dried with magnesium sulfate, the solvent i. Vak. removed and the residue recrystallized from diethyl ether.

Yield: 25g (80%), m.p .: 119-121 ⁰ C.

Example 3

(+) / (-) - 7-Acetamido-2-tert-butoxycarbonylamido-1,2,3,4-tetrahydronaphthalene 25g (95mmol) 7-amino-2-tert-butoxycarbonylamido-1,2,3,4 tetrahydronaphthalene and 14.5 ml dOOmmol) triethylamine are dissolved in 120 ml of anhydrous tetrahydrofuran and treated at room temperature with 9.9 ml (105 mmol) of acetic anhydride.

The mixture is stirred for 1 hour at room temperature and then added 450 ml of ice water. The precipitated crystals are filtered off with suction and washed with 200 ml of water, with 35 ml of acetone and with 60 ml of diethyl ether and dried in a circulating air dryer to constant weight.

Yield: 25,9g (93%), m.p .: 193-195 ⁰ C.

Example 4

(+) / (- l ^ Acetamido ^ -amino-I ^ .S ^ tetrahydronaphthalene hydrochloride

50 g (0.16 ml) 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 approximately 10 minutes, during which the temperature is allowed to rise to 70.degree. The mixture is allowed to cool to room temperature, the precipitated crystals are filtered off, washed once each with 100 ml of acetone and 100 ml of diethyl ether and dried in a convection oven first at room temperature, then at 8O ⁰ C under atmospheric pressure to constant weight.

Yield: 36g (91%) m.p .: 26O ⁰ C

Belspiel5

(+! / (- J ^ -Acetamido) -propylamino-I ^. S ^ -tetrahydronaphthalene hydrochloride (alkylation)

83.8 g (0.41 mol) of (+) - (- J ^ -acetamido -amino) -tetrahydronaphthalene and 75.6 g (0.61 mol) of propyl bromide are dissolved in 900 ml of tetrahydrofuran, with 84 g (0.84 mol The mixture is then heated to reflux temperature for 7 hours, then a further 75.6 g (0.61 mol) of propyl bromide are added and the mixture is boiled for a further 7 hours, allowed to cool to room temperature, filtered and concentrated by evaporation in vacuo The organic phase is dried with magnesium sulfate, concentrated by evaporation of the drying agent in vacuo and the remaining residue on silica gel (particle size 0.063 to 0.2 mm) with a mixture of methylene chloride and methanol (80 :. After chromatographic isolation, concentration of the eluate in vacuo and reaction of the residue with a solution of hydrogen chloride in diethyl ether, the title compound is precipitated as hydrochloride, filtered off and removed in a circulating air drying cabinet to Ge Constant weight dried.

Yield: 43,4g (38%) M.p .: 171 ⁰ C.

Example 6

(+! / (- ^ - Acotamido) -IN-butyl-propylaminoM ^ .S ^ -tetrahydronaphthalene-hydrochloric acid 7g (24,8mmol) (+! / (- J ^ -acetamido ^ -propylamino) ^^^ tetrahydronaphthalene-hydrochloride and 12.8 g (93mmol) of butyl bromide are dissolved in 80 ml of dimethylformamide, treated with 10 g (lOOmmol) Kaliumhyrogencarbonat 9hrs and stirred at 8O ⁰ C. it is allowed to cool to room temperature, filtered and the filtrate i. vac is concentrated., mixed with 250ml of water and

extracted 2 times with 200 ml of ethyl acetate. The combined organic extracts are dried with magnesium sulfate and after filtering off the desiccant i. Vak. concentrated. The remaining residue is chromatographed on silica gel (particle size 0.063 to 0.2 mm) with a mixture of methylene chloride and methanol (80:20).

After the chromatographic isolation of the evaporation of the eluate i. Vak. Urjd 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 weight consistency.

Yield: 5.6 g (67%), m.p .: 208-210 ⁰ C.

Example 7

(+ J / f-1-acetamido) -N-N-diethylamino-1-yl-S-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 treated with 2.2 g of palladium / carbona (10% Pd). It is hydrogenated for 18 hours in an autoclave at 3O ⁰ C and a hydrogen pressure of 600 kPa. It is then filtered off with suction through silica gel and the solvent i. Vak. distilled off. The residue is then treated with 150 ml of diethyl ether and washed twice with 60 ml of water. The organic phase is dried with magnesium sulfate, the solvent after filtering off the desiccant i. Vak. and the remaining residue on silica gel (particle size 0.063-0.2 mm) chromatographies (eluent: ethyl acetate / methanol, 80:20). After chromatographic isolation, the eluate is concentrated and the (+) / (-) - acetamido-2-N, N-diethylamino-1,2,3,4-tetrahydronaphthalene is converted into the hydrochloride with ethereal hydrochloric acid. The crystals are filtered off with suction and dried in a circulating air drying cabinet to constant weight.

Yield: 1.7 g (18%) mp:> 265 ° C

Example 8

(+ Vf-J ^ -Acetamido ^ -f-N-butyl-N-propylamino) -I ^. S ^ tetrahydronaphthalene hydrochloride 1 / 5g (4.4mmol)

(+) / (-) -Yy-acetamido-t-N-butyl-N-propylamino-1,3-di-tetrahydronaphthalene hydrochloride are refluxed with 30 ml of 2N HCl for 2 hours, then the solution is concentrated in vacuo, the residue is washed with 20 ml of ethanol, the crystals are filtered off, washed with ethanol and dried in a convection oven to constant weight.

Yield: 1.1 g (75%) mp .:> 167 ⁰ C

Example 9

(+ J / K-l-cyano ^ -F-N / N-dipropylaminoM ^ .S ^ tetrahydronaphthalen

To a solution of 24.6 g (0.1 mol) of 7-amino-2- (N, N-dipropylamino) -1,2,3,4-tetrahydronaphthalene in 50 ml of water and 12.5 ml of conc. Sulfuric acid is allowed to flow within a temperature interval of -5 ° C to 0 ° C, a solution of 2.5 g (0.12 mol) of sodium nitrite in 50 ml of water. The mixture is allowed to after-react for 30 min at -5 ⁰ C.

Subsequently, the reaction mixture with a cooled to -5 ⁰ C solution of 40g (0.6 mol) of potassium cyanide and 20g (0.2 mol) of copper (l) cyanide in 200 ml of water, the mixture foams strongly. After the evolution of gas has subsided, stirring is continued for 30 minutes at room temperature. It is the reaction solution with 400ml conc. Ammonia solution alkaline. It is extracted three times with 400 ml of ethyl acetate, the combined organic extracts are washed with 500 ml of water, dried and after removing the desiccant i. Vak. concentrated. The residue is distilled under high vacuum.

Yield: 20.2g (79%) bp: 132-135 (0.06 torr).

Analogously to Example 9 is prepared: (+! / {-! ^ - (N-benzyl-N-propylamino) ^ cyano-I ^ .S ^ -tetrahydronaphthalene

Yield: 58%

Bp .: 180-185 (10- ³ mbar)

Example 10

(+ Vi-J ^ -Carbamoyl) -fN.N-dipropylaminoM ^ .SAtetrahydronaphthalene hydrochloride Dissolve 3.0 g (12 mmol) of 7-cyano-2- (N, N-dipropylamino) -1,2,3,4 tetrahydronaphthalene in a mixture of 18 ml of methanesulfonic acid and 2 ml of water and the reaction mixture is heated for 1 hour to 11O ⁰ C. Then allowed to cool, the reaction mixture is poured onto ice and made alkaline with about 60 ml of concentrated ammonia solution extracted, the combined organic extracts washed with 100 ml of water, dried and i. Vak.

concentrated. The residual base is dissolved in acetone and the hydrochloride is precipitated with ethereal hydrochloric acid.

Yield: 3.0 g (81%), m.p .: 251-253 ⁰ C.

Analogously to Example 10 is shown: (2R) -7-carbamoyl-2- (N, N-dipropylamino) -1,2,3,4-tetrahydronaphthalene hydrochloride

Yield: 78%

Mp .: 255 ° C

[a) _o 2O = (+) 76.7 ° {C = 1; methanol)

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

Yield: 79%

M .: 252-254 "C

[a] ₀ 20 = -71.9 "(C = 1, methanol)

(+ / (- l ^ -in-benzyl-N-carbamoyl ^ propylaminoJ-i ^^^ - tetrahydronaphthalen-hydrochloride

Yield: 65% m.p .: 142-144 ⁰ C.

Example 11

(+ J / il ^ -hydroxycarbonyl-iN-N-dipropylamino) -is-tetrahydronaphthalene hydrochloride 8.1 g (31.5 mmol) of 7-cyano-2- {N, N-dipropylamino) -1,2,3 , 4-tetrahydronaphthalene are concentrated with 150ml. Hydrochloric acid and heated for 8 hours under reflux. Subsequently, the reaction mixture i. Vak. concentrated, the residue is mixed with 100 ml of acetone and the precipitated crystals are filtered off with suction. The crystals are washed once with 30 ml of cold water and once each with 50 ml of acetone and diethyl ether and then dried in a drying oven at 50 ⁰ C.

Yield: 6.2g (63%) mp: 223-226 ° C

Example 12

2- (N, N-Dipropylamino) -7-methyl-carbarnoyl-1,2,3,4-tetrahydronaphthalene hydrochloride 5g (16 mmol) 7-hydroxycarbonyl-2- (N, N-dipropyl-amino) -1,2,3 , 4-tetrahydronaphthalene hydrochloride are heated with 1.8 ml (24 mmol) of thionyl chloride for 30 min under reflux and exclusion of moisture.

Then distilled the excess thionyl chloride i. Vak. and the residue is combined with 100 ml of dichloroethane.

The solution was cooled to 0 ° C and leaves a solution of 36g (1.1 mol) of methylamine in 300ml abs. Run tetrahydrofuran so that the reaction mixture is not heated to a temperature above 10 ° C. The mixture is allowed to react for 30 minutes at room temperature, the solvent is i. Vßk. and the residue is mixed with 150 ml of potassium carbonate solution (20 g K ₂ CO ₃ in 150 ml of water). The mixture is extracted three times with 150 ml of ethyl acetate, washed the combined organic extracts with 150 ml Wasse ~, dried and after removing the desiccant i. Vak. concentrated. The residual base is dissolved in acetone and treated to precipitate the hydrochloride with ethereal hydrochloric acid.

Yield: 4.6 g (88%) Schrnp .: 222-224 ⁰ C.

Analogously to Example 12 is prepared: 7-ethylcarbamoyl-2- (N, N-dipropylamino) -1,2,3,4-tetrahydronaphlhalin hydrochloride

Yield: 92% m.p .: 195-196 ⁰ C.

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

Yield: 75%

M .: 233-235 ⁰ C

[alo20 = +73.5 "(C = 1, methanol)

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

Yield: 71%

M .: 233-235 ⁰ C

(a) _D 20 = -73.6 ° (C = 1, methanol)

Example 13

(2R) -7-Carbamoyl-2-propylamino-1,2,3,4-tetrahydronaphthalene hydrochloride 28.5g (85mmol) (2h) -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 / carbon (10%). Hydrogenated for 5 hours in an autoclave at 20 ⁰ C and a hydrogen pressure of 5 bar. Hydrogen uptake is complete after consumption of the calculated amount. The catalyst is suctioned off over silica gel and the filtrate is concentrated. Vak. on. The residual base is dissolved in ethanol and the hydrochloride is precipitated with ethereal hydrochloric acid.

Yield: 15.4 g (68%), m.p .: 242-244 ⁰ C [a] 20 _D = (+) 70.7 ° (C = 1; methanol)

Analogously to Example 13 is shown: (2S) -7-carbamoyl-2-propylamino-1,2,3,4-tetrahydronaphthalene hydrochloride

Yield: 73% m.p .: 244-246 ⁰ C [a) = -68.9 o2o ° (C = 1; methanol)

(+ / (- ^ J ^ carbamoyl propylamino-I ^ .S ^ tetrahydronaphthalen-Hydrochlorld

Yield: 97% mp .: 255-257 ⁰ C

{+ ^ - ^ methylcarbamoyl propylamino-I ^ .SAtetrahydronaphthalin hydrochloride

Yield: 91% m.p .: 245-247 ⁰ C [aJ _D 20 = + 60.5 ° (C = 1; methanol)

Example 14

(2R) -2- (N-allyl-N-propylamino) -7-carbamoyl-1,2,3,4-tetrahydronaphthalene hydrochloride 7.3g (27mmol) (2R) -7-carbamoyl-2-propylamino-1 , 2,3,4 (etrahydronaphthalin hydrochloride, 6,4ml (74mmol) of allyl bromide and 6.6 g (41 mmol) of potassium carbonate are stirred at 35 ⁰ C in 73ml of dimethylformamide for 4 hours. then the reaction mixture is evaporated down i.. concentrated The residue is combined with 200 ml of water and extracted twice with 150 ml of ethyl acetate each time, the combined organic extracts are washed with 100 ml of water, dried and, after removal of the drying agent in vacuo, the residue is recrystallised once from ether, after which the purified base is added dissolved in methanol and the hydrochloride precipitated with ethereal hydrochloric acid.

Yield: 67% m.p .: 233-235 ° C [a] _D 20 = -81.1 ° (C = 1, methanol)

Analogously to Example 14 is prepared: (-! ^ - (N-Allyl-N-propylaminoJ ^ -carbamoyl-l ^. S ^ -tetrahydronaphthalene hydrochloride

Yield: 62% m.p .: 228-233 ⁰ C _{o al 2O = -80.1 ° (C = 1; methanol)

(+ JA-i ^ carbamoyl ^ -in-ethyl-N-propylaminoJ-I ^ .S ^ tetrahydronaphthalene hydrochloride

Yield: 72% m.p .: 168-17O ⁰ C

(+ L ^ -IN-allyl-N-propylaminoJ ^ -methyl-I ^ .S ^ tetrahydronaphthalene hydrochloride

Yield: 72% m.p .: 223-225 "C [alo2 O = +83.9" (C = 1, methanol)

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

Yield: 84% m.p .:> 100 ° CZers. [aJ _D 20 = + 70.9 ° (C = 1, methanol)

(+ L ^ ^ -methylcarbamoyl -IN-phenylethyl-N-propylaminoJ-I ^ .SAtetrahydronaphthalin hydrochloride

Yield: 69% m.p .; > 80 ° CZers. [a) o2O = + 50.5 ° (C = 1, methanol)

Example 15

(+ (^ - (N-Methoxycarbonylethyl-N-propyl-1-ylmethyl) -carbamoyl-1-yl-S-tetrahydronaphthalene hydrochloride 1.5g (5,3mmol) (2R) -2-propylam (o-7-methylcarbamoyl -1,2 _# 3,4-tetrahydronaphthalene-hydrochloride and 1.4 g of potassium carbonate are dissolved in 15ml methanol, treated with 2 ml of methyl acrylate and heated to SO ^0C. It i warmed "jesarnt 36h, with all 9 h another 2 ml Acrylester added The reaction mixture is then concentrated by evaporation, the residue is combined with 50 ml of water and extracted twice with 50 ml of ether each time, the combined organic extracts are dried, concentrated and the residue is filtered through a short silica gel column (about 5 g of silica gel and 200 ml The suitable fractions are concentrated and the hydrochloride is precipitated with ethereal hydrochloric acid.

Yield: 1.4 g = 71% m.p .:> 65 ° C

fa) _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 active substances according to the invention and 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. As tablets, dragees, capsules, pills, suppositories and ampoules are present, the active substance content corresponds to a fraction or a multiple of a single dose. The dosage units may contain, for example, 1,2,3 or 4 single doses or Vs, 73 or ¹ A of a single dose. A single dose 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 dose.

By non-toxic, inert pharmaceutically acceptable excipients are meant solid, semi-solid or liquid diluents, fillers and formulation aids of any kind.

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

Tablets, dragees, capsules, pills and granules may contain the active ingredient (s) in addition to the usual excipients, such as (a) fillers and extenders, e.g. As starches, lactose, cane sugar, glucose mannitol and silica, (b) binders, for. B.

Carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. Glycerine, (d) disintegrants, e.g. B.

Agar-agar, calcium carbonate and sodium carbonate, (e) solution retarder, e.g. Paraffin and (f) absorption enhancer, e.g.

quaternary ammonium compounds, (g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, (h) adsorbents, e.g. B.

Kaolin and bentonite and (i) lubricants e.g. As 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 may be provided with the usual, optionally containing opacifying, coatings and shells and also be composed so that they deliver the active substance or only optionally delayed in a certain part of the intestinal tract, where as embedding masses z. B.

Polymer substances and waxes can be used.

The active substance (s) may optionally also be present in microencapsulated form with one or more of the excipients specified above.

Suppositories may contain the usual water-soluble or water-insoluble excipients in addition to the active substance or substances, for. As polyethylene glycols, fats, z. As cocoa fat and higher esters (eg., Cu-alcohol with Ci ₆ fatty acid) or mixtures of these substances.

Solutions and emulsions may contain, in addition to the active substance (s), the customary carriers such as 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, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofuryl alcohol, polyethylphenyl glycols and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions may also be present in sterile and blood isotonic form.

Suspensions may in addition to the active ingredient or the usual carriers such as liquid diluents, for. P. water, ethyl alcohol, propylene glycol, suspending agent, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, Aluminiummethahydroxid, bentonite, agar-agar and tragacanth or mixtures of these substances.

The said formulation forms may also contain colorants, preservatives and odor and flavor improving additives, e.g. Saccharin, included.

The therapeutically active compounds should preferably be described in the abovementioned pharmaceutical preparations in.

a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95 wt .-% of the total mixture.

The pharmaceutical preparations listed above may contain, in addition to the compounds according to the invention, other active pharmaceutical ingredients.

The preparation of the abovementioned pharmaceutical preparations is carried out in the customary manner by known methods,

z. B. by mixing the active substance or substances with the carrier or excipients.

The preparations mentioned can be administered orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously). Suitable preparations are injection solutions, solutions and suspensions for the therapy in question.

In general, it has proved to be advantageous in human medicine, the active compound or compounds 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, optionally in the form of several single doses, to achieve the desired To give results. A single gift contains the one or more.

active compounds according to the invention of 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 stated dosages, depending on the type and body weight of the object to be treated, the nature and severity of the disease, the method of preparation and the application of the drug and the period or interval within which the administration takes place.

Thus, in some cases it may be sufficient to manage with less than the above amount of active ingredient while in

In other cases, the above-mentioned amount of active ingredient must be exceeded. The definition of the respectively required optimum dosage and mode of administration of the active ingredients can be easily achieved by any person skilled in the art on the basis of his specialist knowledge.

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

1. tablets

The tablet contains the following ingredients: Active ingredient according to formula 1 0.020 parts

Stearic acid 0.010 parts Dextrose 1.890 parts

total 1,92OTeIIe

manufacturing The Stoffo be mixed together in a known manner and the mixture pressed into tablets, each of which weighs 1.92 g

and 20 mg of active ingredient.

2nd ointment

The ointment is composed of the following ingredients: Active ingredient according to Formal 50 mg

Neribas ointment (commodity 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 mixed intimately into an ointment. This gives a 0.5% ointment. The distribution of the active ingredient in the base is optically controlled under the microscope.

3. Cream composition:

Active ingredient according to formula 1 50 mg Neribas ointment (commodity Scherax) ad 10 g manufacturing

The active ingredient is triturated with 0.5 g of cream base and the remaining base incorporated in portions of 1.0 g gradually with the pestle. This gives a 0.5% lge cream. The distribution of the active ingredient in the base is optically controlled under the microscope.

4. Ampoule solution 1.0 mg Composition: 45.0 mg Active ingredient according to formula 1 ad 5.0 ml sodium chloride Aqua pro inj.

manufacturing

The active ingredient is dissolved at its own pH or optionally at pH 5.5 to 6.5 in water and added sodium chloride as isotonicity. The resulting solution is filtered pyrogen-free and the filtrate filled under aseptic conditions in ampoules, which are then sterilized and sealed. The ampoules contain 1 mg, 5 mg and 10 mg active substance.

5. Suppositories

Each suppository contains: Active ingredient according to Formal 1.0 parts Cocoa butter (mp .: 36-37 ⁰ C) 1 200.0 parts Yarn Wax 5.0 parts manufacturing Cocoa butter and carnauba wax are melted together. At 45 ° C, the active ingredient is added and stirred until a

complete dispersion is formed.

The mixture is poured into shapes of appropriate size and the suppositories packed appropriately.

Claims (10)

1. 2-Amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes (2-amino-7-carbamoyltetralines) of the general formula 1 R ^{1 is} Cr-Ce-alkyl; R ^{2 is} hydrogen, C ₁ -C ₁₂ -AlkVl, Ca-Ce-alkenyl, C ₃ -C ₆ alkynyl, - (CH ₂ ) _n -OR ⁴ , - (CH ₂ J _n -SR ⁴ , - (CH ₂ ) _n -C-OR ⁵ , R ^{4 is} hydrogen, C ₁ -C ₄ -alkyl, acyl, R ⁶ C ₁ -C ₈ -alkyl; X is hydrogen, hydroxy, halogen, C ₁ -C ₆ -alkyl, halomethyl, C ₁ -C ₆ -alkoxy, η is a number _1, 2, 3, 4, 5 or 6; R ³ is hydrogen, Cr-C _e alkyl may mean their enantiomers, mixtures of enantiomers, the racemate and their acid addition salts. 2. 2-Amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes (2-amino-7-carbamoyl-tetralines) of general formula 1 wc τίη R ^{1 is} C ₁ -C ₆ -alkyl; R ^{2 is} C ₁ -C ₁₀ -alkyl, C ₁ -C -alkenyl, C ₃ -C ₄ -alkynyl, - (CH ₂ ) _n -OR ⁴ , R ^{4 is} hydrogen, methyl, ethyl, C ₁ -C ⁴ -alkylcarbonyl, η is a number 1,2,3,4 or 5; R ^{3 is} hydrogen, C ₁ -C ₄ -A ^ yI may mean their enantiomers, mixtures of enantiomers, the racemate and their acid addition salts. 3. 2-Arnino-7-carbarnoyl-1,2,3,4-tetrahydronaphthalenes (2-amino-7-carbamoyltetralines) of the general formula 1 R ¹ is ethyl, propyl, butyl, R ² Cr-Cy-alkyl, Cr-C ₄ alkenyl, C ₃ -C ₄ -AIkInVl, - (CH ₂ J _n -OR ^4, R ⁴ is methyl, ethyl, acetyl, trifluoroacetyl , Ethylcarbonyl, η is a number 1,2,3 or 4; R ^{3 is} hydrogen, methyl, ethyl, propyl may mean their enantiomers, mixtures of enantiomers, the racemate and their acid addition salts. 4. (+ Vf-J ^ -Carbamoyl) - iNiN-dipropylamino-1-yl-S-tetrahydronaphthalene, its enantiomers, mixtures of enantiomers, racemates and its acid addition salts. 5. (+! / (- ^ - (N, N-Dipropylamino) -methylcarbamoyl-1H-tetrahydronaphthalene, its enantiomers, mixtures of enantiomers, racemates and its acid addition salts. 6. 2-amino-7-cyano-1,2,3,4-tetrahydronaphthalenes of the general formula 8 as Intermediates in which R ¹ and R ^{2 have} the meanings mentioned in claim 1. (8th) 7. Pharmaceutical preparations, characterized by a content of a compound according to any one of claims 1 to 5. 8. Use of compounds according to any one of claims 1 to 5 as a medicament. 9. Use of compounds according to any one of claims 1 to 5 in the preparation of pharmezeutischen preparations for the treatment of diseases based on a disorder of dopaminergic systems. 10. A process for the preparation of 2-amino-7-carbamoyl-1,2,3,4-tetrahydronaphthalenes of the general formula 1