DD280098A5 - PROCESS FOR PREPARING 8-SUBSTITUTED 2-AMINOTETRALINES - Google Patents

Abstract

The invention relates to a process for the preparation of 8-substituted 2-aminotetralines of general formula I in which the substituents have the meaning given in the description, from the corresponding aminotetralines or tetralones. The new compounds can be used in medicines that have a superior effect on the central nervous system. Formula (I)

Description

2 а осоо ^?

Process for the preparation of 8-substituted 2-aminotetalines

Field of application of the invention

The invention relates to a process for the preparation of 8-substituted 2-aminotetralins which can be used in medicaments,

Characteristics of the known prior art

From EP-A 141 488 it is known that 8-hydroxy-2-alkylaminotetraline or 8-amino-2-dialkylaminotetralines act on the central nervous system.

Object of the invention

The aim of the invention is the search for new drugs with improved properties, which can be used in particular for the treatment of diseases of the central nervous system.

Explanation of the essence of the invention

There have now been new 8-substituted 2-aminotetralines of the general formula (I)

in which

R - represents halogen, cyano or a group of the formula -NR ⁴ R ⁵ , -COR ⁶ , - (CH ₂ JX, -O- (CH ₂ J ₃ -X or -CH = CH- (CH ₂ ) _b - X stands,

I: SO О г. г-

wherein

R and R are the same or different and

- hydrogen or

7 R

a group of the formula -COR or -SC ^ R,

I would like to

R ⁷ - is hydrogen, or

- stands for a group -NHR, or

- represents alkoxy, or

- is aryl, aryloxy, aralkyl, aralkoxy or heteroaryl, where said radicals may be substituted by the same or different substituents up to three times by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino .

R ⁸ - is cycloalkyl, or

- is alkyl which may be substituted by cyano, halogen, trifluoromethyl, trifluoromethoxy or alkoxycarbonyl, or

- is aryl, aralkyl or heteroaryl, where said radicals may be substituted equally or differently by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino up to 3 times, or

Le A 24 869-foreign countries

I 5 О С

is a group -NR ¹⁰ R ¹¹ in which

R ¹⁰ and R are the same or different

and hydrogen, alkyl, aryl or aralkyl

and

R ^{9 is} hydrogen, or

- represents cycloalkyl, or

- is optionally substituted by cyano, halogen, trifluoromethyl or trifluoromethoxy alkyl, or

- represents aryl, aralkyl or heteroaryl, where the radicals mentioned may be substituted, equally or differently, by up to 3 times by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino,

R is hydrogen, hydroxy, amino, alkoxy, aryloxy or aralkoxy,

a - a number 1 to 10, b - a number 0 to 8 means

and

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¹ ^ S О О 9 b

X is a group of the formula -NR ¹² R ¹³ , -COR ¹⁴ , -SO ₂ R ¹⁵ or -OR ¹⁶ ,

wherein

R and R ^{13 are the} same or different and

- represent hydrogen, alkyl, aryl or aralkyl, where the aryl radicals may be substituted by halogen, cyano, alkyl, alkoxy or trifluoromethyl,

or

- represent a group of the formula -COR ¹⁴ , -SO ₂ R ¹⁵ or - (CH ₂ ) _C -NR ¹² R ¹³ ,

R is hydrogen, or

- a group -NHR ¹⁷ means, or

- alkyl or alkoxy, or

Aryl, aryloxy, aralkyl, aralkoxy or heteroaryl, it being possible for the radicals mentioned to be substituted equally or differently by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino,

R ^{15 is} cycloalkyl, or

Alkyl, which may be substituted by cyano, halogen, trifluoromethyl, trifluoromethoxy or alkoxycarbonyl, or

- aryl, aralkyl or heteroaryl, where the radicals mentioned up to 3-fold

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2 H о О о д

may be the same or different alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino, or

a group -NR ¹⁰ R ¹¹ means

I would like to

R and R have the abovementioned meaning,

R ^{16 is} hydrogen, alkyl, aryl, aralkyl or

a group of the formula -CONR ¹⁰ R ¹¹ means

R ^{17 is} hydrogen, or

- Cycloalkyl means, or

- optionally substituted by cyano, halogen, trifluoromethyl or trifluoromethoxy alkyl, or

Aryl, aralkyl or heteroaryl, it being possible for the radicals mentioned to be substituted equally or differently by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino,

and

с - a number 1 to 8 means

Le A 24 869-Aus 1 and

L OU О О

or where

and R together with the nitrogen atom form a ring of the series

H ₂ C <

> 0

0 *

O = C

| CH ₂ ) _n

| CH ₂ ) _n r-

2 >

or -N form N-A,

wherein

η - a number 1 or 2 means

and

A - represents hydrogen or cycloalkyl,

or

Le к 24 869-Auslar \ d

- is alkyl which may be substituted by halogen, hydroxy, amino, alkylamino, dialkylamino, carbamoyl or sulphamoyl,

or

- is aryl, hetsroaryl, aralkyl, alkoxycarbonyl, alkylsulfonyl, phenylsulfonyl, tolylsulfonyl, benzylsulfonyl, formyl, carbamoyl or sulfamoyl,

ρ R - is hydrogen or alkyl

R ³ - is alkyl,

however

R does not mean NH ₂ , though

2 3 R and R are PropyI

and their salts found.

The substances according to the invention surprisingly show a superior effect on the central nervous system and can be used for the therapeutic treatment of humans and animals.

The materials of this invention have multiple asymmetric carbon atoms and therefore may exist in various stereochemical forms.

28Q ί) ο

<> о

Both the individual isomers, as well as their mixtures are the subject of the invention. For example, the following isomeric forms of the substituted basic 2-aminotetralines may be mentioned:

The substituted basic 2-aminotetralines according to the invention can also be present in the form of their salts. In general, salts with inorganic or organic acids may be mentioned here.

In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the substituted basic 2-aminotetralins may be salts of the substances according to the invention with mineral acid, carboxylic acids or sulfonic acids. Particular preference is given for example to salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzoic sulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid or benzoic acid.

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230

In the context of the present invention, the substituents generally have the following meanings:

Alkyl is generally a branched hydrocarbon radical having 1 to 12 carbon atoms, preference is given to lower alkyl having 1 to about 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl , Octyl and isooctyl.

Alkenyl is in general a straight-chain or branched hydrocarbon radical having 2 to 12 carbon atoms and one or more, preferably one or two double bonds. The lower alkyl radical having 2 to about 6 carbon atoms and one double bond is preferred. An alkenyl radical having 2 to 4 is particularly preferred Carbon atoms and a double bond, for example allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl and isooctenyl,

Cycloalkyl is generally a cyclic hydrocarbon radical having from 5 to 8 carbon atoms. The cyclopentane and cyclohexane rings are preferred. Examples which may be mentioned are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Aryl is generally an aromatic radical having from 6 to about 12 carbon atoms. Preferred aryl radicals are phenyl, naphthyl and biphenyl.

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- OI; ·., У _d

In general , aralkyl is an aryl radical having 7 to 14 carbon atoms bound via an alkylene chain. Preference is given to aralkyl radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part. The following aralkyl radicals may be mentioned as examples: benzyl, naphthylmethy1, phenethyl and phenylpropyl.

Alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms bonded via an oxygen atom. Lower alkoxy having 1 to about 6 carbon atoms is preferred. Particularly preferred is an alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.

Aryloxy is generally an aromatic radical having from 6 to about 12 carbon atoms which is bonded via an oxygen atom. Preferred aryloxy radicals are phenoxy or naphthyloxy.

Aralkoxy is generally an aralkyl radical having 7 to 14 carbon atoms, wherein the alkylene chain is bonded via an oxygen atom. Aralkoxy radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. The following aralkoxy radicals may be mentioned as examples: benzyloxy, naphthylmethoxy, phenethoxy and phenylpropoxy.

Le A 24 869-foreign countries

2 Ь О J ; й

Alkylthio is generally a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms bound via a sulfur atom. Preferred is lower alkylthio having 1 to about 6 carbon atoms.

Particularly preferred is an alkylthio radical having 1 to 4 carbon atoms. Examples which may be mentioned are methylthio, ethylthio, propylthio, isopropylthio , butylthio, isobutylthio, pentylthio, isopentylthio, hexylthio, isohexylthio, heptylthio, isoheptylthio , octylthio or isooctylthio.

Acyl is generally phenyl or straight or branched lower alkyl having from 1 to about 6 carbon atoms attached via a carbonyl group. Preference is given to phenyl and alkyl radicals having up to 4 carbon atoms. Examples which may be mentioned: benzoyl, acetyl, ethyl carbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.

Alkoxycarbonyl , for example, by the formula -C-OAlkyl О

being represented.

Alkyl here stands for a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Lower alkoxycarbonyl having 1 to about 6 carbon atoms in the alkyl moiety is preferred. Particularly preferred is an alkoxycarbonyl having 1 to 4 carbon atoms in the

Le A 24 869-foreign countries

Alkyl moiety. For example, the following alkoxycarbonyl radicals may be mentioned: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isabutoxycarbonyl.

Aryloxycarbonyl may, for example, be represented by the formula -COO-aryl. Aryl is in this case in general an aromatic radical having 6 to 12 carbon atoms, for example be mentioned: phenoxycarbonyl and Naphthyloxycarbonyl.

For example, alkoxycarbonyl can be represented by the formula -COO-aralkyl. Aralkyl is in this case generally an aryl radical having 7 to 14 carbon atoms bonded via an alkylene chain; aralkyl radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. Examples which may be mentioned as aralkoxycarbonyl radicals are: benzyloxycarbonyl, naphthylmethyloxycarbonyl,

Heteroaryl represents for the purposes of the definition given above in general represents a 5- to 6-membered aromatic ring which may contain as hetero atoms oxygen, sulfur and / or nitrogen and to which a further aromatic ring can be fused. Preference is given to 5- and 6-membered aromatic rings which contain an oxygen, a sulfur and / or up to 2 nitrogen atoms and which are optionally benzo-fused. Particularly preferred heteroaryl radicals which may be mentioned are: thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, thia-

Le A 24 869-foreign countries

2 з о е S з

zalyl, benzo-liazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl and indolyl.

Halogen is generally fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. Halogen is particularly preferably fluorine or chlorine.

Preference is given to those compounds of the general formula (I)

in which

R * - is fluorine, chlorine, bromine or cyano, or

- is a group of the formula -NR ⁴ R ⁵ , -COR ⁶ , - (CH ₂ J ₃ -X-O- (CH ₂ ) _a -X or -CH = CH- (CH ₂ ) _b -X,

where г in

R and R are the same or different and

- hydrogen or

a group of the formula -COR ⁷ or -SO ₂ R ⁸ ,

in which

R ⁷ - is hydrogen, or

- stands for a group -NHR, or

- represents lower alkoxy, or

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2 P. OJ 9 g

optionally substituted by lower alkyl, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, dimethylamino or diethylamino-substituted phenyl, benzyl, benzyloxy, thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl stands,

is cyclopropyl, cyclopentyl or cyclohexyl, or

is optionally substituted by cyano, fluoro, chloro, bromo, trifluoromethyl or lower alkoxycarbonyl lower alkyl, or

is optionally substituted by lower alkyl, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, dimethylamino or diethylamino-substituted phenyl, benzyl, thienyl, furyl, pyrimidyl, pyridyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl, or a group of the formula -NR ¹⁰ R ¹¹ ,

where г in

R and R * are the same or different and are hydrogen, lower alkyl or phenyl

Le A 24 869-foreign countries

and

R ^{9 is} hydrogen, or

- represents optionally substituted by cyano, fluorine, chlorine or bromine lower alkyl, or

- phenyl optionally substituted by lower alkyl, lower alkoxy, fluorine, chlorine, bromine, trifluoromethyl, dimethylamino or diethylamino, benzyl, thienyl, furyl pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl,

R is hydrogen, hydroxy, amino, lower alkoxy or benzyloxy,

a - a number 1 to 8, b - a number Q to 6 means

and

X - a group of the formula -NR ¹² R ¹³ , -COR ¹⁴ , -SOoR

or -OR ¹⁶ means

in which

Le A 24 869-Aus 1 and

R and R are the same or different and

- is hydrogen, lower alkyl, phenyl or benzyl, where the radicals mentioned may be substituted by fluorine, chlorine, bromine, lower alkyl, lower alkoxy or trifluoromethyl, or

- represent a group of the formula -COR ¹⁴ , -SO ₂ R ¹⁵ or - (CH ₂ ) _C -NR ¹² R ¹³ ,

R ¹⁴ - a group -NHR ¹⁷ means, or

- Lower alkyl or lower alkoxy, or

phenyl optionally substituted by lower alkyl, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, dimethylamino or diethylamino, benzyl, benzyloxy, thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl,

R - cyclopropyl, cyclopentyl, cyclohexyl, or

- optionally substituted by cyano, fluoro, chloro, bromo, trifluoromethyl or lower alkoxycarbonyl lower alkyl, or

optionally mono- or polysubstituted by different or by lower alkyl, lower alkoxy, fluorine, chlorine, bromine, trifluoromethyl, dimethylamino or diethylamino-substituted phenyl, naphthyl, benzyl,

Le A 24 869-foreign countries

- rl

и O

Thienyl, furyl, pyrimidyl, pyridyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl, or

a group -NR ¹⁰ R ¹¹ means

in which

R and R have the abovementioned meaning,

R ^{16 is} hydrogen, lower alkyl, phenyl or benzyl,

R ¹ "- means hydrogen, or

- optionally substituted by cyano, fluorine, chlorine or bromine substituted lower alkyl, or

phenyl optionally substituted by lower alkyl, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, dimethylamines or diethylamino, benzyl, thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl,

and

с - a number 1 to 6 means or where Le A 24 869-foreign

2 8 ΰ O 9 B

R ¹² and R ¹³ together with the nitrogen atom one ring of the series

H ₂ C- (CH ₂ ) _n H о СчуС H 2

° 2?

^ N

or

- (CH ₂ )

O = C N -CH

6 ⁿ 5

\ ^ Ы я

wherein

η - a number 1 or 2 means

R ² - is hydrogen or lower alkyl

R ³ - is lower alkyl,

however

form,

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R ¹ - is not NH ₂ , when R and R ^ propyl and their salts.

Particular preference is given to those compounds of the general formula (I)

in which

R * - for chlorine, bromine, cyano or

- is a group of the formula -NR ⁴ R ⁵ , -COR ⁶ , - (CH ₂ J ₃ -X, -O- (CH ₂ ) _a -X or -CH = CH- (CH ₂ ) _b -X,

wherein

R ¹ * and R are the same or different and

- hydrogen or

a group of the formula -COR ⁷ or -SO ₂ R ⁸ ,

where г in

R - is hydrogen, or

- stands for a group -NHR, or

- is methoxy, ethoxy, propoxy or isopropoxy, or

Le A 24 869-foreign countries

^ O O Q я

- is phenyl, benzyl, benzyloxy, thienyl, furyl, pyridyl, pyrimidyl, quinolyl or isoquinolyl optionally substituted by methyl, methoxy, fluorine or chlorine,

R ⁸ - is optionally substituted by fluorine, chlorine, methoxycarbonyl, ethoxycarbonyl, propoxycarbanyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl substituted ethyl, propyl, isopropyl, butyl or isobutyl, or

- is optionally substituted by methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, fluorine or chlorine, phenyl, thienyl, furyl, pyridyl, pyrimidyl, quinolyl or isoquinolyl, or

- is a group -NR ¹⁰ R ¹¹ ,

wherein

R and R are the same or different

and hydrogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl

and

Le A 24 869-foreign countries

2 Я л

R ^{9 is} hydrogen, or

- is optionally substituted by fluorine or chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl or isohexyl, or

- is phenyl which may be substituted by fluorine, chlorine, methyl or methoxy,

R ° is hydrogen, hydroxy, amino, methoxy, ethoxy, propoxy, butoxy, isopropoxy or isobutoxy,

a - a number 1 to 6, b - a number 0 to 4 means

and

X is a group of the formula -NR ¹² R ¹³ , -COR ¹⁴ , -SO ₂ R ¹⁵ or -OR ¹⁶ ,

in which

R ¹² and R ^{1 are the} same or different, and

for hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or

- For optionally substituted by fluorine, chlorine, methyl or methoxy substituted phenyl, or

Le A 24 869-foreign countries

- for a group -COR ¹⁴ , -SO ₂ R ¹⁵ or

stand,

R ^{14 is} hydrogen, or

- a group -NHR ¹ means, or

Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, or

phenyl optionally substituted by methyl, methoxy, fluorine or chlorine, benzyl, benzyloxy, thienyl, furyl, pyridyl, pyrimidyl, quinolyl or isoquinolyl,

R ¹ ^ - optionally by fluorine, chlorine, methane

oxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbony1, butoxycarbony1 or isobutoxycarbony1 substituted methyl, ethyl, propyl, isopropyl, butyl or isobutyl, or

- optionally mono- or polysubstituted or differently by methyl, ethyl, propyl, isopropyl, methoxy, fluorine or chlorine-substituted phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, quinolyl or isoquinolyl, or

a group -NR ¹⁰ R ¹¹ means

in which

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'- ^; - O ö 9 ö

R ¹⁰ and R ^{11 have} the abovementioned meaning,

R ^{16 is} hydrogen, methyl, ethyl, propyl,

Isopropyl, phenyl or benzyl,

R ^{17 is} hydrogen, or

- optionally substituted by fluorine or chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl or isohexyl, or

Phenyl, which may be substituted by fluorine, chlorine, methyl or methoxy,

and

с - a number 1 to 4 means

R - represents hydrogen, methyl, ethyl, propyl or isopropyl

R ³ - is methyl, ethyl, propyl or isopropyl,

however

R ¹ - does not mean NH2, though

R ² and R ^{3 are} propyl,

and their salts.

Le A 24 869-foreign countries

с: о

Very particular preference is given to those compounds of the general formula (I)

in which

R - for chlorine, bromine, cyano or

- is a group of the formula -NR ⁴ R ⁵ , -COR ⁶ , - (CH ₂ ) _a -X, -O- (CH ₂ ) _a -X or -CH = CH- (CH ₂ ) _b -X,

wor in

R ^{4 is} hydrogen,

a group of the formula -COR ⁷ or -SO ₂ R ⁸ ,

wor in

R ⁷ - is hydrogen, or

- stands for a group -NHR, or

- is methoxy or ethoxy,

R ⁸ - is trifluoromethyl, phenyl, tolyl, or

- is a group -NR ¹⁰ R ¹¹ ,

wherein

R and R are the same or different and denote hydrogen, methyl or ethyl,

and

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... '''и О с g

R ^{9 is} hydrogen, or

- for methyl, ethyl, propyl, isopropyl or butyl, or

- stands for phenyl,

R ° is hydrogen, hydroxy, amino, methoxy or ethoxy,

a - a number 1 to 4, b - a number 0 to 2 means

and

X is a group of the formula -NR ¹² R ¹³ , -COR ¹⁴ , -SO ₂ R ¹⁵ or -OR ¹⁶ ,

I would like to

R and R are the same or different, and

- for hydrogen, methyl, ethyl, propyl, or

- for a group -COR ¹⁴ , -SO ₂ R ¹⁵ or

SO ₂

- (CH ₇ JN O

stand,

R ^{14 is} hydrogen, or

• 1

- a group -NHR 'means, or

Methyl, ethyl, prepyl, methoxy or ethoxy,

Le A 24 869-foreign countries

'J P -> \

Trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl or isobutyl, or

optionally substituted by one or more methyl or chlorine-substituted phenyl, or naphthyl,

a group -NR ¹⁰ R ¹¹ means

in which

R and R have the abovementioned meaning,

R ^{16 is} hydrogen, methyl, ethyl or propyl,

7

R is hydrogen, or

Methyl, ethyl, propyl, isopropyl, butyl or isobutyl, or

- Phenyl means

and

с - a number 2 to 4 means

R ² and R ^{3 are} propyl and their salts.

By way of example, the following 8-substituted 2-aminotetraines are mentioned:

Le A 24 869-foreign countries

- · о

2-dipropylamino-8-chloro-l, 2,3,4-tetrahydronaphthalene, 2-dipropylamino-8-bromo-1,2,3,4-l-l-halonronaphthalene, 2-dipropylamino-8-cyano-1,2,3 , 4-tetrahydronaphthalene, 2-dipropylamino-8- (3-butyl-ureido) -l, 2,3,4-tetrahydronaphthalene, 2-dipropylamino-8-formamido-1,2,3,4-tetrahydronaphthalene, 2- Dipropylamino-8-carbamoyl-1,2,3,4-tetrahydronaphthalene, 2-di-propylamines-1,2,3,4-tetrahydahaphthalene-8-carboxylic acid, 2-dipropylamino-8-ethoxycarbonyl-1,2,3 , 4-tetrahydronaphthalene, 2-dipropylamino-8-formyl-1,2,3,4-tetrahydronaphthalene, 2-dipropylamino-8-hydroxymethyl-1,2,3,4-tetrahydronaphthalene, г-Оіргоруіатіпо-в-атіпоте ^ уі-1,2,3,4-tetrahydahaphthalene in, 2-dipropylamino-8-aminomethyl-1,2,2,4,4-tetrahydronaphthalene hydrochloride, 2-dipropylamino-8-sulfoamidamido-methyl-1,2,3,4- tetrahydronaphthalene, 2-diprrorinamino-8-butylsulfonamidomethyl-1,2,2,4,4-tetrahydronaphthalene, 2-dipropylamino-8-ethoxycarbony1-amidomethyl-1,2,2,4,4-tetrahydronaphthalene, 2-dipropylamino-8-e thoxycarbonylamidomethyl-1,2,3,4-tetrahydronaphthalen Hydra chloride, 2-dipropylamino-8- (3,3-diethylureido) methyl-l, 2,3 _i 4-tetrahydronaphthalene, 2-dipropylamino-8-ureidomethyl-1,2, 3,4-tetrahydronaphthalene, 2-dipropylamino-8- (3-methylureido) methyl-1,2,3,4-tetrahydronaphthalene,

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о о 9 a

2-dipropyl-amino-8-formamido-ethyl-1,2,3,4-tetrahydronaph-lhalin,

2-dipropylamino-8- (2-hydroxyethoxy) -1,2,3,4-tetrahydronaphthalene hydrochloride,

2-dipropylamino-8-carbamoylethoxy-1,2,3,4-tetrahydronaph-lhalin,

2-dipropylamino-8- (2-aminoethoxy) -1,2,3,4-tetrahydronaphthalene,

2-dipropylamino-8- (2-methanesulfonamido-methoxy) -1,2,3,4-tetrahydronaphtha 1 in,

2-dipropylamino-8- (2-butylsulfonamido-ethoxy) -1,2,3,4-tetrahydronaphthalene,

2-dipropylamino-8- (2-propionylamido-ethoxy) -l, 2,3,4-tetrahydronaphthalene;

2-dipropyl amino-8- (2-ethoxycarbonylamidoethoxy) -1,2,3,4-tetrahydronaphthalene,

2-dipropylamino-8- [2- (3,3-diethylureido) ethoxy3-1,2,3,4-tetrahydronaphthalene,

2-dipropylamino-8-ureidoethoxy-1,2,3,4-tetrahydronaphtha-1 in,

2-dipropylamino-8-C2- (3-methyl) ethoxy] -1,2,3,4-tetrahydronaphthalene,

2-dipropylamino-8-C2- (3-butylureido) ethoxy3-1,2,3,4-tetrahydronaphthalene,

2-dipropylamino-8- (2-formylamidoethoxy) -1,2,3,4-tetrahydronaphthalene in,

2-dipropylamino-8- [2- (N, N-dimethylaminosulfonyl) etheny1] -1,2,3,4-tetrahydronaphthalene,

2-dipropylamino-8- [2- (N, N-dimethylaminosulphonyl) ethyl] -1,2,3,4-tetrahydronaphthalene,

2-dipropyl-amino-8- (2-nitro-ethenyl) -1,2,3,4-tetrahydronaphthalene in,

Le A 24 869-foreign countries

  ) q ... л ~.

Z-dipropylamino-e- (2-amino-ethy1) -l, 2,3,4-tetrahydranaphthalin,

2-D ipropylami.no-8- (2-methanesulfonyldiethyl) -1,2,4,4-tetrahydronaphthalene Hydrochi or id, 2-dipropylamino-8- (2-butanesulfanamido-ethyl) -l, 2 , 3,4-tetrahydronaphthalene, 2-dipropylamino-8- [2- (p-chlorobenzenesulfonamido) ethyl] -1,2,3,4-tetrahydronaphthalene, 2-dipropylamino-8- (2-ethoxycarbonylamido-ethyl) -1, 2,3,4-tetrahydronaphthalene, 2-dipegorollino-8- (2-benzyl-oxycarbonyl-amido-ethyl) -1,2,3,4-tetrahydronaphthalene, 2-dipropylamino-8- (2-ureido-ethyl) -l, 2,3,4-tetrahydronaphthalene,

2-Dipropylamino-8- [2- (3-methylureido) ethyl]] -, 2,3,4-tetrahydronaphthalene, 2-dipropylamino-8- (2-formylamidoethyl) -1,2,3,4-tetrahydronaphthalene in.

In the context of the present invention, the 8-halo-aminotetralins (Ia) correspond to the general formula

(Ia)

in which

R ^ and R ^ have the meaning given

Y - stands for halogen or cyano.

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9 8

In the context of the present invention, the diaminotetralins (Ib) correspond to the general formula

(Ib),

in which

Z - represents a group of the formula -NR R, in which

R and R are the same or different and

- hydrogen or

7 '

a group of the formula -COR or

-SO ₂ R ⁸ mean

I would like to

'· R - for hydrogen, or

- represents alkoxy, or

- is aryl, aryloxy, aralkoxy, aralkyl or heteroaryl, where said radicals may be substituted equally or differently by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino up to 3-fold .

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'2

and

R - has the specified meaning and

R and R have the meaning given.

In the context of the present invention, the 8-ureido-aminotetralins (Ic) correspond to the general formula

(Ic), NHCONHR ⁹

in which

OO Q «

R ₁ R and R have the meaning given.

In the context of the present invention, the 8-acyl-aminotetralins (Id) correspond to the general formula

(Id)

COR ⁶ '

in which

R ⁶ - is hydroxy, amino, alkoxy, aryloxy or aralkoxy

and R have the meaning given,

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In the context of the present invention, the 8-formyl-aminotetralins (Ie) correspond to the general formula

(Ie),

CHO

we are sooner

R and R have the meaning given.

In the context of the present invention, the 8-methyleneaminotetralins (If) correspond to the general formula

(If)

in which

R, R and X are as defined above.

In the context of the present invention, the 8 · alkylene-aminotetralins (Ig) correspond to the general formula

dg),

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Z Яп О о

in which

W - is a group of the formula - (CH ₂ ) _a '-X or -CH = CH- (CH ₂ ) _b -X,

R, R, X and b are as defined above

a 'is a number 2 to 10.

In the context of the present invention, the 8-ethylene-aminotetralins (Ih) correspond to the general formula

< lh),

in which I R, R and X have the meaning given.

A process for the preparation of the 8-haloaminotetralines of the general formula (Ia) according to the invention has been disclosed.

(Ia),

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in which Y - stands for halogen or cyano,

R ² - is hydrogen or alkyl,

R ³ - is alkyl, and the salts thereof are found, which is characterized in that CA] 8-aminotetralines of the general formula (II)

(II)

in which R and R ^{3 have} the meaning given,

in inert solvents in the presence of acids with nitrites,

then the resulting diazonium salts with copper salts of the general formula (III)

CuY (III),

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in which Y has the meaning given, if appropriate in the presence of auxiliaries

and in the case of the preparation of the salts, reacting with the corresponding acids,

or that [t] tetralone of the general formula (IV)

in which R ¹⁸ - represents chlorine or bromine, first with amines of the general formula (V) / R ²

HN (V),

\ ³

in which R and R have the meaning given,

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"J * O Q 9 8

in inert solvents, if appropriate in the presence of auxiliaries,

then reducing the intermediate compounds in inert solvents,

then optionally replace halogen with cyano

and then in the case of preparing the salts with the corresponding acids.

The process according to the invention can be illustrated by the following formula scheme:

Process variant A:

Diazotization

HCl

N-

cl "

Decomposition with

CuCl

Process variant B:

Reduces ive amination

N (C ₃ H ₇ J ₂

Bromine-cyan exchange

N (C ₃ H ₇ ) ₂

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2 Я; о 9 В

Driving variant A:

When carrying out process A according to the invention, the diazonium salts are generally 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, or acids such as mineral acids or carboxylic acids. Preferred are water and / or acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or acetic acid. It is likewise possible to use mixtures of the abovementioned solvents.

As acids in general mineral acids are used. Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or else mixtures of said acids are preferably used.

Nitrites are generally alkali metal nitrites, such as sodium or potassium nitrite. Preferably, sodium nitrite is used.

As auxiliaries alkali or Erdalkalihalogenide or cyanides are generally used. Preference is given to sodium chloride, sodium bromide or sodium cyanide.

The reaction is generally carried out in a temperature range of -10 ⁰ C to +150 ⁰ C, preferably from ⁰ ° C to +100 ⁰ C,

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2 '^ Г; о 9 3

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 in such a way that first the 8-aminotetralin in concentrated aqueous acids is treated with a solution of nitrite in water and then the reaction solution with copper (I) halides or copper (I) cyanide, optionally in water solved, treated. The diazonium salt is generally not isolated. Hydrochloric acid and copper (I) chloride id are preferably used in the introduction of the chlorine atom (Y = Cl), hydrobromic acid and copper (I) bromide are introduced during the introduction of the bromine atom (Y = Br), and the nitrile ion (Y = CN) sulfuric acid and copper (I) cyanide, optionally in the presence of sodium cyanide.

The workup is generally carried out by neutralization of the reaction mixture with alkali metal hydroxides or carbonates, and extraction, crystallization and / or chromatography of the resulting free bases from which their salts are obtained by reaction with appropriate acids.

The 8-aminotetralins used as starting compounds are known [EP-Al 41 488].

By way of example, the following 8-aminotetralins may be mentioned: 8-amino-2-dimethylamino-1,2,3,4-tetrahydronaphthalene, 8-amino-2-diethylamino-1,2,3,4-tetrahydronaphthalene, 8-amino 2-di-pyryl-1-amino-1,2,3,4-tetrahydronaphthalene,

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2Я0 09Я

іпо-г- (N-ethyl-N-methyl) amino-1,2,3,4-tetrahydronaphthalene;

8-amino-2- (N-methyl-N-propyl) amino-1,2,3,4-tetrahydronaphthalene;

8-amino-2- (N-ethyl-N-propyl) amino-1,2,3,4-tetrahydronaphthalene;

Process variant B:

The preparation of the intermediate compounds by reacting the tetralone (IV) with amines (V) is carried out in inert organic solvents, if appropriate in the presence of a catalyst and optionally in the presence of a water-binding agent.

In the case of reaction with primary amines, the intermediates are Schiff's bases and in the case of reaction with secondary amines, the intermediates are enamines or immonium salts.

The process according to the invention can be carried out in two steps, i. be carried out with isolation of the intermediate compounds. It is likewise possible to carry out the process according to the invention as a one-pot process.

Suitable inert solvents here are the customary organic solvents which do not change under the reaction conditions. These preferably include alcohols, such as methanol, ethanol, propanol or isopropanol, or ethers, such as diethyl ether, butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or halogenated hydrocarbons, such as, for example, methylene chloride, chloroform or carbon tetrachloride.

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or hydrocarbons, such as benzene, toluene, xylene, or petroleum fractions, or amides, such as dimethylformamide or hexamethylphosphoric acid triacid, or acetic acid,

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

Proton acids are generally used as catalysts. These include preferably inorganic acids such as hydrochloric acid or sulfuric acid, or organic carboxylic acids having 1 to 6 carbon atoms, optionally substituted by fluorine, chlorine and / or bromine, such as acetic acid, trifluoroacetic acid, trichloroacetic acid or propionic acid, or sulfonic acids with C ₁ -C ₁ ^ - alkyl radicals or with aryl radicals such as, for example, methanesulfonic acid, ethanesulfonic acid, benzoic sulfonic acid or toluenesulfonic acid,

The water formed in the reaction may optionally be mixed with the solvent used during or after the reaction e.g. by distillation or by addition of water-binding agents such as phosphorus pentoxide, or preferably by molecular sieve.

The reaction is generally carried out in a temperature range from O ⁰ C to +200 ⁰ C, preferably from + 20 ° C to +150 ⁰ C.

In the azeotropic distillation of the water formed in the reaction with the solvents used, it is preferable to work at the boiling temperature of the azeotrope.

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'' J Q А Л л _ ^ U ν. · Ν

The reaction may be carried out at normal, elevated and reduced pressure (e.g., 0.5-5 bar). In general, one works at atmospheric pressure.

In carrying out the reaction, the starting materials are generally used in a molar ratio of tetra-ion (IV) to amine (V) of 0.5: 2 to 1: 2. Preference is given to using molar amounts of the reactants.

The reduction of the enamines is carried out either by hydrogen in water or inert organic solvents such as alcohols, ethers or halogenated hydrocarbons, or mixtures thereof, with catalysts such as Raney nickel, palladium, palladium on animal charcoal or platinum, or with hydrides in inert solvents, optionally in Presence of a catalyst.

The reaction is preferably carried out with hydrides, such as complex borohydrides or aluminum hydrides. Particular preference is given to using sodium borohydride, lithium aluminum hydride or sodium cyanoborohydride.

Suitable solvents here are all inert organic solvents which do not change under the reaction conditions. These preferably include alcohols such as methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or amides such as hexamethylphosphoric triamide, or dimethylformamide or acetic acid. It is also possible to use mixtures of said solvents.

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As catalysts in the reduction, proton acids are generally used. These include preferably inorganic acids such as hydrochloric acid or sulfuric acid, or organic carboxylic acids having 1-6 C atoms, optionally substituted by fluorine, chlorine and / or bromine, such as acetic acid, trifluoroacetic acid, trichloroacetic acid or propionic acid, or sulfonic acids with C ^ -C ^ -Alkylresten or with aryl radicals such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.

In carrying out the process according to the invention, it has proven to be favorable, the reaction of the tetralone (IV) with the amines (V) in an inert solvent, preferably in ethyl acetate or in alcohols such as methanol, ethanol, propanol or isopropanol, or mixtures thereof in the presence of inorganic or organic acids such as hydrochloric acid or acetic acid and in the presence of a reducing agent, preferably complex hydrides such as sodium borohydride or sodium cyanoborohydride, optionally in the presence of a dehydrating agent, preferably molecular sieve, as a one-pot process.

In this case, the reaction is carried out in a temperature range from O ⁰ C to +150 ⁰ C, preferably from ^{0 0} C to + 100 ⁰ C at atmospheric pressure. It is also possible to carry out the reaction at reduced pressure or at overpressure (eg in the bomb tube).

If the process according to the invention is carried out as a one-pot reaction, it has proved to be favorable to use the amine

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2 8 O ΰ }

in an up to 10-fold, preferably in an up to S-fold excess over the tetraion use.

The replacement of halogen, especially bromine by cyano, is generally carried out with copper (I) cyanide in inert solvents, preferably amides such as dimethylformamide or hexamethylphosphoric triamide in a temperature range from +20 ⁰ C to +200 ⁰ C, preferably from +50 ⁰ C bis +150 ⁰ C at normal pressure,

The amines used as starting materials are known or can be prepared by known processes [Houben-Weyl's "Methods of Organic Chemistry" XI / 1 and XI / 2].

The following amines may be mentioned by way of example: methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, methyl-propylamine, ethyl-methylamine, ethyl-propylamine.

The tetralones used as starting materials are partly new and can be prepared by known methods of Friedel-Crafts acylation from 2-halo-phenylacetic acid chlorides or bromides, aluminum chloride and ethers [Houben-Weyl's "Methods of Organic Chemistry" VII / 2a, 141; G. P. Johnson, Org. Synth., Coll. Vol. IV, 900 (1963) 3.

By way of example, mention may be made of the following tetralones: 8-chloro-tetralone-2, 8-bromo-tetrachloro-2-one.

In addition, a process for the preparation of diaminotetralines of the general formula (Ib) according to the invention

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о;, с. _s

(Ib)

where г in

Z - represents a group of the formula -NR ⁴ R ⁵ ,

where г in

and R are the same or different and

- for hydrogen, or

a group of the formula -COR ⁷ 'or -SO ₂ R ⁸ ,

I would like to

R - is hydrogen, or is alkoxy, or

is aryl, aryloxy, aralkyl, aralkoxy or heteroaryl, where said radicals may be substituted by the same or different substituents up to 3 times by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino

and

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R ⁸ - is cycloalkyl, or

is alkyl which may be substituted by cyano, halogen, Trifluormethy1, trifluoromethoxy or alkoxycarbonyl, or

is aryl, aralkyl or heteroaryl, where said radicals may be substituted equally or differently by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino, or a group up to 3 times -NR ¹⁰ R ¹¹ stands,

wor in

R and R ^{11 are the} same or different and denote hydrogen, alkyl, aryl or aralkyl,

R ² - is hydrogen or alkyl,

R ³ - is alkyl,

however

R ¹ does not mean NH ² , though

R ² and R ^{3 are} propyl,

and their salts found,

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C ! \ ι

which is characterized in that 8-aminotetralines of the general formula (II)

(II)

in which R and R have the abovementioned meaning,

with acylating or sulfonating agents of the general formula (VI)

VR ¹⁹ (VI) in which R ^{19 is} a group of the formula -COR ⁷ or -SO ₂ R ⁸ ,

V - for halogen, or

- stands for the rest -OR ²⁰ , where г in

R has the same meaning as R and may be the same or different with this,

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"Q

in inert solvents, if appropriate in the presence of bases

and then in the case of preparing the salts with the corresponding acids.

The process according to the invention can be illustrated by the following schemes. "

a)

N (CH ₂ CH ₂ CH ₃ )

+ H ₃ CSO ₂ Cl

N (CH ₂ CH ₂ CH ₃ )

NHSO ₂ CH ₃

b)

NH-

N (CH ₂ CH ₂ CH ₃ J ₂

(H ₃ CCO) ₂ O

N (CH ₂ CH ₂ CH ₃ J ₂

NHCOCH ₃

Suitable inert solvents here are the customary organic solvents which do not change under the reaction conditions. These include preferably ethers, such as diethyl ether, butyl methyl ether, dioxane, tetrahydro

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furan, glycol dimethyl ether or diethylene glycol dimethyl ether, or halohydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, dichloroethylene or trichlorethylene, or hydrocarbons such as benzene, toluene, xylene or petroleum fractions, or alcohols such as methanol, ethanol, propanol or isopropanol, or carboxylic acids such as formic acid, Acetic or propionic acid, or carboxylic anhydrides such as propionic anhydride or acetic anhydride, or acetone, ethyl acetate or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned,

As bases, the usual basic compounds for basic reactions can be used. These include preferably alkali metal or alkaline earth metal hydroxides, or alkali metal or alkaline earth metal carbonates such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate, or alkahialkaholates such as sodium methoxide, sodium ethanoate, potassium methoxide or potassium ethoxide, or alkali metal amides such as sodium amide or Lithium diisopropylamide, or organic amines such as triethylamine, tripropylamine, pyridine, piperidine or N, N-dimethylaminopyridine.

The reaction is generally carried out in a temperature range from -30 ° C to +100 ⁰ C, preferably from ^{0 0} C to + 80 ° 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).

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Acylating agents (general formula VI where R ¹⁹ = COR ⁷ ) are generally carboxylic acid halides or anhydrides, preferably carboxylic acid chlorides or bromides, or symmetrical or asymmetrical carboxylic acid anhydrides, preference being given to using mixed anhydrides with formic acid, acetic acid or propionic acid in the asymmetrical anhydrides ,

Sulfonyl halides or sulfonic acid anhydrides, preferably sulfonyl chlorides or bromides, or symmetrical or unsymmetrical sulfonic acid anhydrides, are preferably used as sulfonating agents (general formula VI where R = -SOOR). In the case of unsymmetrical anhydrides, preference is given to mixed anhydrides with methane, ethane, benzene or Toluene sulfonic acid can be used.

When carrying out the process according to the invention, the acylating or sulfonating agents are generally used in an amount of from 1 to 10 mol, preferably from 1 to 5 mol, relative to 1 mol of 8-aminotetralin. The base is generally employed in an amount of from 1 to 5, preferably from 1 to 2 mol, based on 1 mol of the acylating or sulfonating agent.

In addition, a process for the preparation of the 8-ureido-aminotetralines of the general formula (Ic) according to the invention

(Ic)

NHCONHR ⁹

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in which

R ² - is hydrogen or alkyl,

R ³ - is alkyl

R ⁹ - is hydrogen, or

- represents cycloalkyl, or

- optionally substituted by cyano, halogen,

Trifluoromethyl or trifluoromethoxy substituted alkyl, or

- is aryl, aralkyl or heteroaryl, where the radicals mentioned may be substituted by the same or different substituents up to three times by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoro-methylthio, amino, alkylamino or dialkylamino,

and their salts found,

which is characterized in that one

8-aminotetralines of the general formula (II)

(II)

I \ R ³ NH ₂

in which

R and R have the meaning given,

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z $ o о9

9e

in inert solvents, if appropriate in the presence of bases with isocyanates of the general formula (VII)

R ⁹ N = C = O (VII) in which

R - has the meaning given,

implements,

and then in the case of preparing the salts with the corresponding acids.

The process according to the invention can be illustrated by the following scheme:

N (CH ₂ CH ₂ CH ₃ ) ₂

N (CH ₂ CH ₂ CH ₃ J ₂ H ₃ CN = C = O NHCONHCH ₃

Suitable inert solvents are the customary organic solvents which do not change under the reaction conditions. These include preferably ethers such as diethyl ether, butyl methyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, dichloroethylene or trichloroethyl

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^ С О 9 $

len, or hydrocarbons such as benzene, toluene, xylene or petroleum fractions, or amides such as dimethylformamide or hexamethylphosphoric triamide, or ethyl acetate, acetonitrile or pyridine. It is also possible to use mixtures of said solvents.

Suitable bases here are the customary organic amines. These preferably include trialkylamines such as triethylamine or tripropylamine, or tertiary organic bases such as pyridine, N, N-dimethylaminopyridine, picoline, piperidine, morpholine or 1,5-Diazabieye IoC4,3,0] non-5-ene or 1.5 Diazabicyclo [5.4.0 jundec-5-ene,

The reaction is generally carried out in a temperature range from -30 ⁰ C to + 100 ⁰ C, preferably from ^{0 0} C to + 80 ° 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).

When carrying out the process according to the invention, the isocyanates are generally used in an amount of from 1 to 3, preferably from 1 to 2 mol, based on 1 mol of 8-aminotetralin. The base is generally used in an amount of 0.01 to 1 mol, preferably from 0.1 to 0.5 mol, based on 1 mol of the isocyanate.

The process can be carried out, for example, by reacting the 8-aminotetralin in an inert solvent

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2 ^ ·: о о ^

mixed with isocyanate and base and optionally heated. The workup is carried out by extraction, chromatography and / or crystallization.

In the case of the preparation of the unsubstituted 8-ureidoaminotetraline (R ^y = H), one uses Alkalι cyanate, preferably sodium or potassium cyanate in water and / or acids such as hydrochloric acid, hydrobromic acid or sulfuric acid.

In addition, a process for the preparation of the inventive 8-acylaminotetralines of the general formula (Id)

^(Id)

in which

R ² - is hydrogen or alkyl, R ³ - is alkyl

R is hydroxy, amino, alkoxy, aryloxy or aralkoxy,

and their salts found,

characterized in that one

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8-cyanotetralines of the general formula (VIII)

> 2

in which

R and R ° have the abovementioned meaning hydrolyzed,

in the case of the production of the carboxylic acid esters, the carboxylic acids obtained are esterified,

and in the case of preparing the salts with the corresponding acids.

The process according to the invention can be illustrated by the following scheme:

N (CH ₂ CH ₂ CH ₃ ) ₂

N (CH ₂ CH ₂ CH ₃ ) ₂

CONH ₂

-N (CH ₂ CH ₂ CH ₃ J ₂

N (CH ₂ CH ₂ CH ₃ J ₂

COOCH.

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When carrying out the process according to the invention, the amides and then the carboxylic acids are generally formed during the hydrolysis. The carboxylic acids can also be prepared without isolation of the amides. From the carboxylic acids are obtained by esterification of the esters of the invention. Again, you can work without isolation of the amides or carboxylic acids. The carboxylic acids are preferably prepared without isolation of the amides in one step, while the carboxylic esters are prepared from the isolated carboxylic acids.

The hydrolysis to the amides or carboxylic acids according to the invention is generally carried out with water in inert solvents in the presence of bases.

Suitable inert solvents here are water or alcohols such as methanol, ethanol, propanol, isoprapanol, butanol or glycol, or amides such as dimethylformamide or hexamethylphosphoric triamide, or ethers such as dioxane, tetrahydrofuran, glycymethyl ether, glykaldimethyl ether or diethyl glycol dimethyl ether. It is also possible to use mixtures of the solvents mentioned.

Suitable bases are the usual basic compounds in the hydrolysis. These include preferably alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium carbonate, sodium bicarbonate or potassium carbonate, or alkali metal alcoholates such as, for example, sodium methoxide, sodium ethanolate, potassium methoxide, potassium ethanolate or potassium tert-butoxide.

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og

The hydrolysis is in general carried out in a temperature range from ⁰ ° C to +200 ⁰ C, preferably +20 ⁰ C to +150 ⁰ C.

The hydrolysis 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).

When carrying out the hydrolysis according to the invention, the bases are generally used in an amount of from 1 to 10, preferably from 1 to 5 times, based on 1 mol of the 8-cyano-aminotetralins.

The esterification of the carboxylic acids of the invention to the carboxylic acid esters of the invention is generally carried out with the corresponding alcohols in the presence of acids in inert solvents.

Suitable inert solvents here are the customary organic solvents which do not change under the reaction conditions. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as diethyl ether, dioxane or tetrahydrofuran, or halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride. It is also possible to use mixtures of the solvents mentioned.

Suitable acids in the esterification are the customary inorganic acids. These preferably include mineral acids such as hydrochloric, hydrobromic, sulfuric or phosphoric acid.

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г ·.

The esterification is generally carried out in a temperature range from +10 ⁰ C to +150 ⁰ C, preferably from + 20 ° C to + 100 ⁰ C.

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

When carrying out the esterification, the acids are generally used in an amount of from 1 to 50, preferably from 1 to 20 mol, based on 1 mol of the carboxylic acid. The alcohols are generally used in excess. It has proved to be beneficial in this case, the alcohols with which is esterified, at the same time use as a solvent,

Preferably, an ethereal or alcoholic hydrogen chloride solution is used as the acid, wherein as alcohol in turn the alcohol is used, with which the carboxylic acid is esterified.

The process according to the invention can be carried out, for example, as follows:

The 8-cyano-aminotetralin is heated together with a base in an inert solvent, the length of the reaction and the level of temperature depending on whether the carboxylic acid amide or the carboxylic acid is to be prepared. For esterification, the corresponding carboxylic acid is heated in an inert solvent in the presence of an acid, it being possible for the resulting water of reaction to be distilled off with the solvent.

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Oh it g

The used as starting materials 8-cyano-inninotetral ine are new and can be prepared by the method described above.

As 8-cyano-aminotetralins can be used according to the invention for example:

8-cyano-2-dimethyl-amino-1,2,3,4-tetrahydronaphthalene, 8-cyano-2-diethyl-amino-1,2,3,4-tetrahydronaphthalene, 8-cyano-2-dipropylamino-1,2, 3,4-tetrahydronaphthalene, 8-cyano-2- (N-ethyl-N-methyl) amino-1,2,3,4-tetrahydronaphthalene,

8-cyano-2- (N-ethyl-N-propyl) amino-1,2,3,4-tetrahydronaphthalene in,

8-cyano-2- (N-methyl-N-propyl) amino-1,2,3,4-tetrahydronaphthalene in,

In addition, a process for the preparation of the 8-formyl-aminotetralines according to the invention of the general formula (Ie)

CHO in we Icher

üj- is hydrogen or alkyl,

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R ³ - is alkyl and its salts are found, which is characterized in that

8-Halogen-substituted 2-aminotetralines of the general formula (IX)

(IX) \ R ³

shark

in which R and R have the abovementioned meaning

Hal is fluorine, chlorine, bromine, iodine, preferably chlorine or bromine,

in inert solvents, if appropriate in the presence of auxiliaries with magnesium and formamides of the general formula (X)

R ² K

N-CHO (X),

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in which

R ^ * and R ^ are the same or different and are methyl, ethyl, propyl, phenyl or pyridyl, or

R ^ * and Έ *. together with the nitrogen atom form a piperidine ring,

implements

and then in the case of preparing the salts with the corresponding acids.

The process according to the invention can be illustrated by the following scheme:

N (CH ₂ CH ₂ CH ₃ ) ₂

MgBr

N (CH ₂ CH ₂ CH ₃ )

N-formylpiperidine N (CH ₂ CH ₂ CH ₃ J ₂

CHO

Le A 24 869-foreign countries

Suitable inert solvents here are the customary organic solvents which do not change under the reaction conditions. These include, preferably, ethers such as diethyl ether, butyl methyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene or xylene, or amides such as dimethylformamide or hexamethylphosphoric acid. It is also possible to use mixtures of said solvents.

In general, substances which are customary for the activation of a Grignard reaction are used as auxiliaries. These preferably include iodine or iodorganisehe compounds or anthracene, preferably iodine or iodoethane.

The reaction is generally carried out in a temperature range of -30 ⁰ C to +100 ⁰ C, preferably from ⁰ ° C to + 50 ° 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).

When carrying out the process according to the invention, the formamides are generally used in an amount of from 1 to 5 mol, preferably from 1 to 2 mol, based on 1 mol of the starting compound.

The process according to the invention can be carried out, for example, as follows:

Magnesium powder or magnesium turnings are placed in a suitable solvent, a solution of the 8-halo-sub-

Le A 24 869-foreign countries

Substituted 2-arainoLetralins in a suitable solvent is added dropwise and then the reaction mixture with the corresponding formamide, optionally dissolved in an inert solvent, added. After hydrolysis of the reaction mixture is worked up by extraction, chromatography and / or crystallization.

The 8-halogen-substituted 2-aminotetralins used as starting materials are new and can be prepared by the process already described above.

As 8-halo-substituted 2-aminotetralins, for example, according to the invention can be used: 8-Bram-2-dimethylamino-1,2,3,4-tetrahydronaphthai in, 8-bromo-2-diethyl amino-1,2,3,4 tetrahydronaphthalene, 8-bromo-2-di-pyrimethyl-1,2,3,4-tetrahydronaphthalene, 8-chloro-2-dimethylamino-1,2,3,4-tetrahydronaphthalene, 8-chloro-2-diethy1-amino-1 , 2,3,4-tetrahydronaphthalene, 8-chloro-2-dipropylamino-1,2,3,4-tetrahydronaphthalene, 8-bromo-2- (N-ethyl-N-methyl) amino-1,2,3, 4-tetrahydronaphtha 1, 8-bromo-2- (N-ethyl-N-propyl) amino-1,2,3,4-tetrahydronaphthalene, 8-Bromo-2- (N-methyl-N-propyl) -amino 1,2,3,4-tetrahydronaphthalene, 8-chloro-2- (N-ethyl-N-methyl) amino-1,2,3,4-tetrahydronaphthalene, 8-chloro-2- (N-ethyl -N-propyl) amino-1,2,3,4-tetrahydronaphthalene, 8-chloro-2- (N-methyl-propyl) amino-1,2,3,4-tetrahydronaphthalene.

Le A 24 869-foreign countries

 j О 9 ö

In addition, a process for the preparation of the inventive 8-methyleneaminotetralines of the general formula (If)

(If)

in which

R ² - is hydrogen or alkyl,

R ³ - is alkyl

X is a group of the formula -NR ¹² R ¹³ , -COR ¹⁴ , -SO ₂ R ¹⁵ or -OR ¹⁶ ,

wor in

R and R are the same or different and

- represent hydrogen, alkyl, aryl or aralkyl, where the aryl radicals may be substituted by halogen, cyano, alkyl, alkoxy or trifluoromethyl, or

- represent a group of the formula -COR ¹⁴ , -SO ₂ R ¹⁵ or - (CH ₂ ) _C -NR ¹² R ¹³ ,

Le A 24 869-foreign countries

ü 0 9 3

R ^{14 is} hydrogen, or

1 T ⁷

- a group -NHR means, or

- alkyl or alkoxy, or

Aryl, aryloxy, aralkyl, aralkoxy or heteroaryl, it being possible for the radicals mentioned to be substituted equally or differently by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino,

R ^{15 is} cycloalkyl, or

- alkyl, which may be substituted by cyano, halogen, trifluoromethyl, trifluoromethoxy or alkoxycarbonyl, or

Aryl, aralkyl or heteroaryl, it being possible for the radicals mentioned to be substituted equally or differently by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino, or

a group -NR ¹⁰ R ¹¹ means

in which

R ¹⁰ and R ^{1 are the} same or different and

are hydrogen, alkyl, aryl or aralkyl,

R ^{16 is} hydrogen, alkyl, aryl, aralkyl or a group of the formula -COR ¹⁰ R ¹¹ ,

Le A 24 869-foreign countries

and

Is hydrogen, or cycloalkyl, or

optionally substituted by cyano, halogen, trifluoromethyl or trifluoromethoxy alkyl, or

Aryl, aralkyl or heteroaryl, where the aryl radical may be monosubstituted by identical or different substituents by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino,

с - a number 1 to 8 means

or where

R and R together with the nitrogen atom one

Ring of the series

H ₂ C- (CH ₂ ) _n

(CH ₂ ) _n (CH ₂ ) _n

 N ^ SO

Le A 24 869-foreign countries

or -N form N-A,

wherein

η - a number 1 or 2 means

and

A - is hydrogen or cycloalkyl, or

is alkyl which may be substituted by halogen, hydroxy, amino, alkylamino, dialkylaraino, carbamoyl or sulfaraoyl, or

is aryl, heteroaryl, aralkyl, alkoxycarbonyl, alkylsulfonyl, phenylsulfonyl, tolylsulfonyl, benzylsulfonyl, formyl, carbamoyl or sulfamoyl,

R ² - is hydrogen or alkyl,

R ³ - is alkyl,

however

R ¹ does not mean NH ₂ , if

R ² and R ^{3 are} propyl,

Le A 24 869-Aus land

and their salts found,

which is characterized in that tetralines of the general formula (XI)

(XI)

I \ R ³ R ²³

in which

R ² - is hydrogen or alkyl, R ³ - is alkyl

R ^{23 is} a group of the formula -COR ²⁴ or -CN,

where г in

R is hydrogen, hydroxy, alkoxy or amino,

reduced in inert solvents,

then optionally functional groups are converted into other functional groups by reduction, hydrolysis, oxidation or reaction with electrophotographic reagents,

and then reacting with the corresponding acid in the case of preparation of the salts.

Le A 24 869-foreign countries

2 S β l

U -J Q

The process according to the invention can be explained, for example, by the following equation schemes:

a)

b)

N (CH ₂ CH ₂ CH ₃ J ₂ I reduction

N (CH ₂ CH ₂ CH ₃ ) ₂

CH ₂ NH ₂

₃ cso ₂ ci

N (CH ₂ CH ₂ CH ₃ ) ₂

CH ₂ NHSO ₂ CH ₃

COOH

N (CH ₂ CH ₂ CH ₃ J ₂

Reducing ion

N (CH ₂ CH ₂ CH ₃ J ₂

CH ₂ OH

I + (H ₃ CCO) ₂ O

N (CH ₂ CH ₂ CH ₃ J ₂

CH ₂ OCOCH ₃

Le A 24 869-foreign countries

* О О 9 g

The reduction is carried out either by hydrogen in water or inert organic solvents such as alcohols, ethers or halogenated hydrocarbons or mixtures thereof, with catalysts such as metals or precious metals or their salts, such as Raney nickel, palladium, palladium on animal charcoal, platinum or platinum oxide, or with hydrides in inert solvents, optionally in the presence of a catalyst.

The reduction is preferably carried out using metal hydrides or complex metal hydrides, such as aluminum hydrides or complex borohydrides or aluminum hydrides. Particular preference is given to using sodium borohydride, lithium aluminum hydride, sodium aluminum hydride, aluminum hydride, sodium cyanoborohydride or lithium trimethoxyhydridoaluminate, if appropriate in the presence of aluminum chloride.

Suitable solvents are all inert organic solvents which do not change under the reaction conditions. These preferably include alcohols such as methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or amides such as hexamethylphosphoric triamide or dimethylformamide, or acetic acid, trichloroacetic acid or trifluoroacetic acid, or halohydrocarbons such as methylene chloride, chloroform or carbon tetrachloride. It is also possible to use mixtures of said solvents.

As catalysts in the reduction acids are generally used. These preferably include inorganic acids such as hydrochloric acid, hydrobromic acid or sulfuric acid.

Le A 24 869-Auslan d

O Q О

acid, or organic carboxylic acids having 1 to 4 carbon atoms, or sulfonic acids having 1 to 4 carbon atoms such as formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfanic acid, benzenesulfonic acid or toluenesulfonic acid.

Particularly preferred is the reduction in inert solvents, preferably in ethyl acetate or in alcohols such as methanol, ethanol, propanol or isopropanol or mixtures thereof, in the presence of inorganic or organic acids such as hydrochloric acid or acetic acid and in the presence of a reducing agent, preferably complex hydrides such as sodium borohydride, lithium aluminum hydride or sodium cyanoborohydride.

The reduction is in general carried out in a temperature range of -20 ⁰ C to +100 ⁰ C, preferably from ⁰ ° C to +80 ⁰ C,

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

In carrying out the reduction, the reducing agent is generally used in an amount of from 1 to 6, preferably from 1 to 3 mol, based on 1 mol of the starting compound.

The inventive method can be carried out, for example, by the reducing agent in a

Le A 24 869-foreign countries

О О 9

inert solvents with the tetralins, if appropriate in an inert solvent, and optionally heated. The workup is carried out in the usual way by extraction, chromatography and / or crystallization,

In addition, a process for the preparation of the inventive 8-alkylene-aminotetralines of the general formula (Ig)

(Ig)

in which

R ² - is hydrogen or alkyl, R ³ - is alkyl

W - represents a group of the formula - (CH ₂ ) _a '-X or -CH = CH- (CH ₂ ) _b -X,

wor in

X is a group of the formula -NR ¹² R ¹³ , -COR ¹⁴ , -SO ₂ R ¹⁵ or -OR ¹⁶ ,

wor in

Le A 24 869-foreign countries

^г 'О

R ¹ ^ and R are the same or different and

- represent hydrogen, alkyl, aryl or aralkyl, where the aryl radicals may be substituted by halogen, cyano, alkyl, alkoxy or trifluoromethyl,

or

- represent a group of the formula -COR ¹⁴ , -SO ₂ R ¹⁵ or - (CH ₂ ) _C -NR ¹² R ¹³ ,

R ^{14 is} hydrogen, or

- a group -NHR means, or

- alkyl or alkoxy, or

Aryl, aryloxy, aralkyl, aralkoxy or heteroaryl, it being possible for the radicals mentioned to be substituted equally or differently by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino,

R ^{15 is} cycloalkyl, or

- alkyl, which may be substituted by cyano, halogen, Trifluormethy1, trifluoromethoxy or alkoxycarbonyl, or

Aryl, aralkyl or heteroaryl, it being possible for the radicals mentioned to be substituted equally or differently by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino, or

a group -NR ¹⁰ R ¹¹ means

Le A 24 869-foreign countries

'J U ('

in which

R ¹⁰ and R ^{11 have} the abovementioned meaning,

R ^{16 is} hydrogen, alkyl, aryl, aralkyl or

a group of the formula -CONR ¹⁰ R ¹¹ means

R ^{17 is} hydrogen, or

- Cycloalkyl means, or

- optionally substituted by cyano, halogen, trifluoromethyl or trifluoromethoxy alkyl, or

Aryl, aralkyl or heteroaryl, it being possible for the radicals mentioned to be substituted equally or differently by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino,

and

- a number 1 to 8 means

or where

R ¹² and R ¹³ together with the nitrogen atom one ring of the series

Le A 24 869-foreign countries

° O 9 g

> О:

H ₂ C- (CH ₂ ) _n H o C \ ^ j * -CH о

O = C

I ίί

< ^CH ₂ 'n Г i ^CH 2> n

>

or -N form N-A,

wherein

η - a number 1 or 2 means

and

A - represents hydrogen or cycloalkyl,

or

is alkyl represented by halogen, hydroxy,

Amino, alkylamino, dialkylamino, carbamoyl

or sulfamoyl may be substituted,

or

Le A 24 869-foreign countries

-3ÖÖ98

is aryl, heteroaryl, aralkyl, alkoxycarbonyl, alkylsulfonyl, phenylsulfonyl, tolylsulfonyl, benzylsulfonyl, formyl, carbamoyl or sulfamoyl,

a ¹ - a number 2 to 10 means

b - a number 0 to 8 means

and their salts found,

which is characterized in that 8-formylaminotetralines of the general formula (Ie)

(Ie), CHO

in which

R and R have the meaning given,

in inert solvents in the presence of bases with phosphorus compounds of the general formula (XII)

U- (CH ₂ J _31-1 -X '(XII)

Le A 24 869-foreign countries

>: о с о

in which

X - has the meaning given for X, or - stands for Nitro,

a '- has the meaning given above

U - for a group of the formula

_R 25 OR ²⁵

- P (R ²⁵ ) _? T ", -PR ²⁶ or -P-OR ²⁶ ,

!! i! о о

I would like to

R ²⁵ and R ^{26 are the} same or different and are alkyl or phenyl

and

T is a halide anion, preferably chloride, bromide or iodide,

implements,

then optionally functional groups converted by reduction, hydrolysis, oxidation or reaction with electrophilic reagents into other functional groups

Le A 24 869-foreign countries

oο _9δ

and then in the case of preparing the salts with the corresponding acids.

The process according to the invention can be illustrated by the following formula scheme:

CHO

N (CH ₂ CH ₂ CH ₃ ) 2 + (H ₅ C ₂ O) ₂ P-CH ₂ CH ₂ CH ₂ N (CH ₃ ^

N (CH ₂ CH ₂ CH ₃ J ₂

N (CH ₃ J ₂

N (CH ₂ CH ₂ CH ₃ J ₂

N (CH ₃ J ₂

Suitable inert solvents here are the customary organic solvents which do not change under the reaction conditions. These include, preferably, ethers, such as diethyl ether, butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether,

Le A 24 869-foreign countries

0 9

or hydrocarbons such as benzene, toluene, xylene, or petroleum fractions, or amides such as dimethylformamide or hexamethylphosphoric triamide, or alcohols such as methanol, ethanol, propanol or isopropanol, or dimethyl sulfoxide. It is also possible to use mixtures of the solvents mentioned.

Suitable bases are the usual basic compounds, for basic reactions. These include preferably alkali metal or alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonate such as sodium carbonate, sodium bicarbonate or potassium carbonate, or alkali metal alcoholates such as sodium methoxide, sodium ethanolate, potassium methoxide, potassium ethoxide or potassium tert-butylate, or amides such as sodium amide or lithium diisopropylamide , or organolithium compounds such as phenyllithium or butyl 1ithium.

The choice of solvent or of the base depends on the stability, sensitivity to hydrolysis or CH acidity of the corresponding phosphorus compound. Particular preference is given to using ethers such as diethyl ether, tetrahydrofuran or dioxane as solvents, or hydrocarbons such as benzene, toluene or xylene or dimethylformamide. Particularly suitable bases are alkali metal alkoxides, such as sodium dimethoxide, sodium ethanolate, potassium methoxide, potassium ethoxide or potassium tert-butylate, or organolithium compounds, such as phenyl-1-lithium or butyl-1-lithium.

The reaction is generally carried out in a temperature range from -30 ⁰ C to +150 ⁰ C, preferably from O ⁰ C to + 100 ⁰ C.

Le A 24 869-foreign countries

ΰ 09

The reaction may be carried out at normal, elevated or reduced pressure (e.g., 0.5 to 5 bar). In general, one works at atmospheric pressure.

In carrying out the reaction, the phosphorus compounds are generally employed in an amount of from 1 to 2 mol, preferably in molar amounts, relative to 1 mol of the 8-formylaminotetraline. The bases are generally used in an amount of from 1 to 5, preferably from 1 to 2 mol, based on 1 mol of the phosphorus compound e.

The process of the invention can be carried out, for example, by adding to the phosphorus compounds, dissolved or suspended in a suitable solvent, the base and then the 8-formyl-aminotetraline, optionally in a suitable solvent, and optionally heated. The work-up is carried out in the usual way by extraction, chromatography and / or crystallization.

In carrying out the process of the invention, it is also possible, instead of the phosphonium salts (U = -P (R ²⁵ ) ₃ ⁺ T ~) the corresponding phosphoranes C (R ²⁵ ) ₃ P = CH- (CH ₂ ) _a _2 ~ ^x ^ directly used, which has previously been prepared from the corresponding phosphonium salts and bases in a separate reaction. However, it has proved to be advantageous to carry out the reaction with the phosphorus compounds in the presence of bases as a one-pot process. As a particular variant of a one-pot process, the reaction can also be carried out in the form of a phase-transfer-catalyzed reaction, depending on the stability of the phosphorus compounds

Le A 24 869-foreign countries

- ^ О С о о

Solvents ethers, hydrocarbons and halogenated hydrocarbons can be used and used as bases aqueous sodium hydroxide or Kaiiumhydroxidlösungen.

The phosphorus compounds of the general formula (XII) used as starting materials are known or can be prepared by known methods. Chouben-Weyl's "Methods of Organic Chemistry" Bd XII / 1, 33, 167].

In addition, a process variant for the preparation of the inventive 8-ethylene-aminotetralines of the general formula (Ih)

(Ih)

in which

R ² - is hydrogen or alkyl,

R ³ - is hydrogen or alkyl

X is a group of the formula -NR ¹² R ¹³ , -COR ¹⁴ , -SO ₂ R ¹⁵ or -OR ¹⁶ ,

Le A 24 869-foreign countries

О О 9 3

wherein

R and R ¹ ^ are the same or different and

- represent hydrogen, alkyl, aryl or aralkyl, where the aryl radicals may be substituted by halogen, cyano, alkyl, alkoxy or trifluoromethyl,

or

- represent a group of the formula -COR ¹⁴ , -SC ^ R ¹⁵ or - (CH ₂ ) _C -NR ¹² R ¹³ ,

R ^{14 is} hydrogen, or

- a group -NHR means, or

- alkyl or alkoxy, or

Aryl, aryloxy, aralkyl, aralkoxy or heteroaryl, it being possible for the radicals mentioned to be substituted equally or differently by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino,

R ^{15 is} cycloalkyl, or

- alkyl, which may be substituted by cyano, halogen, trifluoromethyl, trifluoromethoxy or alkoxycarbonyl, or

Aryl, aralkyl or heteroaryl, it being possible for the radicals mentioned to be substituted equally or differently by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino, or

a group -NR ¹⁰ R ¹¹ means

Le A 24 869-foreign countries

с В

I would like to

R ¹ and R have the abovementioned meaning,

R ^{16 is} hydrogen, alkyl, aryl, aralkyl or a group of the formula -CONR ¹⁰ R ¹¹ ,

R is hydrogen, or

- Cycloalkyl means, or

- optionally substituted by cyano, halogen, trifluoromethyl or trifluoromethoxy alkyl, or

Aryl, aralkyl or heteroaryl, it being possible for the abovementioned radicals to be substituted identically or differently by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino up to 3 times,

с - a number from 1 to 8, or where 1 ¹ P 1 * 4

R and R together with the nitrogen atom form a ring of the series

H ₂ c- (CH ₂ ) _n

♦ σ

Π о w ⁴ *. • υπ '"

² ^ N '

Le A 24 869-foreign countries

2s ·., ₉

O = C Ii-C ₆ H ₅

LJ

or -N form N-A,

where г in

η - a number 1 or 2 means

and

A - is hydrogen or cycloalkyl, or

- is alkyl which may be substituted by halogen, hydroxy, amino, alkylamino, dialkylamino, carbamoyl or sulfamoyl,

or

- is aryl, heteroaryl, aralkyl, alkoxycarbonyl, alkylsulfonyl, phenylsulfonyl, tolylsulfonyl, Вепгуіsulfonyl, formyl, carbamoyl or sulfamoyl

and their salts found,

which is characterized in that one

Le A 24 869-foreign countries

О О о g

8-formylaminotetralines of the general formula (Ie)

(Ie), CHO

in which

о о

R and R have the abovementioned meaning,

in inert solvents, if appropriate in the presence of condensing agents with CH-acidic compounds of the general formula (XIII)

H ₃ CX '(XIII)

in we I rather

X - has the meaning given for X, or - stands for Nitro,

ums et 2 t,

then optionally functional groups converted by reduction, hydrolysis, oxidation or reaction with electrophilic reagents in other funktianelle groups

and then reacting with the corresponding acid in the case of preparation of the salts.

The process according to the invention can be explained, for example, by the following formula scheme:

Le A 24 869-foreign countries

CHO

CHO

N (CH ₂ CH ₂ CH ₃ ) 2 ^H 3 ^C " ^NO 2

Condensate ion

• Ν (CH ₂ CH ₂ CH ₃ )

Reducing ion

N (CH ₂ CH ₂ CH ₃ ) ₂

SO ₂ N (CH ₃ ) ₂

H ₃ CSO ₂ N (CH ₃ ) ₂

Condensate ion

N (CH ₂ CH ₂ CH ₃ J ₂

Reducing ion

N (CH ₂ CH ₂ CH ₃ ) ₂

SO ₂ N (CH ₃ ) ₂ Le A 24 869-Foreign countries

ο и Q 9 $

Suitable inert solvents are the customary solvents which do not change under the reaction conditions. These include preferably water or alcohols such as methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, butyl methyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, or halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride, or hydrocarbons such as benzene, toluene, xylene, or petroleum fractions, or amides such as dimethylformamide or hexamethylphosphoric triamide, or dimethyl sulfoxide or acetic acid. It is also possible to use mixtures of said solvents.

As the condensing agent, bases are generally used. These include preferably alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium carbonate or potassium carbonate, or alkali metal such as sodium, sodium, potassium, potassium, Kai ium-tert, butoxide or ammonia, or ammonium acetate, or organic amines such as diethylamine, Triethylamine, diisopropylamine, tripropylamine, pyridine, piperidine, morpholine or Ν, Ν-dimethylaminopyridine or picoline.

The reaction is generally carried out in a temperature range from O ⁰ C to +150 ⁰ C, preferably from + 20 ° C to + 100 ⁰ C.

The reaction may be carried out at normal, elevated or reduced pressure (e.g., 0.5 to 5 bar). In general, one works at atmospheric pressure.

Le A 24 869-foreign countries

2,0g

In carrying out the reaction, the CH-acidic compounds are generally used in an amount of from 0.1 to 100, preferably from 0.5 to 50, particularly preferably from 1 to 10 mol, based on 1 mol of 8-formyl-aminotetralin.

The process according to the invention can be carried out, for example, by mixing the 8-formylaminotetralin with the CH-acidic compound, if appropriate in an inert solvent and, if appropriate, with bases and, if appropriate, heating. The work-up is carried out in the usual way by extraction, chromatography and / or crystallization. Here too it is possible to carry out the process according to the invention by a phase-transfer-catalyzed variant.

The conversion of functional groups into other functional groups in the production processes listed above takes place, depending on the nature of the functional group, by oxidation, reduction, hydrolysis or by reaction with electrophilic reagents and will be explained individually below:

1. The reduction of the nitrile group to the amino group is generally carried out with metal hydrides, preferably with lithium aluminum hydride, aluminum hydride (prepared for example by reaction of lithium aluminum hydride with lÜttige sulfuric acid or aluminum chloride) or mixtures thereof in inert solvents such as ethers or chlorohydrocarbons, preferably in ethers such as Tetrahydrofuran, diethyl ether or dioxane in a temperature range from -20 ⁰ C to + 100 ⁰ C,

Le A 24 869-foreign countries

preferably from ⁰ ° C to + 50 ° C at atmospheric pressure, the reduction is also by hydrogenating the nitrile in inert solvents such as alcohols eg methanol, ethanol, propanol or isopropanol in the presence of a noble metal catalyst such as platinum, palladium, palladium on animal charcoal or Raney Niekel, in a temperature range of O ⁰ C to +150 ⁰ C, preferably from room temperature to + 100 ⁰ C at atmospheric pressure or at overpressure possible.

The reaction can be illustrated by the following scheme:

N (CH ₂ CH ₂ CH ₃ ) ₂ Reduct ion

N (CH ₂ CH ₂ CH ₃ ) ₂

2. The conversion of carbamates into N-methylamines is generally carried out by reduction with hydrides, preferably with lithium aluminum hydride in inert solvents such as ethers, hydrocarbons or chlorinated hydrocarbons, preferably in ethers such as diethyl ether, tetrahydrofuran or dioxane, in a temperature range from ^{0 0} C to +150 ⁰ C, preferably from + 20 ° C to + 100 ⁰ C at atmospheric pressure.

The reaction can be illustrated by the following scheme:

Le A 24 869-foreign countries

- S О О ς ν

Ν (CH ₂ CH ₂ CH ₃ )

Reducing ion

NHCOOC ₂ H ₅

N (CH ₂ CH ₂ CH ₃ ) ₂

NHCH ₃

3. The reduction of alkoxycarbonyl groups in alcohol groups is generally carried out with hydrides, preferably with lithium aluminum hydride in inert solvents such as ethers, hydrocarbons or halogenated hydrocarbons or mixtures thereof, preferably in ethers such as diethyl ether, tetrahydrofuran or dioxane in a temperature range of O ⁰ C to +150 ⁰ C, preferably from +20 ⁰ C to + 100 ⁰ C at atmospheric pressure.

The reaction can be illustrated by the following scheme:

COOC ₂ H ₅

N (CH ₂ CH ₂ CH ₃ J ₂

Reducing ion

N (CH ₂ CH ₂ CH ₃ ) ₂

- * CH ₂ OH

Le A 24 869-foreign countries

2 о С О g а

4, The hydrolysis of the Ni trilgruppe to the carboxamide group is generally carried out with the aid of strong mineral acids, preferably with hydrogen chloride in inert solvents such as water and / or alcohols such as methanol, ethanol, propanol or isopropanol in a temperature range from ^{0 0} C to +150 ⁰ C, preferably from + 20 ⁰ C to + 100 ⁰ C at atmospheric pressure.

The reaction can be explained by the following scheme:

N (CH ₂ CH ₂ CH ₃ J ₂

hydrolysis

N (CH ₂ CH ₂ CH ₃ ) ₂

CONH '

5. Reaction of NH- or OH-acidic compounds with electrophilic reagents gives a multiplicity of further compounds according to the invention:

a) The conversion of amines into carbonamides is generally carried out by reaction with carboxylic acid esters in inert solvents such as ethers or hydrocarbons, or mixtures thereof, preferably in ethers such as diethyl ether, tetrahydrofuran or dioxane, optionally in the presence of bases such as alkali metals, alkali metal hydrides, AlkalialKoholate or organolithium compounds, preferably in the presence of alkali metals such as sodium, or alkali metal hydrides such as

Le A 24 869- Auslands

о9a

Sodium hydride or potassium hydride in a temperature range of +20 ⁰ C to +150 ⁰ C, preferably at the boiling point of the solvent used at atmospheric pressure,

Moreover, it is possible, the amides with carboxylic acid halides or anhydrides, preferably with carboxylic acid chlorides in inert solvents such as ethers, hydrocarbons or halogenated hydrocarbons or mixtures thereof, preferably in ethers such as diethyl ether, tetrahydrofuran, or halogenated hydrocarbons such as methylene chloride or chloroform, optionally in the presence of bases as alkali metal carbonates, for example sodium carbonate or potassium carbonate, or organic amines such as triethylamine or pyridine, in a temperature range from -20 ⁰ C to +100 ⁰ C, preferably from ^{0 0} C to +60 ⁰ C at atmospheric pressure to produce

The reaction can be illustrated by the following scheme:

N (CH ₂ CH ₂ CH ₃ )

OCH ^

NHC

N (CH ₂ CH ₂ CHg) ₂

Le A 24 869-foreign countries

 1 year

⁸ С О 9 p

Die) The conversion of amines into carbamates is generally carried out with carbonic acid esters, preferably with unsymmetrical carbonic acid esters, more preferably with carbonic acid esters bearing a Phenylesterrest, in inert solvents such as ethers, hydrocarbons or halogenated hydrocarbons, or mixtures thereof, preferably in ethers such as diethyl ether, Tetrahydrofuran or dioxane, in a temperature range of + 20 ° C to + 150 ⁰ C, preferably from +20 ⁰ C to + 100 ⁰ C at atmospheric pressure.

The reaction can be explained by the following scheme:

N (CH ₂ CH ₂ CH ₃ )

OCOOC ₂ H ₅

N (CH ₂ CH ₂ CH ₃ J ₂

NHCOOC ₂ H ₅

c) The conversion of amines into ureas is generally carried out by reaction with isocyanates in inert solvents such as ethers, hydrocarbons or halogenated hydrocarbons, or mixtures thereof, preferably in ethers such as diethyl ether or tetrahydrofuran, or in halogenated hydrocarbons such as methylene

Le A 24 869-foreign countries

chloric! or chloroform, in a temperature range from -20 ⁰ C to +150 ⁰ C, preferably from ^{0 0} C to + 100 ⁰ C at atmospheric pressure.

The reaction can be explained by the following scheme:

N (CH ₂ CH ₂ CH ₃ ).

N (CH ₂ CH ₂ CH ₃ J ₂

NHCONHC ₆ H ₅

d) The conversion of amides into sulfonamides or Aminosulfamoylderivate is generally carried out with SuI-fonsäurehalogeniden or, with Amidosulfonsäurehalogeniden, preferably with the corresponding chlorides in inert solvents such as ethers, hydrocarbons or halogenated hydrocarbons, or mixtures thereof, preferably in halogenated hydrocarbons such as methylene chloride or chloroform optionally in the presence of bases such as alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides or organic amines, preferably with alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, or organic amines such as triethyl

Le A 24 869-foreign countries

amine or pyridine, in a temperature range from -20 ⁰ C to + 100 ⁰ C, preferably from ^{0 0} C to + 50 ⁰ C at atmospheric pressure,

The reaction can be illustrated by the following scheme:

N (CH ₂ CH ₂ CH ₃ J ₂

+ (H ₃ C) ₂ NSO ₂ Cl

N (CHOCH ₇ CHO)

NHSO ₂ CH ₃

NHSO ₂ N (CHg) ₂

e) The conversion of the hydroxy group into carbonic acid esters is generally carried out by reaction with haloformates, preferably with chloroformates in inert solvents such as ethers, hydrocarbons or halogenated hydrocarbons, preferably in halogenated hydrocarbons such as methylene chloride or chloroform, or in ethers such as diethyl ether or tetrahydrofuran, optionally in the presence of bases such as alkali metal hydroxides, alkali metal carbonates or organic amines, preferably

Le A 24 869-foreign countries

in the presence of organic amines such as triethylamine, pyridine, picoline or dimethylaminopyridine in a temperature range from -20 ° C to +100 ⁰ C, preferably from ⁰ ° C to +30 ⁰ C at normal pressure,

The reaction can be illustrated by the following scheme:

N (CH ₂ CH ₂ CH ₃ ) ₂

ClCOOC ₂ H ₅

N (CH ₂ CH ₂ CH ₃ ) ₂

OCOOC ₂ H ₅

f) Cyclic sulfonamides are generally prepared by reaction of intramolecular electrophiles in inert dipolar aprotic solvents, preferably in dimethylformamide, hexamethylphosphoric triamide or dimethylsulfoxide, optionally in the presence of bases such as alkali metals, alkali metal hydrides, alkali amides, alkali metal alcoholates or organolithium compounds, preferably in the presence of alkali metal hydrides such as Sodium hydride or potassium hydride, or alkali amides such as sodium amide or lithium diisopropylamide, optionally in the presence of catalytic amounts of an alkali iodide, for example sodium iodide or potassium iodide, in a temperature range

Le A 24 869-foreign countries

2 Ό Q С} й

from -20 ⁰ C to + 10O ⁰ C, preferably prepared from ^{0 0} C to + 50 ° C at atmospheric pressure.

The reaction can be illustrated by the following scheme:

N (CH ₂ CH ₂ CH ₃ J ₂

1 cyclization

N (CH ₂ CH ₂ CH ₃ ) ₂

NHSO

6. A further variation of the method according to the invention with respect to the functional groups in R ¹ results from the reduction of the double bond in R ¹ , whereby present nitro groups (X '= NO ₂ ) are simultaneously reduced to the amino group. The reduction is generally carried out with metal hydrides, preferably with lithium aluminum hydride, aluminum hydride (prepared for example by reaction of lithium aluminum hydride with sulfuric acid and aluminum chloride), sodium borohydride, lithium borohydride or mixtures thereof in inert solvents such as ethers or chlorinated hydrocarbons, preferably in ethers such as tetrahydrofuran, dioxane or diethyl ether in a Temperaturbreich from -20 ⁰ C to 100 ⁰ C, preferably from ⁰ ° C to +80 ⁰ C at atmospheric pressure.

Le A 24 869-foreign countries

i. O ν U 9 Ч

Charcoal or Raney Niekel, optionally in the presence of acids such as hydrochloric acid, acetic acid, trichloro or trifluoroacetic acid, in a temperature range from ⁰ ° C to +200 ⁰ C, preferably from + 20 ° C to +100 ⁰ C in normal or at To perform overpressure.

The reaction can be illustrated by the following scheme:

N (CH ₂ CH ₂ CH ₃ )

N (CH ₂ CH ₂ CH ₃ ) ₂ Reduct ion

Compounds of the formula (I) with R =O (CH ₂ ) _a X (in which a and X have the specific meaning) can be obtained from the corresponding 8-hydroxy-2-alkylamino-tetralines, The 8-hydroxy-2- Alkylamino-tetralines are known (EP-A-1-41 488) or can be prepared from the corresponding halogen compounds of the formula (I) »

The 8-hydroxy-2-alkylamino-tetralines can be prepared by reacting under known alkylation conditions with compounds of the formula

Y- (CH ₂ ) _a -X in which

Y is -Cl, -Br or -OSO ^ alkyl (C ₁ to C ₄ ) and X and a have the abovementioned meaning,

implements.

Le A 24 869-Au ξ 1 and

я о о 9 а

The compounds prepared according to the invention are suitable for the treatment of disorders of the central nervous system such as states of anxiety, tension and depression, central nervous system-related sexual dysfunctions and sleep disorders. Furthermore, they are suitable for eliminating cognitive deficits, for improving learning and memory performance and for treating Alzheimer's disease. Furthermore, these active substances are also suitable for modulating the cardiovascular system. They also interfere with the regulation of cerebral blood flow and thus represent effective agents for combating migraine. Likewise, the compounds of the invention can be used to combat pain. They are also suitable for combating diseases of the intestinal tract, which are characterized by disorders of the serotoninergic system.

The new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. In this case, should be present in each case in эіпзг concentration of about 0.5 to 90 wt .- ^ ₀ of the total mixture, the therapeutically active compound, ie, in amounts which are sufficient to achieve the dosage range indicated.

The formulations are prepared, for example, by stretching the active compounds with solvents and / or excipients, if appropriate using emulsifiers and / or dispersants, wherein z. B, in the case of using water as a diluent,

if organic solvents such as solvents can be used.

As auxiliaries are listed, for example; Water, non-toxic organic solvents, such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut / sesame oil), alcohols (e.g., ethyl alcohol, glycerin), carriers, e.g. ground natural minerals (eg kaolins, clays, talc, chalk), ground synthetic minerals (eg fumed silica, silicates), sugars (eg pipe, milk and dextrose), emulsifiers (eg polyoxyethylene fatty acid esters), polyoxyethylene fatty alcohol ethers (For example, lignin-sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (for example, magnesium stearate, talc, stearic acid and sodium sulfate).

The application is carried out in a customary manner, preferably orally or parenterally, in particular perlingually or intravenously. In the case of oral administration, tablets may, of course, besides the abovementioned excipients, also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various adjuvants such as starch, preferably potato starch, gelatin and the like. Furthermore, lubricants, such as magnesium stearate, sodium lauryl sulfate and talc can be used for tableting. In the case of aqueous suspensions, the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.

Le A 24869-Aus1 and

In the case of parenteral administration, solutions of the active ingredients may be employed using suitable liquid carrier materials.

In general, it has proved to be advantageous to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight to achieve effective results when administered intravenously, and for oral administration, the dosage is about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg of body weight,

Nevertheless, it may be necessary to deviate from the stated amounts, depending on the body weight or the type of administration route, the individual behavior towards the drug, the nature of its formulation and the time or interval at which it is administered , Thus, in some cases it may be sufficient to make do with less than the aforementioned minimum amount, while in other cases, the above upper limit must be exceeded, In the case of the application of larger quantities, it may be advisable to distribute them in several single doses over the day.

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Manufacturing objectives example 1

2-dibroboro amino-8-chiogo-1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ ) ₂

700 mg (2.8 mmol) of 2-dipropylamino-8-aroi.no- 1, 2, 3, 4-tetrahydronaphthahlin were dissolved in 2.5 ml of water and 1.14 ml (13.7 mmol) of 37% hydrochloric acid , A solution of 195 mg of sodium nitrite and 0.45 ml of water was added dropwise thereto at an internal temperature of ⁰ ° C. The solution was then stirred at ⁰ ° C. after 15 minutes.

Meanwhile, 396 mg (4 mmol) of copper (I) chloride was dissolved in 1.6 ml of water, and the solution was cooled to ⁰ ° C. Were added dropwise carefully the upper reaction solution to the heated and approach 30 min at +95 ⁰ C until nitrogen evolution ceased.

The reaction mixture was neutralized with aqueous potassium bicarbonate solution and extracted with dichloromethane. The organic phase was dried over sodium sulfate and the solvent was separated. The residue was purified by column chromatography on silica gel. The eluent used was dichloromethane / methanol 20: 2.

Yield: 74У. of theory (oily product) R _f : 0.64

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2 SQ С 9 В

The base was made from a petroleum benzene solution with ethereal hydrogen chloride solution as Hydrochloric! failures. The Hydrochloric! was a highly hygroscopic, colorless, crystalline product.

Example 2 Process variant A:

2-dipropylamino-8-bromo-1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ J ₂

The reaction was carried out by using copper (I) bromide and 47% ідег hydrobromic acid analogous to the reaction for 2-dipropylamino-8-chloro-1,2,3,4-tetrahydronaphthalene (Example 1).

Yield: 32% of theory (oily product) R _f : 0.73 (dichloromethane / methanol 20: 2)

The base was precipitated from a petroleum benzene solution with ethereal hydrogen chloride solution as the hydrochloride. The hydrochloride was a highly hygroscopic, colorless, crystalline product.

Process variant B : 1, 8-bromo-2-tetralone

br

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2 Я О О <з $

83.5 g of aluminum chloride (0.63 mmol) were added to 1.8 l of methylene chloride at 0 - +5 ⁰ C. 105 g (0.49 mol) of 2-bromophenyl-acetic acid chloride (dissolved in 200 ml of methylene chloride) were added dropwise at 0 - +5 ⁰ C in 30 min. After stirring for 30 min at 0 - +5 ⁰ C, 50 g of ethylene were introduced so that the reaction temperature +10 ⁰ C did not exceed. The mixture was stirred for 2 h at 20 - +25 ⁰ C. The aluminum complex was destroyed by cautious addition of 500 ml of ice water, the phases were separated and the aqueous phase extracted with 250 ml of methylene chloride. From the dried methylene chloride phase, the title compound was obtained in a yield of 109 g as a yellow oil (GC content 97%) and used without further purification,

2. S-bromo - ^ -dipropylamino-1,2,3,4-tetrahydronaphthalene

a) Enamine synthesis : 385 g (1.71 mol) of 8-bromo-2-tetralone and 165 g of propylamine (2.8 mol) were dissolved in 700 ml of benzene in the presence of 1.5 g of ion exchange resin Amberlyst 15 on a water separator for 2 h stirred under reflux, the ion exchange resin was filtered off and the filtrate was concentrated under reduced pressure, the remaining residue (437 g) was used as crude product in the reductive alkylation,

b) Reductive alkylation : 437 g of crude enamine (a) were initially charged at 0 - + 5 ⁰ C in 3 1 propionic acid. At 0 + 10 ⁰ C, 310 g of sodium borohydride were added in portions. After completion of the addition, the reaction temperature was slowly increased to +50 ⁰ C and held for 2 h. Subsequently, the reaction temperature was raised to +120 ⁰ C and held for 3 h. The cooled reaction solution was diluted with 10 1 of ice water and by addition of

Le A 24 869-foreign countries

г. Я О С С, - »

Sodium hydroxide solution (45%) made weakly alkaline. By extraction with chloroform and fractional distillation 320 g of the final product were (bp 128 -135 ⁰ C; 0.07 mm) was obtained (GC 90% strength),

If the reaction is stopped after two hours of stirring at +50 ⁰ C and worked up as described, the secondary amine e-bromo ^ -propylaminotetrahydronaphthalene is obtained,

Example 3 Process variant A:

2-dipropylamino-8-cyano-1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ ) ₂

Under nitrogen, 6.0 g (24 mmol) of 2-dipropylamino-8-amino-1,2,3,4-tetrahydronaphthalene were dissolved in 36 g (120 mmol) of 33% sulfuric acid. Thereafter, at ^{0 0} C to max. +5 ⁰ C added dropwise a solution of 1.7 g (24 mmol) of sodium nitrite in 5 ml of water. Subsequently, the reaction solution was stirred after 30 min at the same temperature and then in a heated to + 50 ⁰ C solution of 2.9 g (32 mmol) of copper (I) cyanide, 8.7 g (177 mmol) of sodium cyanide and 39 ml Water dripped. The mixture was then stirred for 1 h at 5 0 ° C until the evolution of nitrogen was complete.

Le A 24 869-foreign countries

iodine О

The mixture was then stirred in 500 ml of ice-water and the mixture was adjusted to pH 10 with 2N sodium hydroxide solution. Thereafter, the mixture was extracted with dichloromethane and the organic phase was washed neutral with water. The solution was dried over sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography on silica gel. Toluene / methanol 85:15 was used as eluant, yield: 48% of theory (oil) R _f : 0.63 (toluene / methanol 83:17)

Process variant B:

152 g of 8-bromo-2-dipropylamino-1,2,3,4-tetrahydronaphthalene (Example 2) (0.49 mol) and 66 g of copper (I) cyanide were stirred in 450 ml of dimethylformamide at 150 ⁰ C for 6 h. The cooled reaction mixture was added to a mixture of 150 ml of ethylenediamine and 450 ml of H 2 O and stirred for 1 h at room temperature. The crude product obtained by extraction with ethyl acetate was fractionally distilled. The product was obtained as a colorless oil (bp, 140-150 ^° C., 0.1 mm) in a yield of 73 g (GC 95%).

Example 4

2-dipropylamino-8- (3-butyl-ureido) -1,2,3,4-tetrahydronaphthalene

-N (CH ₂ CH ₂ CH ₃ ) ₂ NH

CONHCH ₂ CH ₂ CH ₂ Ch ₃

Le A 24 869-foreign countries

Я С Ö 9 3

0.7 g (2.8 mmol) of Z-dipropylamino-e-amino-1,2,3,4-tetrahydronaphthalene were dissolved in 3 ml of toluene. The solution was treated with 0.34 g (3.4 mmol) of butyl isocyanate Then the solvent was distilled off under vacuum and the residue was purified by column chromatography on silica gel. The eluent used was ethyl acetate / methanol / triethylamine 20: 1: 0.1, yield: 51 °. of theory (oily substance) R _f : 0.51

After dissolving in petroleum benzine, the base was converted by dropwise addition of ethereal hydrogen chloride solution in the hydrochloride. The hydrochloride was a colorless, slightly hygroscopic, crystalline substance,

At game 5

2-dipropylamino-8-formamido-1,2,3,4-tetrahydronaphthalene

-N (CH ₂ CH ₂ CH ₃ ) ₂ NHCHO

1.06 g (10.4 mmol) of acetic anhydride and 0.48 g (10.4 mmol) of formic acid were combined and heated at 50 ° C for 3.5 hours. After cooling, the solution of 0.85 g (3.5 mmol) of 2-dipropylamino-8-amino-1,2,3,4-tetrahydronaphthalene and 5 ml of formic acid was added dropwise, and the mixture was stirred at room temperature for 17 h,

Subsequently, the solvent was distilled off in vacuo and the residue dissolved in dichloromethane. The solution

Le A 24 869-foreign countries

was then washed with aqueous potassium bicarbonate solution and dried over sodium sulfate. Subsequently, the solvent was distilled off. The residue was purified by column chromatography on alumina 90 (alumina from Merck, activity grade II-III). The eluent used was cyclohexane / methanol / triethylamine 20: 0.5: 0.1. Yield: 42% of theory (crystalline substance) R _f : 0.6 2

The base was, after dissolution in diethyl ether, by dropwise addition of an ethereal hydrogen chloride solution into the hydrochloride. The hydrochloride was a colorless, highly hygroscopic, crystalline substance.

Example 6

2-dipropylamino-8-carbamoyl-1,2,3,4-tetrahydronaphthalene

CONH ₂

Under nitrogen, 1.0 g (4 mmol) of 2-dipropylamino-8-cyano-1,2,3,4-tetrahydronaphthalene and 0.5 g (8 mmol) of potassium hydroxide in 10 ml of tert-butanol were refluxed for 6 hours. After cooling, the reaction solution was diluted with 20 ml of saturated sodium chloride solution and extracted with dichloromethane. The organic phase was dried with sodium sulfate and the solvent was distilled off in vacuo. The residue was crystallized from 10 ml of diisopropyl ether.

Le A 24 869-foreign countries

"7 Ял р

Yield: 56% of theory (beige powder) M.p .: 105-106 ^° C.

R _f : 0.25 (silica gel dichloromethane / methano 1 75:25)

Example 7

2-dipropylamino-1,2,3,4-tetrahydronaphthalen-8-carboxylic acid

^ N (CH ₂ CH ₂ CH ₃ ) ₂ COOH

Under nitrogen, 256 mg (1 mmol) of 2-dipropylamino-8-cyano-1,2,3,4-tetrahydronaphthalene, 132 mg (2 mmol) of potassium hydroxide and 36 mg (2 mmol) of water in 1 ml of ethylene glycol were stirred for 20 h at + 150 ⁰ C stirred. After cooling, the reaction solution was diluted with 6 ml of water and extracted with dichloromethane. The aqueous phase was then adjusted to pH 1-2 with 2.75 ml of 1N hydrochloric acid and extracted again with dichloromethane. Subsequently, the aqueous phase was adjusted to pH 5 with 25% ammonia solution. Thereafter, the water was distilled off in vacuo and the residue dried at + 50 ° C and 0.05 mb vacuum to constant weight. Then the residue was dissolved in absolute tetrahydrofuran. After the insoluble salts were filtered off, the solution was freed of the solvent under vacuum. The residue left as the reaction product as an almost colorless oil, yield: 44У · the theory

R _f : 0.67 (silica gel, dichloromethane / methano1 / 25% ammonia solution 67: 27: 6)

Le A 24 869-foreign countries

Example 1 8

Z-dipropylamino-e-ethoxycarbonyl-1,2,3,4-tetrahydronaphthalene

-N (CH ₂ CH ₂ CH ₃ ) ₂ COOC ₂ H ₅

300 mg (1.1 mmol) of 2-dipropylamino-1,2,3,4-tetrahydronaphthalene-8-carboxylic acid were stirred in 30 ml of absolute ethanol and 3 ml of a solution of hydrogen chloride in diethyl ether (190 mg / ml) at room temperature until the reaction was complete. The solvent was then distilled off under reduced pressure and the residue was dissolved in 10 ml of dichloromethane. The solution was washed once with 0.1 N sodium hydroxide solution and twice with water and dried over sodium sulfate. The solvent was then distilled off under vacuum. The reaction product remained as an almost colorless oil.

Yield: 64У. the theory

R _f : 0.97 (silica gel, dichloromethane / methanol / 25% ammonia solution 6 7: 27: 6)

Example 9

2-dipropylamino-8-formyl-1,2,3,4-tetrahydronaphthalene

CHO

Le A 24 869-foreign countries

3.75 g (154.4 mmol) of magnesium powder were placed under argon in 100 ml of dry tetrahydrofuran. A few drops of iodoethane were added, and then a solution of 31.9 g (103 mmol) of Z-dipropylamino-e-bromo-1,2,3, A- tetrahydronaphthalene and 20 ml of absolutely dry tetrahydrofuran was added dropwise at ⁰ ° C. The mixture was stirred at + 60 ° C for 3 h. It was then cooled to room temperature and added dropwise at this temperature 12.8 g (113.3 mmol) of N-formylpiperidine. It was stirred for 30 min at room temperature and then hydrolyzed with 3 N hydrochloric acid. It was then adjusted to pH 12 and extracted with ethyl acetate. It was chromatographed with cyclohexane / ethyl acetate / triethylamine: 80: 19: 1 over silica gel 60, 63-200 [im,

Yield: 65.5% of theory (oil) R _f : 0.342 (diisopropyl ether / triethylamine 99: 1)

At game 10

2-dipropylamino-8-hydroxymethyl-1,2,3,4-tetrahydronaphthalene

-N (CH ₂ CH ₂ CH ₃ J ₂ CH ₂ OH

Under nitrogen, 15 mg (0.4 mmol) of lithium aluminum hydride were suspended in 2 ml of diethyl ether. To the suspension was carefully added dropwise a solution of 210 mg (0.7 mmol) of 2-dipropylamino-8-ethoxycarbonyl-1,2,3,4-tetrahydronaphthalene in 1 ml of diethyl ether. The mixture was then stirred for a further 5 hours at room temperature.

Le A 24 869-foreign countries

о О О й я

Thereafter, only 5 mg (0.05 mmol) of ethyl acetate, then 15 mg of water, then 20 mg of 15% strength sodium hydroxide solution and finally 50 mg of water were added dropwise and the mixture was stirred for 0.5 h. The reaction was diluted with 3 ml of diethyl ether. The precipitate was filtered off and the filtrate was washed with water and the solvent was removed. The oily residue was dried in vacuum of 0.05 mb and a temperature of 50 ° C to constant weight.

Yield: 71% of theory

R _f : 0.28 (silica gel, toluene / methanol 85:15)

Example 11

8-acetyl-amino-2-dipropylamino-1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ )

NHCOCH ₃

24 g (0.094 mol) of в-Суапо-г-аіргоруіатіпо-1,2,3,4-tetrahydronaphthal in were placed in 100 ml of tetrahydrofuran (absolute); 4.5 g of lithium aluminum hydride (0.12 mol) were added in portions at +20 - +30 ⁰ C. After refluxing for two hours, the excess lithium aluminum hydride was destroyed by the addition of water and sodium hydroxide. The precipitated inorganic solid was filtered off with suction and washed with 50 ml of tetrahydrofuran. The remaining after drying and concentration of the filtrate crude product (25 g) was dissolved in 200 ml of methylene chloride and treated with 10 g of triethylamine. After addition of 0.2 g of dimethylaminopyridine as the acylation catalyst, 1 g

Le A 24 869-foreign countries

Ί ö ö ö g

Acetane hydride at + 20 - +25 ⁰ C added dropwise. After 12 hours of stirring at +20 - +25 ⁰ C, the reaction solution was washed with sodium bicarbonate and water, dried and concentrated. The resulting crude product (30 g) was recrystallized from hexane / ethyl acetate (10: 1). The product was isolated as a solid in a yield of 75% of theory

Mp. 99-100 ⁰ C.

Example 12

2-dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ J ₂

CH ₂ NH ₂

Under nitrogen, 10.6 g (35 mmol) of 2-dipropylamino-8-acetamidomethyl-1,2,3,4-tetrahydronaphthalene in 100 ml of ethanol and 23.1 g (350 mmol) of potassium hydroxide at 90 ° C for 24 h Reflux heated. The mixture was then stirred into 1 liter of ice-water and the mixture was extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. The solvent was distilled off in vacuo. The residual reaction product was purified by column chromatography on silica gel with methanol / triethylamine 95: 5 as eluant

Yield: 59 * /. of theory (oil) R _f : 0.62

Le A 24 869-foreign countries

2 S и О 9 8

Example 13

2-Di ρгоруlamino-8-aminomethyl-1,2,3,4-tetrahydronaph-L-halo hydrochloride

The compound of Example 12 was dissolved in ether. By dropwise addition of ethereal hydrogen chloride solution, the hydrochloride was precipitated, which was then filtered off with suction and dried at room temperature in vacuo. Yield: 3.6 g, mp. 97-100 ⁰ C.

At game 14

2-dipropylamino-8-methylsulfonamido-methyl-1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ ) ₂

NH-SO ₂ -CH ₃

Under nitrogen, 1.6 g (6 mmo1) of 2-dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene were dissolved in 16 ml of dichloromethane. At max. +25 ⁰ C were then added dropwise 0.7 g (6 mmo1) of methanesulfonyl chloride, was then allowed to stir the reaction solution 18h at room temperature. Thereafter, 16 ml of water was added. The mixture was adjusted to pH 10 with 1 N sodium hydroxide solution. The organic phase was separated and washed with water. After drying over sodium sulfate, the solvent was distilled off in vacuo. The residue was purified by column chromatography

Le A 24 869-foreign countries

ö 9 g

Silica gel with diisopropyl ether / isopropanol / triethylamine 65: 70: 5 as eluent purified, yield: 76 * /. of the theory (oil) R _f : 0.55

Example1 15

2-dipropylamino-8-butylsulfonamidomethyl-1,2,2,4,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ J ₂

NH-SO ₂ -C ₄ H ₉

Under nitrogen, 1.6 g (6 mmol) of Z-dipropylamino-1-aminomethyl-1,2,2,4,4-tetrahydronaphthalene were dissolved in 16 ml of dichloromethane. At max. +25 ⁰ C were then (6 mmol) Butansulfonsäurechlorid added dropwise 0.9 g. Then, the reaction solution was allowed to stir at room temperature for 18 hours, then 16 ml of water was added. The mixture was adjusted to pH 10 with 1N sodium hydroxide solution. The organic phase was separated and washed with water. After drying over sodium sulfate, the solvent was distilled off in vacuo. The residue was purified by column chromatography on silica gel with diisopropyl ether / triethylamine 99.5: 0.5 as eluent. Further purification was achieved when the base was dissolved in ether and by dropwise addition in ethereal hydrogen chloride solution was converted into the hydrochloride. After addition of water and separation of the organic phase, the base was added by addition of Na

Le A 24 869-foreign countries

Tronlauge re-released and isolated by extraction with ether,

Yield: 49У. the theory (oil)

R f: 0.10 (silica gel, diisopropyl ether / triethylamine 99.5: 0.5

Example 1 16

2-dipropylamino-8-ethoxycarbonylamido-methyl-1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ ) ₂

NHCOOC ₂ H ₅

Under nitrogen, 1.6 g (6 mmol) of 2-dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene were dissolved in 16 ml of diethyl ether, while cooling 0.58 ml of ethyl chloroformate at max. +5 ⁰ C added dropwise. The mixture was then stirred for a further 1 h at +5 ⁰ C and then stirred into ice water. The aqueous phase was adjusted to pH 10 with 1 N sodium hydroxide solution and then extracted with ether. The resulting organic phase was washed with water and dried over sodium sulfate. The solvent was distilled off and the remaining residue was purified by column chromatography on silica gel. The eluent used was diisopropyl ether / triethylamine 99.5: 0.5

R _f : 0.20

Le A 24 869-foreign countries

2Я0 О 9 p

Example 17

2-dibromo-1-amino-8-ethoxycarbonyl-amido-methyl-1,2,3,4-tetrahydronaphthalene hydrochloride id

The free base of the compound from Example 16 was converted into the hydrochloride after dissolving in diisopropyl ether with ethereal hydrogen chloride solution. The strongly hygroscopic hydrochloride was filtered off with suction and dried in vacuo, yield: 18 '/. the theory

At game 18

2 ~ dipropylamino-8- (3,3-diethylureido) methyl-l, 2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ ) ₂

NHCON (C ₂ H ₅ ) ₂

Under nitrogen, 1.6 g (6 mmol) of 2-ethyl-1, 2, 3, 4-tetrahydronaphthal dissolved in 16 ml of dichloromethane. At max. +25 ⁰ C were then added dropwise 0.81 g (6 mmol) Diethylcarbamidsäurechlorid. The mixture was then allowed to stir for 26 h at room temperature. Then the mixture was stirred into 160 ml of ice water. The mixture was adjusted to pH 9 with 1 N sodium hydroxide solution and extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. Subsequently, the solvent was distilled off. The return

Le A 24 869-foreign countries

was purified by column chromatography. The eluent used was diisopropyl ether / isopropanol / triethylamine 80: 19.5: 0.5. The final product was crystallized from petroleum spirit 30-50 and was dried at + 40 ° C in vacuo

Yield: 64% of theory, mp. 86-87 ⁰ CR _f: 0.42.

Example 19

2-dipropylamino-8-acid idomethy1-1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ ) ₂

NHCONH ₂

Under nitrogen, 2.6 g (10 mmol) of 2-dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene were dissolved in 22 ml of 1N hydrochloric acid. Then, a solution of 0.81 g (10 mmol) of potassium cyanate and 6 ml of water was added dropwise at max. + 25 ⁰ C and allowed to react the reaction for 4 h at room temperature. Thereafter, 20 ml of diethyl ether were added. The aqueous phase was separated and adjusted to pH 9 with 1 N sodium hydroxide solution. The precipitated reaction product was filtered off and dried at + 40 ° C in a vacuum. By recrystallization from methanol, the product was purified.

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О -ч>

Yield: 38У. of theory mp: 182.5 - 183.5 ⁰ C

R _f : 0.5 5

Example 21

Z-dipropylamino-e- (3-methylureido) methyl-l, 2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ )

NHCONHCH ₃

Under nitrogen, 1.6 g (6 mmol) of 2-dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene were dissolved in 16 ml of toluene. At max. +25 ⁰ C were added dropwise 0.34 g (6 mmol) of methyl isocyanate. The mixture was then allowed to stir for a further 1.5 h at room temperature. Thereafter, the crystallized reaction product was filtered off and dried under vacuum at + 40 ° C.

Yield: 65У. of the theory R _f : 0.45

Example 20

2-Di ρгору1 amino-8-formamidomethyl-1,2,3,4-tetrahydronäphthalin

Le A 24 869-foreign countries

2 * 0 0 ) g

N (CH ₂ CH ₂ CH ₃ ) 2

NHCHO

Under nitrogen, 2.04 ml (21.5 mmol) of acetic anhydride and 0.86 ml (22.8 mmol) of formic acid for 2 h at +60 ⁰ C were stirred. After cooling to room temperature, 2.6 g (10 mmol) of 2-dipropylamino-8-aminomethy1-1,2,3,4-tetrahydronaphthalene were added dropwise at max, +25 ⁰ C. After 15 minutes post-reaction, 5 ml of ether were added. The mixture was then stirred for a further 18 hours at room temperature and then diluted with 20 ml of ether and 20 ml of water. The aqueous phase was adjusted to pH 9 with 1 N sodium hydroxide solution and extracted with ether. The resulting organic phase was washed with water, dried over sodium sulfate and the solvent was distilled off. The residue was recrystallized from petroleum benzine 60/80. Yield: 46% of theory, mp. 74.5 to 75.5 C ⁰

Be itpiel 22

2-dipropylamino-8- (2-hydroxyethoxy) -1,2,3,4-tetrahydronaphthalene hydrachloride

Le A 24 869-foreign countries

N (CH ₂ CH ₂ CH ₃ ) 2

χ HCl

0.7 g (23 mmol) of sodium hydride (80% in paraffin) was placed in 5 ml of diethylene glycol dimethyl ether. At +25 ⁰ C was added dropwise to a solution of 4.9 g (20 mmol) of 2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene and 20 ml of diethylene glycol dimethyl ether. The mixture was stirred for 30 min at +50 ⁰ C after. After cooling to + 25 ⁰ C was added dropwise 2.5 g (20 mmol) of 2-bromoethanol. The mixture was stirred for 2 h at +100 ⁰ C. The cooled mixture was poured onto water and extracted 2 times with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. Unreacted starting material was removed by chromatography on chloroform over basic alumina step I. Then was chromatographed on silica gel 60, 40-63 to with diisopropyl ether / ethanol 3: 2nd 700 mg of a viscous oil were obtained. It was dissolved in ether and precipitated with hydrochloric acid hydrochloride. It was extracted with water and washed once more with ether. Subsequently, methylene chloride was added and adjusted to pH 11 with ammonia. The organic phase was separated, dried with sodium sulfate and filtered. Then hydrochloric acid was again precipitated with ethereal hydrochloric acid. It was evaporated to dryness and received, a glassy residue.

Yield: 6% of theory R _f : 0.392 (diisopropyl ether: ethanol 3: 2)

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Я Г,

Example 23

г-Оіргоруіатіпо-в-сагЬатоуітеіЬоху-1,2,3, 4-tetrahydranaphthalene

N (CH ₂ CH ₂ CH ₃ )

OCH ₂ CONH ₂

0.35 g (11 mmol) of an 8% sodium hydride dispersion in oil was washed with petroleum ether and then suspended in diglyme under nitrogen. With gentle cooling, a solution of 2.50 g (10 mmol) of 2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene and 5.9 ml of diglyme was added at +20 - +25 ⁰ C within 30 min dropwise. The mixture was then stirred for a further 30 min and then heated to + 50 ⁰ C for 15 min, then 0.94 g (10 mmol) of chloroacetamide were added in portions at +20 - +25 ⁰ C. The mixture was then heated for 1 h to +135 ⁰ C and stirred after cooling in 100 ml of ice water. The precipitate was filtered off and dried at + 40 ° C under vacuum. The crude substance was purified by recrystallizing twice from isopropanol

Yield: 50 '/. of theory mp: 132-132.5 ⁰ CR _f : 0.43 (silica gel; toluene / methanol 70:30)

Example 24

2-dipropylamino-8- (2-aminoethoxy) -1,2,3,4-tetrahydronaphthalene

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О О

N (CH ₂ CH ₂ CH ₃ )

12.5 g (0.328 mol) of lithium aluminum hydride were placed under nitrogen in 200 ml of absolute ether. To this was added in small portions a suspension of 25 g (0.082 mol) of 2-dipropylamino-8- (carbonamido-methoxy) -1,2,3,4-tetrahydronaphthalene in 500 ml of absolute ether, stirred for 4 h at +25 ⁰ C and then carefully decomposed with water. It was filtered off with suction and the residue washed thoroughly 3 times with ether. The ether phase was separated, dried over sodium sulfate and then evaporated to dryness. It was chromatographed on silica gel 60, 40-63 mm with isopropanol / triethylamine 95: 5. Yield: 73.6У. of the theory R _f : 0.208

Example 25

2-dipropylamino-8- (2-methanesulfonamido-ethoxy) - 1, 2, 3, 4-tetrahydronaphthalene

• N (CH ₂ CH ₂ CH ₃ ) ₂

NHSO ₂ CH ₃

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£ о С U 9 і

1.45 g (5 mmol) of Z-dipropylamino-e- (2-aminoethoxy) -1,2,3,4-tetrahydronaphthalene and 1.38 g (10 mmol) of potassium carbonate were initially charged in 20 ml of toluene. 0.63 g (5.5 mmol) of methanesulfonyl chloride were added dropwise and the mixture was stirred at room temperature for 3 h. Then it was filtered off and evaporated. The residue obtained was stirred with petroleum ether and filtered with suction. It was chromatographed with diisopropyl ether / ethanol 3: 2 on silica gel 60, 40 -63 μπι, the product was recrystallized from petroleum ether with activated charcoal.

Yield: 30У. of the theory mp.: 76 ⁰ C

Example 26

-V- (2-butanesulfonamidoethoxy) -1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ ) ₂

NHSO ₂ C ₄ H ₉

2.5 g (8.6 mmol) of 2-dipropylamino-8- (2-amino-ethoxy) -1,2,3,4-tetrahydronaphthalene and 2.4 g (17.2 mmol) of potassium carbonate were dissolved in 40 ml of toluene submitted. 1.5 g (9.5 mmol) of butanesulfonyl chloride were added dropwise, and the mixture was then stirred at room temperature for a further 2 hours. Then it was filtered off and concentrated by rotary evaporation. It was chromatographed with diisopropyl ether / ethanol 3: 2 on silica gel 60, 40 - 63 μίτι, it was recrystallized from petroleum ether, yield: 27% of theory R _f : 0.517

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Example 27

2-Dipropylamino-8- (2-propionylamido-ethoxy) - 1, 2, 3, 4 · tetrahydronaphtha 1 in

• Ν (CH ₂ CH ₂ CH ₃ ) 2

NHCOC ₂ H ₅

1.45 g (5 mmol) of г-гіргоруіатіпо-в- (2-aminoethoxy) -1,2,3,4-tetrahydronaphthalene and 1.38 g (10 mmol) of potassium carbonate were initially charged in 20 ml of toluene. 0.5 g (5.5 mmol) of propionic acid chloride was then added dropwise and the mixture was subsequently stirred at reflux for 30 minutes. Then it was filtered off and evaporated. The residue was stirred with η-hexane and filtered with suction.

Yield: 75% of theory, mp. 67-68 ⁰ C

Example 28

2-Dipropylamino-8- (2-ethoxycarbonylamidoethoxy) -1,2,3,4-tetrahydronaphthalene

NHCOOC ₂ H ₅

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' ^p O О с

_ о

1.45 g (5 mmol) of г-гроргоруіатіпо-в- (2-aminoethoxy) -1,2,3,4-tetrahydronaphthalene and 1.38 g (10 mmol) of potassium carbonate were initially charged in 20 ml of toluene. 0.53 ml (5.5 mmol) of ethyl chloroformate were then added dropwise and the mixture was stirred at + 25 ° C. for a further 20 minutes. Then it was filtered off and evaporated. It was chromatographed with diisopropyl ether / ethanol 3, 2 over silica gel 60, 40-63 цт. Yield: 71.8 '/. Theory R _f : 0.492

Example 29

2-dipropylamino-8- [2- (3,3-diethylureido) -ethoxy] -l, 2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ ) ₂

NHCON (C ₂ H ₅ J ₂

1.45 g (5 mmol) of 2-dipropylamino-8- (2-aminoethoxy) -1,2,3,4-tetrahydronaphthalene and 1.38 g (10 mmol) of potassium carbonate were initially charged in 20 ml of toluene. Then 0.77 g (5.5 mmol) Diethylcarbamidsäurechlorid was added, and stirred for 2 h at + 100 ⁰ C after. Then it was filtered off and evaporated. It was chromatographed with diisopropyl ether / ethanol 3: 2 over silica gel 60, 40 - 63 цт. Yield: 56.4% of theory R _f : 0.408

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30 υ

Example 30

Z-dipropylamino-e-ureidoethoxy-1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ )

NHCONH ₂

1.45 g (5 mmol) of 2-dipropylamino-8- (2-aminoethoxy) -1,2,3,4-tetrahydronaphthalene were dissolved in 10 ml of water and 10 ml of 1N hydrochloric acid. At a temperature of +60 ⁰ C, a solution of 4.1 g (50 mmol) of potassium cyanate and ml of water was then added dropwise. The mixture was stirred for 3 h at + 60 ° C, wherein the reaction product precipitated. It was sucked off and the residue was stirred hot with petroleum ether, after cooling was filtered off with suction

Yield: 83.8% of theory mp. 107-108 ⁰ C.

Be itpiel 31

2-dipropylamino-8-C2- (3-methyl) ethoxy] -1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ J ₂

NHCONHCH

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⁷ ) S л η . * «

<- ^u WU · '«

1.45 g (5 mmol) of З-Оіргоруіатіпо-в- (2-aminoethoxy) -1,2,3,4-tetrahydronaphthalene were placed in 20 ml of toluene. It catalyzed with 3 drops of triethylamine, and then added dropwise 0.325 ml (5.5 mmol) of methyl isocyanate. The mixture was stirred for 1 h at + 25 ⁰ C after. It was evaporated and the resulting residue was stirred hot with diisopropyl ether. It was cooled and sucked off

Yield: 80.5% of theory mp. 104-105 ⁰ C.

Example 32

2-dipropylamino-8- [2- (3-butylureido) ethoxy] -l, 2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ ) ₂

NHCONHC ₄ H ₉

1.45 g (5 mmol) of 2-dipropylamino-8- (2-aminoethoxy) -1,2,3,4-tetrahydronaphtha were initially charged in 25 ml of toluene. It was catalyzed with 1 drop of triethylamine and then added dropwise 0.63 ml (5.5 mmol) of butyl isocyanate. The mixture was stirred for 2 h at room temperature. It was evaporated to dryness and the residue crystallized from petroleum ether / diisopropyl ether,

Yield: 82% of theory mp.: 90-91 ⁰ C

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- β О О

Example 33

2-Dipropylamines-8- (2-fluoromidamidoethoxy) -1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ )

NHCHO

1.02 ml (10.8 mmol) of acetic anhydride and 0.86 ml (22.8 mmol) of formic acid were heated to + 60 ° C for 4 h. It was then cooled to room temperature and 1.45 g (5 mmol) of 2-dipropylamino-8- (2-amino-ethoxy) -1,2,3,4-tetrahydronaphthalene was added dropwise. After the exothermic reaction had subsided, stirring was then continued for 2 hours at room temperature. Then ethyl acetate was added and the mixture was adjusted to pH 11 with 1 molar sodium hydroxide solution. The aqueous phase was extracted once more with ethyl acetate. The organic phases were combined, dried over sodium sulfate and evaporated. The residue was recrystallized from petroleum ether with activated charcoal

Yield: 58.4% of theory M.p .: 93 ^° C.

Example 34

2-dipropylamino-8- [2- (N, N-dimethylaminosulfonyl) ethenyl] -1,2,3,4-tetrahydronaphthalene

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2 8 О С с э

-N (CH ₂ CH ₂ CH ₃ ) 2 HC = CH

SO ₂ -N (CH ₃ ) ₂

1.23 g (10 mmol) of methanesulfonic acid dimethylamide and 150 mg (1 mmol) of benzyltriethylammonium chloride were stirred vigorously with 20 ml of 50% sodium hydroxide solution in 20 ml of methylene chloride at room temperature for 15 minutes. Thereafter, a solution of 7.8 g (30 mmol) of 2-dipropylamino-8-formyl-1,2,3,4-tetrahydronaphthalene in 5 ml of methylene chloride, and stirred overnight, then was diluted with plenty of water and extracted several times with methylene chloride. The organic phase was dried over sodium sulfate and then evaporated. It was chromatographed on silica gel 60, 63-200 pm, with a) cyclohexane / ethyl acetate / triethylamine: 80: 19: 1 and b) cyclohexane / ethyl acetate / triethylamine: 50: 49: 1. Yield: 50.7% of theory R _f : 0.617 (diisopropyl ether: ethanol 3: 2)

Example 3 5

2-Dipropylamino-8-C 2- (Ν, Ν-dimethylaminosulfonyl) ethyl] -1,2,3,4-tetrahydronaphthalene

-N (CH ₂ CH ₂ CH ₃ J ₂ SO ₂ N (CH ₃ ) ₂

Le A 24 869-foreign countries

О л

о О Одр

320 mg (8 mmol) of lithium aluminum hydride were placed under argon in 20 ml of absolute diethyl ether. A solution of 1.46 g (4 mmol) of 2-diisopropylamino-8- [2- (Ν, Ν-dimethylaminosulfonyl) ethenyl] -1,2,3,4-tetrahydronaphthalene in 10 ml of absolute diethyl ether was then added dropwise. The mixture was stirred for 2.5 h under reflux. It was then carefully decomposed with water, filtered off and washed the residue thoroughly with ethyl acetate. Then the phases were separated and the organic phase dried over sodium sulfate and then evaporated. It was recrystallized from isopropanol / water, filtered off and dried under high vacuum at +50 ⁰ C. Yield: 55.2% of theory mp. : 84 ° C

Example 36

2-Diρгору1-amino-8- (2-ni-t-ethenyl) -1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ ) ₂

CH = CH-NO ₂

14 g (54 mmol) of 2-dipropylamino-8-formyl-1,2,3,4-tetrahydronaphthalene, 14 ml of nitromethane and 5.6 g (73 raraol) of ammonium acetate were stirred in 56 ml of glacial acetic acid for 2 h under reflux. After cooling, the mixture was adjusted to pH 12 with 5 molar sodium hydroxide solution and extracted 3 times with ethyl acetate. The organic phase was dried with sodium sulfate and then evaporated. It was chromatographed with diisopropyl ether / triethylamine 99.5: 0.5 on silica gel 60, 63 - 200 μπι.

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о о - < _г

Yield: 52.1% of theory

¹ H-NMR (300 MHz, CDCl ₁₃ ): proton of the ni troethylenrestes:

5 = 7.38 ppm; J = 15 Hz, IH,

δ = 8.25 ppm; J = 15 Hz, IH

Example 37

2-dipropylamino-8- (2-aminoethyl) -1,2,3,4-tetrahydronaphthalene

• N (CH ₂ CH ₂ CH ₃ ) ₂

820 mg (20.4 mmol) of sodium borohydride were initially charged under nitrogen in 30 ml of absolute tetrahydrofuran at ⁰ ° C. At this temperature, 3.24 ml (25.8 mmol) of boron trifluoride-diethyl ether complex were added dropwise, followed by stirring for 15 minutes at room temperature. A solution of 1.3 g (4.3 mmol) of 2-dipropylamino-8- (2-nitro-ethenyl) -1,2,3,4-tetrahydronaphthalene and 10 ml of absolute tetrahydrofuran was then added dropwise, and the mixture was stirred , Refluxed for 5 h. After cooling to room temperature, cautiously added dropwise 55 ml of ice water and then acidified with ml of 1N hydrochloric acid, was then continued for 2 hours at + 80 ° C + 85 ⁰ stirred. The cooled aqueous phase was washed twice with 35 ml of ether, then adjusted to pH 12 with 5 molar sodium hydroxide solution and the product extracted with methylene chloride. It was dried over sodium sulfate and

Le A 24 869-foreign countries

9 ι

2oz j -.- 2

steamed. It was then chromatographed with isopropanol / triethylamine 95: 5 on silica gel 60, 40 - 63 [im,

Yield: 50.8% of theory R _f : 0.192

Example 38

2-dipropylamino-S- (2-methanesulfonamido-ethyl) -l, 2,3,4-tetrahydronaphthalene hydrochloride

^ N (CH ₂ CH ₂ CH ₃ ) ₂ χ 1.5 HC1 NHSO ₂ CH ₃

1.2 g (4.4 mmol) of 2-dipropylamino-8- (2-amino-ethyl) -1,2,3,4-tetrahydronaphthalene and 1.21 g (8.8 mmol) of potassium carbonate were dissolved in 20 ml of methylene chloride submitted. At 25 ° C then 550 mg (4.8 mmol) of methanesulfonyl chloride were added dropwise. It was stirred overnight at room temperature. It was then filtered off, washed once with water, dried over sodium sulfate and evaporated. Diethyl ether was added to the residue, methylene chloride was added until everything was dissolved, and the hydrochloride was precipitated with ethereal hydrochloric acid. It was sucked off and dried at 40 ° C in a high vacuum

Yield: 56, 2V. of the theory Mp .: 212 ⁰ C (Zers.)

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L.j., ¹

Example 39

іпо-в- (2-butanesulfonamido-ethyl) -l, 2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ )

NHSO ₂ C ₄ H ₉

1.1 g (4 mmol) of г-Оіргоруіатіпо-в- (2-amino-ethyl) -1 _} 2,3,4-tetrahydronaphthalene and 1.1 g (8 mmol) of potassium carbonate were placed in 20 ml of methylene chloride. 690 mg (4.4 mmol) butanesulfonyl chloride were then added dropwise and the mixture was stirred at room temperature for 5.5 h. Then, 20 ml of water were added and stirred vigorously for 10 minutes, the phases were separated and the aqueous phase was extracted once more with methylene chloride. The organic phases were combined, dried over sodium sulfate and then evaporated. It was chromatographed with ethyl acetate on silica gel 60, 40 - 63 μπ \

Yield: 72.9% of theory R _f : 0.592 (diisopropyl ether: ethanol 3: 2)

Example 40

2-dipropylamino-8-C2- (p-chlorobenzenesulfonamido) ethyl] -1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ ) ₂

Le A 24 869-foreign countries

9 years

1.1 g (4 mmol) of г -іргоруіатіпо-в- (2-amino-ethyl) -1,2,3,4-tetrahydronaphthal were charged with 2 ml of 5O '/. Iger potassium carbonate solution in 15 ml of methylene chloride. With vigorous stirring, a solution of 930 mg (4.4 mmol) of p-chlorobenzenesulfonyl chloride in 15 ml of methylene chloride was then added dropwise. It was stirred for 1 h at room temperature. It was mixed with 20 ml of water and stirred vigorously. The phases were separated and the aqueous phase was extracted once more with methylene chloride. The organic phases were combined, dried over sodium sulfate and evaporated. It was chromatographed with ethyl acetate on silica gel 60, 40 - 63 μπ \

Yield: 97.4% of theory R _f : 0.650 (diisopropyl ether: ethanol 3: 2)

Example 41

2-Dipropylamino-8- (2-ethoxycarbonyl-amido-ethyl) -1,2,3,4-tetrahydronaphthalene

• Ν (CH ₂ CH ₂ CH ₃ ) ₂

NHCOOC ₂ H ₅

1.1 g (4 mmol) of г-іргоруіатіпо-в- (2-amino-ethyl) -1,2,3,4-tetrahydronaphthalene and 1.1 g (8 mmol) of potassium carbonate were initially charged in 20 ml of methylene chloride. At + 25 ° C then added dropwise 0.45 ml (4.4 mmol) of ethyl chloroformate and stirred for 1 h at room temperature. Then, 20 ml of water were added and stirred vigorously for 10 minutes. The phases were separated and the aqueous phase was extracted once more with methylene chloride. The organic ones

Le A 24 869-foreign countries

9 С

Phases were combined, dried over sodium sulfate and then evaporated. It was then dissolved in 30 ml of 3 N hydrochloric acid, extracted 3 times with diethyl ether, adjusted to pH 12 again and the product was extracted with ethyl acetate, dried over sodium sulfate and evaporated. Yield: 85.8У. theory R _f : 0.598 CDiisopropyl ether: ethanol 3: 2)

Example 42

2-Dipropylamino-8- (2-benzyloxycarbonyl-amido-ethyl) -1,2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ ) ₂

NHCOOCH ₂ C ₆ H ₅

3.5 g (12.75 mmol) of 2-dipropylamino-8- (2-amino-ethyl) -1,2,3,4-tetrahydronaphthalene and 3.5 g (25.5 mmol) of potassium carbonate were dissolved in 50 ml of methylene chloride submitted. Then 4.7 ml (14 mmol) of benzyl chloroformate (50% strength solution in toluene) were added dropwise at 25 ° C., followed by stirring at room temperature for a further 2 hours. Then, 50 ml of water were added and stirred vigorously for 10 minutes. The phases were separated and the aqueous phase was extracted once more with methylene chloride. The organic phases were combined, dried over sodium sulfate and then evaporated. It was chromatographed with ethyl acetate on silica gel 60, 40 - 63 μπι, yield: 92.1 '/. theory R _f : 0.567 (diisopropyl ether: ethanol 3: 2)

Le A 24 869-foreign countries

Example 43

Z-dipropylamino-e- (2-ureido-ethyl) -1,2,4,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ )

NHCONH ₂

1.1 g (4 mmol) of 2-dipropylamino-8- (2-aminoethyl) -1,2,3,4-tetrahydronaphthalene were dissolved in 8 ml of water and 8 ml of 1 N hydrochloric acid and heated to + 60 ° C. At this temperature, a solution of 3.24 g (40 mmol) of potassium cyanate and 15 ml of water was added dropwise. The mixture was stirred at + 60 ° C for 1 h. Then it was cooled and filtered with suction. It was recrystallized from petroleum ether / diisopropyl ether with activated charcoal

Yield: 43.4 * /. the theory mp. 123-124 ⁰ C

At game 44

2-dipropylamino-8- [2- (3-methylureido) ethyl] -I, 2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ )

NHCONHCH ₃

Le A 24 869-foreign countries

2S0 0 -.j з

1.3 g (4.7 mmol) of Z-dipropylamino-e- (2-aminoethyl) -1,2,3,4-tetrahydronaphthalene were initially charged in 20 ml of toluene. It was catalyzed with 3 drops of triethylamine and then added dropwise 0.31 ml (5.17 mmol) of methyl isocyanate. The mixture was stirred overnight at room temperature and then evaporated. It was then chromatographed with diisopropyl ether / ethanol / triethylamine on silica gel 60, 40 - 63 pm. The product was stirred with petroleum ether and a little diisopropyl ether and filtered with suction, yield: 21.2 * /. of theory mp: 70 ⁰ C

Example 45

2-dipropylamino-8- (2-formylamido-ethyl) -l, 2,3,4-tetrahydronaphthalene

N (CH ₂ CH ₂ CH ₃ ) ₂

NHCHO

1.02 ml (10.8 mmol) of acetic anhydride and 0.86 ml (22.8 mmol) of formic acid was 4 hours at +50 - +60 ⁰ C heated. The mixture was cooled to room temperature and then added dropwise 1.4 g (5 mmol) of 2-dipropylamino-8- (2-amino-ethyl) -1,2,3,4-tetrahydronaphthalene, keeping the temperature below + 40 ⁰ C. The mixture was subsequently stirred at room temperature for 2 h. It was then adjusted to pH 12 with 5 molar sodium hydroxide solution and extracted with methylene chloride. It was dried over sodium sulfate and then evaporated. It was chromatographed with diisopropyl ether / ethanol 3: 2 on silica gel 60, 40 - 63 ym.

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^ - о и O g

Yield: 56, ЗУ. of the theory R _f : 0.242

(All DCs were carried out on TLC Aluf oil, silica gel 60, F254 5 × 7.5 cm, running height 6 cm).

In game 46

2-dipropylamino-8- [2- (N-methyl-aminosulphonyl) ethenyl] -1,2,3,4-tetrahydronaphthalene

"-Ν (CH ₂ CH ₂ CH ₃ ) HC = CH SO ₂ -NHCH ₃

This compound was prepared in analogy to Example 34. As starting material N-methyl-methane sulfonamide e was used. Yield: 49.6 % of theory R _f : 0.383 (diisopropyl ether! Ethanol 3: 2)

Example 47

2-dipropylamino-8-C2- (N-methylaminosulphonyl) ethyl 3, 1,2,3,4-tetrahydronaphthalene

-N (CH ₂ CH ₂ CH ₃ J ₂ SO ₂ NHCH ₃

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V С

This compound was prepared in analogy to Example 35 by reducing the compound of Example 47 with lithium aluminum hydride

Yield: 33 '/. of the theory R _f : 0.492 (diisopropyl ether! ethanol 3: 2)

Example 48

2-dipropylamino-8- [2- (2-naphthyl) sulfonamido-ethyl] -1,2,3,4-tetrahydronaphthalene

-CH ₂ -CH ₂ -NH-SO ₂

961 mg (3.5 mmol) of 2-dipropylamino-8- (2-amino-ethyl) -1,2,3,4-tetrahydronaphthalene were initially charged in 15 ml of methylene chloride with 1.75 ml of 50% potassium carbonate solution , A solution of 873 mg (3.85 mmol) of naphthalene-2-sulfonic acid chloride and 5 ml of methylene chloride is added dropwise and the mixture is stirred at room temperature for 20 h. Then it was diluted with water and methylene chloride. The organic phase was separated, dried over sodium sulfate and evaporated. The mixture was then chromatographed with cyclohexane / ethyl acetate 1: 1 over silica gel 60, 40-63 mm. Yield: 1.32 g = 81.2% of theory R _f : 0.117 (cyclohexane.'vine ester 1: 1)

Le A 24 869-foreign countries

-: 5 О Ü

Example 49

2-Dipropyl-amino-8- [2- (3,4-dichlorophenyl) -sulfonamido-ethyl-3-1,2,3,4-tetrahydronaphthalene

H ₂ -CH ₂ -NH-SO ₂

^ CH ₂ -CH ₂ -CH ₃

500 mg (1.82 mmol) of 2-dipropylamino-8- (2-amino-ethyl) -1,2,3,4-tetrahydronaphthalene were initially charged in 10 ml of methylene chloride with 1 ml of 50% potassium carbonate solution. A solution of 491 mg (2.0 mmol) of 3,4-dichlorobenzenesulfonyl chloride and 5 ml of methylene chloride was added dropwise and the mixture was stirred at room temperature for 2 h. Then it was diluted with water and methylene chloride. The organic phase was separated, dried over sodium sulfate and evaporated, then chromatographed with cyclohexane / ethyl acetate 1: 1 on silica gel 60, 40-63 μπι. Yield: 3.82 mg = 43.4 V. of theory Rf: 0.121 (cyclohexane: ethyl acetate 1: 1)

Example 50

2-dipropylamino-8-C2-N- (4-N-saccharinyl) n-butylaminoethyl] -1,2,3,4-tetrahydronaphthalene hydrochloride

H ₂ -CH ₂ -NH-CH ₂ -Ch ₂ -CH ₂ -CH ₂ -N

CHO * CH ₂ CHO CH ₂ -CH ₂ -CH ₃

χ HCl

Le A 24 869-foreign countries

8 С О

1.3 g (4.7 mmol) of 2-diPrOPyIaITUnO-S- (2-amino-ethyl) -1,2,3,4-tetrahydronaphthalene and 1.38 g (10 mmol) of potassium carbonate were initially charged in 10 ml of dimethylformamide. A solution of 1.49 g (4.7 mmol) of 4-N-saccharinyln-butyl bromide and 5 ml of dimethylformamide was added dropwise and the mixture was stirred at 80 ° C. for 5 h. It was then poured onto water and extracted with ethyl acetate. The mixture was then chromatographed twice with ethyl acetate and once with cyclohexane: ethyl acetate: tri ethylamine 50: 49: 1 on silica gel, 40-63 μπ \. The viscous oil was dissolved in ether, treated with ethereal hydrochloric acid, evaporated and dried at 50 ° C under high vacuum.

Yield: 300 mg = 11.6 V, the theory R _f : 0.612 (methanol! Triethylamine 95 + 5)

Application examples Example 51

A.) Affinity for 5-HT ₁

Table 1 shows by way of example the high affinity of the compounds according to the invention for subtype 1 5-hydroxytryptamine receptors. The data presented are data obtained from receptor binding studies with calf hippocampal membrane preparations. The radiolabelled ligand used was ³ H-serotonin,

Le A 24 869-foreign countries

Table 1

Compound of Ki (nmol / 1)

At game no.

1 20

2 13 6 7

25 13

26 17 28 4 30 30 33 19 42 5

Le A 24 869-foreign countries

"2 8 О Оч. Ft

Veralei ch

In this test model, the compounds described in EP 41 show R ¹ = OCHg, R = R ³ = P SS ₃ H ₇ and R ¹ = OH, R ² = R ³ = nC ₃ H ₇ Ki values of 3 or 2 nmol / l

B,) Studies on serotonin agonistic / antagonistic action.

To this end, the effect on the serotonin-mediated contraction of the arteria basilaris of the dog is investigated [cf. Peroutka et al., Brain Research 259, 327 (1983)].

Table 2

Connection of the

At game no. Effect antagonist.

25 +

30+

33 +

Comparison from EP 41 468:

R ¹ = 0H, R ² = nC ₃ H ₇ , R ³ = nC ₃ H ₇

Le A 24 86 9-Foreign countries

Claims (2)

JL о sj о » и Claim : Process for the preparation of 8-subslitings Л-ііпііюкЧілІшеп animal general formula (D in which [Ia] R ¹ - represents halogen or cyano, [Ib] R ¹ - represents the group -NR ⁴ R ⁵ ,
wherein R ^ and Rr are the same or different and - for hydrogen, or - means a group of the formula -COR or -SOpR, in which R - represents hydrogen or is alkoxy, or is aryl, aryloxy, aгаікуі, Агэікоху or heteroaryl, wherein said radicals are up to 3 times the same or different by alkyl, alkoxy, alkylthio, halogen, cyano, Trifluormettvl, trifluoromethoxy, trifluoromethane thylthio, amino, alkylamino or dialkylamino substituted г. a skill and 08 LC A 24 869-DD represents cycloalkyl, or represents alkyl represented by cyano, halogen, trifluoromethyl, trifluoromethoxy StPiSHiJ H Li : 8ö or Alkoxycarbony1 may be substituted, or is aryl, Ar alkyl or heteroaryl, where the radicals mentioned can be substituted, equally or differently, by up to 3 times by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino, or for a group -NP ¹⁰ R ¹¹ , wherein R and R ^{11 are the} same or different and are hydrogen, alkyl, aryl or aralkyl, or [Ic] R ¹ - for the group -NHCONHR ⁹ sees wherein R ⁹ - is hydrogen, or - represents cycloalkyl, or - is optionally substituted by cyano, halogen, trifluoromethyl or trifluoromethoxy alkyl, or - is aryl, aralkyl or heteronryl, wherein said radicals substituted up to three times the same or different by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, Tr-i f luorme thoxy, trifluoromethylthio, amino, alkylamino or Dinlkylamino substituted could be, [Id] R ¹ - represents the group -COR ⁶ ', wherein R ⁶ '- is hydroxy, amino, alkoxy, aryloxy or ггиіоху, or [Ie] R ¹ - is formyl, or [IfJ R ¹ - for the group - CH ₂ - X sees, LC A 24 869-DD 2 8 G -С <$ wherein X - represents a group of the formula -NR ¹² R ¹³ , -COR ¹¹¹ , -SO-, R ¹ ' ⁰ or -OR ¹⁶ . wherein R ¹² and R ¹ ^ are the same or different and - represent hydrogen, alkyl, aryl or ЛгзіКуі, wherein the aryl radicals may be substituted by halogen, cyano, alkyl, alkoxy or Trif1uormethy 1, or for a group of the formula -COR ¹ ' ¹ , -SO ₂ R ¹⁵ or - (CH ₂ ) _C -NR ¹² R ¹³ , R ^{14 is} hydrogen, or - a group -NHR ¹⁷ means, or - alkyl or alkoxy, or - Aryl, aryloxy, aralkyl, aralkoxy or HeLcroaryl means, wherein said radicals up to 3 times the same or different  Alkyl, alkoxy, alkylthio, halogen, cyano, trifluorothyIy, Tr i f 1, may be substituted in thio, trifluoromethylthio, amino, alkylamino or dialkylamino, R ^{15 is} cycloalkyl, or - alkyl means that by cyano, halogen, Trifluoromethyl, trifluoromethoxy or alkoxy: carbonyl, or Aryl, aralkyl or heteroaryl, where the radicals mentioned may be identical or different up to three times by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trisubstituted fluoromethoxy, Trif1uormpthy1thiο, amino, alkylamino or dialkylamino, or a group -NR ¹⁰ R ¹¹ means Le A 24 869-DD I would like to 2 δ ο R and R ^{11 are the} same or different and - represent hydrogen, alkyl, aryl or aralkyl, R ^{16 represents} hydrogen, alkyl, aryl, aralkyl or a group -CONR ¹⁰ R ¹¹ , »17 _ Is hydrogen, or cycloalkyl, or optionally substituted by cyano, halogen, trifluoroethyl or trifluoromethoxy alkyl, or Aryl, aralkyl or heteroaryl, wherein the aryl radical is up to 3 times the same or different by alkyl, alkoxy, alkylthio, halogen, cyano, Trifluorraethy1, trifluoromethoxy, Trifluormethy 1thiо, amino, alkylmino or dialkylamino ώ u b s t. i t u i r t u о i η, and C is a number 1 to 8, or where R ¹² and R ¹³ together with the nitrogen atom a ring of the series H ₂ C- (CH ₂ J _n Lc Λ 24 869-DD O = C ι <- Π ι C- or -N form N-A, was in η - a number 1 or 7 means and A - fu. "Is hydrogen or cycloalkyl,
or - is alkyl which may be substituted by halogen, hydroxy, amino, alkylamino, dialkylamino, carbamoyl or sulfamoyl, or - is aryl, heteroaryl, aralkyl, alkoxycarbonyl, alkylsulfonyl, phenylsulfonyl, tosylsulfonyl, benzylsulfonyl, formyl, carbamoyl or sulfamoyl, [Ig] R ¹ - for a group of the formula - (CH ₂ ) _a --X or -CH = СИ- (CH ₂ VX
stands,
wherein a '- a number 2 to 10 means
b - a number O to 8 means
and X - the HedciiUui} 'above, has | II |
otlcr lh] R ¹ - for a group of the formula -CII ₂ CH ₂ -X, Lc Л 24 869-DD ^w » ^ri » /. Ь (i Ow X - the practice has the given meaning, lli] R ¹ - for a group of the formula - O - (CH ₂ ) _a --X, wherein a -a number 1 to 10 means and X has the meaning given to OD, R ² - is hydrogen or alkyl, R ³ - is alkyl, however R ¹ does not mean NH ² , though R ² and R ^{3 are} propyl, and their salts, characterized in that one finds f Ia | for the preparation of the compounds of the formula (Ia) [A] 8-Aminotetra 1 ine of the general formula (II), we are sooner R and R ^{3 have} the meaning given, in inert solvents in the presence of acids with nitrites, then the obtained diazonium salts with copper salts of general formula Lc Λ 24 869-DD CuY (III), 2 В О О О in which Y Гііг is halogen or cyano, if appropriate in the presence of oil feedstocks to give compounds of the formula (Ia) and, in the case of preparation of the salts, reacting with the corresponding acids, or, that [B] tetralone of the general formula HV) in weer R ¹⁸ - is chlorine or bromine, first with amines of the general formula HN (V), \ ³ in which Icher R and R have the meaning given, in inert solvents, if appropriate in the presence of auxiliaries, then reducing the intermediates in inert solvents, then optionally replace halogen with Cynno LC A 24 869-DD ί о О О с * and then in the case of production of the sake with the corresponding acids, or that [Ib] for the preparation of compounds of formula (Ib) 8-Animo-tciralinc the general formula II with acylation or sulfonation center In the general formula VR ¹⁹ (VI) in which R ^{19 is} a group of the formula -COR ⁷ or -SO ₂ R, V - represents halogen, or - represents the radical -OR ²⁰ , wor in R has the same meaning as H and may be the same or different with this, in inert solvents, if appropriate in the presence of bases to give compounds of formula Ib, and then in the case of preparation of the salts with the corresponding acids umsct / i, or that [Ic] for the preparation of compounds of formula (Ic) 8-aniinotelialines Tlci general formula (II) in inert solvents, optionally in the presence of bases with isocyanates of the general formula R ⁹ N = C = O (VII) in we I tend to R - has the meaning given, Le A 24 869-DD 2 8 О О 9 to compounds of l-'ormcl (lc), and then in Ha! 1 animal preparation of the salts with the corresponding acids, or [Id] for the preparation of the compounds of the general formula (Ia) 8-cyanolctralines of the general formula VIII (VIII) in our ears R and R ^J are as defined above ЬпЬрп hydrolys, in the case of the production of the carboxylic acid esters, the carboxylic acids obtained are esterified and in the case of making the sake with corresponding acids, urasetzLj or [Ie] for the preparation of the compounds of general formula (Ic) 8-halogen-substituted 2-aminotetra 1ipr of the general formula (IX) shark in our ears 2T R and R are as defined above Hal is fluorine, chlorine, bromine, iodine, preferably chlorine or bromine, LC A 24 869-DD 2 8ο in inert solvents, if appropriate in the presence of auxiliaries with magnesium and formamides of the general formula R ² K N-CHO (X) in which R * and R ^{22 are the} same or different and are methyl, ethyl, propyl, phenyl or pyridyl stand, or
R ² * and R ²² together with the nitrogen atom a Forming pi peridinring, to give compounds of the formula (Id) and then reacted in the case of preparation of the salts with the corresponding acids, or [If] for the preparation of compounds of formula (If) Tclralinc the general formula Tetraline of the general formula (XI) in which R ² and R ^{3 have} the abovementioned meaning r23 represents a group of the formula -COR ²⁴ or -CN, wherein r24 is hydrogen, hydroxy, alkoxy or amino, reduced in inert solvents, then optionally functional groups are converted into other functional groups by reduction, hydrolysis, oxidation or reaction with electrophilic reagents,
LC A 24 869-DD 2 hours я ·: and then, in the case of preparing the salt, reacting the corresponding acids, or [Ig] to produce the compounds of general formula (Ig) 8-formyl-aminotetralines of the general formula (Ie) CHO in which R and R have the meaning given, in inert solvents in the presence of bases with phosphorus compounds of the general formula U- (CH ₂ ) _a .-! "X" (XII) in we I rather X - has the meaning given for X, or - stands for Nitro, a '- has the meaning given above U - for a group of the formula R ²⁵ OR ²⁵ P (R ²⁵ UT ", -PR ²⁶ or -P-OR ²⁶ stands, Le Л 24 869-DD 2 8 O ö 9 ч I would like to ^R2 and R2 ^{are the} same or different and are alkyl or phenyl and T - is a halide anion, preferably chloride, eromide or iodide, implements, then optionally functional groups converted by reduction, hydrolysis, oxidation or reaction with elecrophilic reagents in other functional groups and then, in the case of preparing the salts, reacting with the corresponding acids, or that one [lh | for the preparation of compounds of the general formula (lh) 8-formylaminotetralinc of the general formula (Ic) in inert solvents, if appropriate in the presence of condensing agents with CH-acidic compounds of the general formula H ₃ CX (XIiI) i η we Icher X - the meaning given for X lint, о ti er - stands for nitro, killed et ζ t, then optionally functional groups by reduction, hydrolysis, oxidation or reaction with ebrktrophiien reagents in other functional !? i-ruppen transferred Lc Л 24 86 ¹ J-DD 2 8 ü О 9 S ¹ and then in the case of the treatment of the salts with. the corresponding acids, or - [Ii] for the preparation of animal compounds of general formula (Ii) 8-hydroxy-aminotetraIine of the general formula (XIV) OH in which R ² and R ^{3 have} the meaning given with halogen compounds of the formula Hai - (CH ₂ ) _a - X (XV) wherein Shark stands for halogen and a and X are as defined above if appropriate in the presence of a base in inert organic solvents, then optionally transferring functional groups into other groups by reduction, hydrolysis, oxidation or reaction with cleftrophilic reagents, and then in the case of preparing the salts with the corresponding acids. Le A 24 869-HD