AU613884B2

AU613884B2 – 8-substituted 2-aminotetralins
– Google Patents

AU613884B2 – 8-substituted 2-aminotetralins
– Google Patents
8-substituted 2-aminotetralins

Download PDF
Info

Publication number
AU613884B2

AU613884B2
AU83029/87A
AU8302987A
AU613884B2
AU 613884 B2
AU613884 B2
AU 613884B2
AU 83029/87 A
AU83029/87 A
AU 83029/87A
AU 8302987 A
AU8302987 A
AU 8302987A
AU 613884 B2
AU613884 B2
AU 613884B2
Authority
AU
Australia
Prior art keywords
denotes
alkyl
hydrogen
cyano
halogen
Prior art date
1986-12-22
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Ceased

Application number
AU83029/87A
Other versions

AU8302987A
(en

Inventor
George S. Allen
Thomas Glaser
Bodo Junge
Bernd Richter
Jorg Traber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Bayer AG

Original Assignee
Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
1986-12-22
Filing date
1987-12-22
Publication date
1991-08-15

1987-12-22
Application filed by Bayer AG
filed
Critical
Bayer AG

1988-06-30
Publication of AU8302987A
publication
Critical
patent/AU8302987A/en

1991-08-15
Application granted
granted
Critical

1991-08-15
Publication of AU613884B2
publication
Critical
patent/AU613884B2/en

2007-12-22
Anticipated expiration
legal-status
Critical

Status
Ceased
legal-status
Critical
Current

Links

Espacenet

Global Dossier

Discuss

Classifications

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS

C07C211/00—Compounds containing amino groups bound to a carbon skeleton

C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms

C07C211/16—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings

C07C211/19—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings containing condensed ring systems

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07D—HETEROCYCLIC COMPOUNDS

C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings

C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P25/00—Drugs for disorders of the nervous system

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P9/00—Drugs for disorders of the cardiovascular system

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS

C07C255/00—Carboxylic acid nitriles

Description

7 2 798-P18/GD/JLY/5116T/2
AUSTRALIA
PATENTS ACT 1952 COMPLETE RPECTFTCATTON
(ORIGINAL)
FOR OFFICE USE s «9 Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art:
TO
Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: BE COMPLETED BY APPLICANT TROPENWERKE GmbH- D 5000 Koeln 80, GERMANY 1 Bodo Junge 2 Bernd Richter 3 Thomas Glaser 4 Jorg Traber George S. Allen ARTHUR S. CAVE CO.
Patent Trade Mark Attorneys Level Barrack Street SYDNEY N.S.W. 2000
AUSTRALIA
Co., KG
I
Complete Specification for the 2-Aminotetralins.
invention entitled 8-Substituted The following statement is a full description of this invention including the best method of performing it known to me:- 1 ASC 49
I_
The invention relates to 8-substituted 2-aminotetraLins, a process for the preparation thereof, and the use thereof in medicaments.
It is known from EP-A1 41,488 that 8-hydroxy-2aLkyLaminotetralins or 8-amino-2-diaLkyLaminotetraLins act on the central nervous system.
New 8-substituted 2-aminotetraLins of the general formuLa (I) 2 93,~iT~ 1 R~3
I.
in which R represents halogen, cyano or represents a group of the formula
-NR
4
R
5
-COR
6
-(CH
2 -0-(CH2)a-X or -CH=CH-(CH2)b-X, wherein R and R are identical or different and denote hydrogen or 7 8 a group of the formula -COR or -SO 2 R where *25 7 R represents hydrogen, or 9 represents an -NHR group, or represents alkoxy, or represents aryl, aryloxy, aralkyL, aralkoxy or heteroaryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino, 8 R represents cycloalkyl, or represents alkyl which may be substituted by cyano, halogen, trifluoromethyl, trifluoromethoxy Le A 24 869 la 20 0 ‘0 0 0 0 25 *::30 :0 4 or aLkyLoxycarbonyL, or represents aryL, araLkyL or heteroaryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by aLkyL, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethyLthio, amino, alkylamino or dialkylamino, or represents an -NR 10
R
1 1 group, wherein
R
0 and R 11 are identical or different and denote hydrogen, alkyl, aryl or aralkyL, and 9 R represents hydrogen, or represents cycloalkyL, or represents alkyl which is optionally substituted by cyano, halogen, trifluoromethyl or trifluoromethoxy, or represents aryl, aralkyL or heteroaryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, aLkyLamino or dialkylamino,
R
6 denotes hydrogen, hydroxyl, amino, alkoxy, aryloxy or aralkoxy, a denotes a number 1 to b denotes a number 0 to 8, and X denotes a group of the formula -NR 1 2
R
13
-COR
1 15 16 -S0 2
R
5 or -OR 16 wherein R12 and R 13 are identical or different and represent hydrogen, alkyL, aryl or aralkyL, where the aryl radicals may be substituted by halogen, cyano, alkyL, alkoxy or trifluoromethyl, or Le A 24 869 2 -7 71 20
S..
025
S
V,
*30 represent a group of the formula -COR 14, -SO 2
R
1 12 13 or -(CH 2 )c-NR R 13 R14 denotes hydrogen, or 17 denotes an -NHR group, or denotes aLkyL or aLkoxy, or denotes aryl, aryLoxy, aralkyL, araLkoxy or heteroaryt, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyl, alkoxy, aLkyLthio, haLogen, cyano, trifluoromethyL, trifluoromethoxy, trifLuoromethyLthio, amino, alkyLamino or dialkyLamino,
R
15 denotes cycLoalkyL, or denotes aLkyL which may be substituted by cyano, haLogen, trifLuoromethyL, trifluoromethoxy or aLkoxycarbonyL, or denotes aryl, araLkyL or heteroaryL, where the radicals mentioned may be up to trisubstituted, identicaLLy or differentLy, by aLkyL, aLkoxy, aLkylLhio, haLogen, cyano, trifLuoromethyL, trifLuoromethoxy, trifluoromethyLthio, amino, aLkyLamino or dialkyLamino, or denotes an -NR 10
R
1 1 group, where
R
10 and R 1 1 have the abovementioned meaning,
R
16 denotes hydrogen, aLkyL, aryL, araLkyL, or 10 11 a group of the formula -CONR 1
R
1 1 R17 denotes hydrogen, or denotes cycloaLkyL, or denotes aLkyL which is optionaLLy substituted by cyano, halogen, trifluoromethyL or trifLuoromethoxy, or denotes aryL, araLkyL or heteroaryL, where the radicals mentioned may be up to trisubstituted, identically or differentLy, by aLkyL, aLkoxy, aLkyLthio, haLogen, cyano, trifLuoromethyL, trifLuoromethoxy, trifluoromethylthio, amino, Le A 24 869 3 aLkyLamino or diaLkyLamino, and c denotes a number 1 to 8, or where
R
1 and R 13 together with the nitrogen atom, form a ring from the series comprising
H
2
C-(CH
2 n I I
H
2 C, rH 2 0 2s 1 12 S S
S
S S S 0
S.
S
S
L=Ci C 6
H
o r -N A w h e r e i n n denotes a number 1 or 2, and A represents hydrogen or cycLoaLkyL, *5 5 S S
S.
S. S S S represents atkyL which may be substituted by haLogen, hydroxyL, amino, aLkyLamino, diaLkyLamino, carbamoyl or suiphamoyL, o r represents aryL, heteroaryL, araLkyL, aLkoxycarbonyl, aLkyLsuLphonyL, phenyLsuLphonyL, toLyLsuLphonyL, benzyLsuLphonyL, formyL, carbamoyL or suLphamoyL, Le A 24 869 -4- 1^ i
I
R represents hydrogen or alkyl, and R represents aLkyL, but where R does not denote NH 2 when R2 and R 3 denote propyL, and the salts thereof, have now been found.
Surprisingly, the substances according to the invention exhibit a superior action on the central nervous system and can be used for therapeutic treatment of humans and animals.
The substances according to the invention have several asymmetrical carbon atoms and can thus exist in various stereochemicaL forms.
The invention relates to the individual isomers and to mixtures thereof. The following isomeric forms of the substituted basic 2-aminotetraLins may be mentioned as examples: 3 1
N
V
V
V.
V. V 20 The substituted basic 2-aminotetralins according to the invention may also exist in the form of their salts.
In general, salts with inorganic or organic acids may be mentionel here.
In the context of the present invention, physio- Logically acceptable salts are preferred. Physiologically acceptable salts of the substituted basic 2-aminotetra ins may be salts of the substances according to the invention with mineral acid, carboxylic acids or sulphonic acids.
Le A 24 869 5 111100 Particularly preferred salts are those, for example, with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesuLphonic acid, benzenesuLphonic acid, naphthalenedisulphonic 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.
In the context of the present invention, the sub- 10 stituents have the following meaning: S* Alkyl represents a branched hydrocarbon radical having 1 to 12 carbon atoms. Lower alkyl having 1 to about 6 carbon atoms is preferred. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.
Alkenyl represents 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 carbon atoms and one double bond is particularly preferred. Examples which may be mentioned are allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, iso- 25 pentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl and isocctenyL.
Cycloalkyl represents a cyclic hydrocarbon radical having 5 to 8 carbon atoms. The cyclopentane and the cyclohexane ring is preferred. Examples which may be mentioned are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Aryl represents an aromatic radical having 6 to about 12 carbon atoms. Preferred aryl radicals are phenyl, naphthyl or biphenyL.
Aralkyl represents an aryl radical, having 7 to 14 carbon atoms, which is bonded via an Le A 24 869 6 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 are the foLLowing araLkyL radicals: benzyl, naphthylmethyl, phenethyL and phenyLpropyL.
Alkoxy represents a straight-chain or branched hydrocarbon radical, having 1 to 12 carbon atoms, which is bonded via an oxygen atom. Lower aLkoxy having 1 to about 6 carbon atoms is preferred. a koxy radical having 1 to 4 carbon atoms is particularLy preferred. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.
Aryloxy represents an aromatic radical, having 6 to about 12 carbon atoms, which is bonded via an oxygen atom. Preferred aryloxy radicals are phenoxy or naphthyLoxy.
Aralkoxy represents an araLkyl radical having 7 to 14 carbon atoms, the alkyLene chain being bonded via an oxygen atom. AraLkoxy radicals having 1 to 6 S. carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. Examples which may be mentioned are the following araLkoxy radicals: S* benzyLoxy, naphthyLmethoxy, phenethoxy and phenylpropoxy.
25 Alkylthio represents a straight-chain or branched hydrocarbon radical, having 1 to 12 carbon atoms, which is bonded via a sulphur atom. Lower alkylthio having 1 to about 6 carbon atoms is preferred.
Analkylthio radical having 1 to 4 carbon atoms is particularly preferred. Examples which may be mentioned are methyLthio, ethyLthio, propyLthio, isopropylthio, butyLthio, isobutylthio, pentyLthio, isopentylthio, hexylthio, isohexyLthio, heptyLthio, isoheptylthio, octyLthio or isooctylthio.
Acyl represents phenyl or straight- Schain or branched lower alkyl, having 1 to about 6 carbon e A 24 869 -J 7 iA atoms, which are bonded via a carbonyl group. PhenyL, and alkyL radicals having up to 4 carbon atoms Are preferred.
Examples which may be mentioned are: benzoyl, acetyl, ethylcarbonyL, propyLcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.
ALkoxycarbonyl is represented by the formula -C-OAlkyl Il In this formula, alkyL represents 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 part is preferred. An aLkoxycarbonyL having 1 to 4 carbon atoms in the alkyL part is particularly preferred. Examples which may be mentioned are the following alkoxycarbonyL radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
Aryloxycarbonyl is represented by the formula -COO-aryl. In this formula, aryl represents, in general, an aromatic radical having 6 to 12 carbon atoms. Examples which may be mentioned are: phenoxycarbonyl and naphthyloxycarbonyl.
Aralkoxycarbonyl is represented by the formula -COO-aralkyl. In this formula, aralkyl represents. in general, an aryl radical, having 7 to i carbon atoms, which is 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 being preferred. Examples which may be mentioned as aralkoxycarbonyl radicals are: benzyloxycarbonyl and naphthylmethyloxycarbonyl.
In the context of the abovementioned definition, heteroaryl represents, in general, a 5- to 6-membered aromatic ring, which may contain, as heteroatoms, oxygen, Le A 24 869 7 ,P A I 8sulphur and/or nitrogen and to which a further aromatic ring may be fused. 5- and 6-membered aromatic rings which contain one oxygen, one sulphur and/or up to 2 nitrogen atoms and which are optionally fused to a benzyL group are preferred. The following may be mentioned as particuLarLy preferred heteroaryL radicaLs: thienyL, furyL, pyridyL, pyrimidyL, pyrazinyL, pyridazinyL, quinoLyL, isoquinoLyL, quinazoLyL, quinoxaLyl, thiazoLyL, benzothiazoLyL, isothiazoLyl, oxazoLyL, benzoxazolyl, isoxazoLyL, imidazoLyL, benzimidazoLyL, pyrazoLyL and indolyL.
In general, halogen represents fluorine, chLorine, bromine or iodine, preferably fLuorine, chLorine or bromine. Halogen particuLarLy pres erably represents fLuorine or chLorine.
Preferred such compounds of the generaL formuLa 0 o* 20 30 *o are those in which R represents fluorine, chLorine, bromine or cyano, or represents a group of the formula -NR R 5 -COR6 -(CH2)a-X, -0-(CH2)a-X or -CH=CH-(CH 2 )b-X, wherein 4 5 R and R are identicaL or different and denote hydrogen, or 7 8 a group of the formuLa -COR or -SO 2 R where 7 R represents hydrogen, or 9 represents an -NHR group, or represents Lower aLkoxy, or represents phenyL, benzyL, benzyloxy, thienyL, furyL, pyridyl, pyrimidyL, quinoLyL, isoquinoLyL, benzothiazoLyL, benzoxazoLyL, thiazoLyl, ox’azoLyL, isoxazolyL or isothiazoLyL which are optionaLLy substituted by Lower aLkyL, Lower aLkoxy, fLuorine, chLorine, bromine, trifluoromethyl, dimethyLamino or diethyLamino, R represents cyclopropyL, cyclopentyL or Le A 24 869 9 2 i 2 0.0.
20 @000 0 25 *0 00 S 0 @0 0 30 .0 0 0 00 0 0 0 cyclohexyL, or represents lower alkyl which is optionally substituted by cyano, fluorine, chlorine, bromine, trifLuoromethyl or lower aLkoxycarbonyL, or represents phenyl, benzyL, thienyL, furyL, pyrimidyl, pyridyL, quinolyL, isoquinolyL, benzothiazoLyL, benzoxazo yL, thiazolyL, oxazolyL, isoxazolyl or isothiazolyl which are optionally substituted by Lower alkyl, lower alkoxy, fluorine, chlorine, bromine, trifLuoromethyl, dimethylamino or diethylamino, or represents a group of the formuLa -NR 10
R
1 1 wherein R and R 1 1 are identical or different and denote hydrogen, lower alkyl or phenyl and
R
9 represents hydrogen, or represents lower alkyl which is optionally substituted by cyano, fluorine, chlorine or bromine, or represents phenyl, benzyl, thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isooxazolyl or isothiazolyl which are optionally substituted by lower alkyl, lower alkoxy, fluorine, chlorine, bromine, trifluoromethyl, dimethylamino or diethylamino,
R
6 denotes hydrogen, hydroxyl, amino, lower alkoxy or benzyloxy, a denotes a number 1 to 8, b denotes a number 0 to 6, and X denotes a group of the formula -NR12R 13
-COR
14
-SO
2
R
15 or -OR 16 where R and R 13 are identical or different and Le A 24 869 10 L A 1 i 1 T I i r.
t i
S
*5 *e
S
5 represent 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
-C
1 4 -S0 2
R
1 5 or -(CH 2 )c-NR 1
R
13 R denotes an -NHR 17 group, or denotes Lower aLkyL or Lower alkoxy, or denotes phenyl, benzyL, benzyLoxy, thienyL, furyl, pyridyl, pyrimidyl, quinoLyL, isoquinolyL, benzothiazoLyL, benzoxazoLyL, thiazoLyl, oxazoLyl, isoxazoLyl or isothiazoLyl, which are optionally substituted by Lower aLkyl, Lower aLkoxy, fLuorine, chlorine, bromine, trifLuoromethyL, dimethyLamino or diethylamino,
R
15 denotes cyclopropyL, cycLopentyL, cyclohexyL, or lower aLkyL which is optionally substituted by cyano, fluorine, chlorine, bromine, trifLuoromethyl or Lower alkoxycarbonyL, or denotes phenyl, naphthyL, benzyL, thienyL, furyL, pyrimidyl, pyridyl, quinoLyl, isoquinoLyL, benzothiazolyl, benzoxazoLyl, thiazoLyl, oxazoLyl, isoxazoLyl or isothiazolyl, which are optionaLLy monosubstituted or polysubstituted by Lower aLkyL, Lower alkoxy, fLucrine, chLorine, bromine, trifLuoromethyl, dimethylamino or diethylamino, the substituents being identical or different, or denctes an -NR 1 0
R
11 group, where Rio and R have the abovementioned meaning,
R
16 denotes hydrogen, Lower alkyl, phenyl or benzyL, R7 denotes hydrogen, or Lower alkyl which is optionalLy substituted by cyano, fLuorine, chlorine or bromine, or phenyL, benzyl, thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzothiazoLyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazoLy’l or 0@ S 0
S
.5 5 0 5 Le A 24 869 11 isothiazolyl which are optionaLLy substituted by lower alkyL, Lower aLkoxy, fluorine, chLorine, bromine, trifLuoromethyL, dimethyLamino or diethyLamino, and c denotes a number 1 to 6, or where 12 13 R and R together with the nitrogen atom, form a ring from the series comprising
A
02 1 1 0
S
S.
S.
*q
S
S
S.
S
5
-C
6
H
5
(CH
2 )n NrISO2 wherein n denotes a number 1 or 2,
R
2 represents hydrogen or Lower aLkyL and
R
3 represents Lower aLkyL, 15 but where R does not represent NH 2 when
R
2 and R 3 denote propyL, and the saLts thereof.
ParticuLarLy preferred such compounds of the general formula are those in which R represents chlorine, bromine, cyano or represents a group of the formuLa -NR 4
R
5
-COR
6 Le A 24 869 12 -(CH2)a-X, -0-(CH2)a-X or -CH=CH-(CH2)b-X, wherein R and R are identical or different and denote hydrogen or 7 8 a group of the formula -COR or -SO 2 R wherein R represents hydrogen, or represents an -NHR group, or represents methoxy, ethoxy, propoxy or isopropoxy, or represents phenyl, benzyl, benzyloxy, thienyl, Sfuryl, pyridyl, pyrimidyl, quinolyl or isoquinolyL which are optionally substituted by methyl, methoxy, fluorine or chlorine,
R
8 represents ethyl, propyl, isopropyl, butyl or isobutyl which are optionally substituted by fluorine, chlorine, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyL, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl, or S 20 represents phenyl, thienyl, furyl, pyridyl, pyrimidyl, quinolyl or isoquinolyl which are optionally substituted by methyl, ethyl, propyl, isopropyL, methoxy, ethoxy, propoxy or isopropoxy, or or 10 11 represents an -NR R group, .wherein •10 11 R and R are identical or differenl and denote hydrogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl, 30 and R represents hydrogen, or S» represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyL, hexyl or isohexyl which are optionally substituted by fluorine or chlorine, or represents phenyl which may be substituted by Le A 24 869 13 fluorine, chlorine, methyl or methoxy, R6 denotes hydrogen, hydroxyl, amino, methoxy, ethoxy, prupoxy, butoxy, isopropoxy or isobutoxy, a denotes a number 1 to 6, b denotes a number 0 to 4, and X denotes a group of the formula -NR 12
R
13
-COR
14 16
-SO
2 R15 or -OR 16 where R12 and R 13 are identical or different and represent hydrogen, methyl, ethyl, propyL, isopropyl, butyl, isobutyl, or represent phenyl which is optionaLLy substituted by fLuorine, chlorine, methyl or methoxy, or 1514 15 Is 0r-‘ represent a -COR -SO 2 R or-(CH2)c; -N group, R denotes hydrogen, or 0 -NR17 denotes an -NHR17 group, or r denotes methyl, ethyl, propyl, isopropyL, SI methoxy, ethoxy, propoxy, isopropoxy, or S 20 denotes phenyl, benzyl, benzyLoxy, thienyl, .9aW furyL, pyridyL, pyrimidyL, quinoLyl or isoquinolyl which are optionally substituted by methyl, methoxy, fluorine or chlorine, 15
R
15 denotes methyl, ethyl, propyL, isopropyl, butyl or isobutyl which are optionalLy substituted by fluorine, chLorine, methoxycarbonyL, ethoxycarbonyL, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl, 9. r or 30 denotes phenyL, naphthyL, thienyL, furyL, pyridyL, pyrimidyL, quinolyl or isoquinoLyl which are optionally monosubstituted or polysubstituted by methyl, ethyl, propyl, isopropyl methox), fluorine or chLorine, the substituents being identical or different, or denotes an -NR 10
R
1 1 group, where Le A 24 869 14 T I 006 SO so a a 0 4 *9 0 9 to
BOB,
a b *I C S L B a .446
R
1 0 and R 1 1 have the abovementioned meaning, R denotes hydrogen, methyl, ethyL, propyL, isopropyL, phenyL or benzyl, 17 R denotes hydrogen, or denotes methyl, ethyL, propyl, isopropyL, butyL, isobutyL, pentyL, isopentyL, hexyl or isohexyL which are optionally substituted by fluorine or chLorine, or denotes phenyl which may be substituted by fluorine, chlorine, methyl or methoxy, and c denotes a number 1 to 4,
R
2 represents hydrogen, methyl, ethyl, propyl or isopropyL, and
R
3 represents methyL, ethyL, propyl or isopropyl, but where R does not denote NH 2 when
R
2 and R 3 denote propyl and the salts thereof.
20 Very particularly preferred such compounds of the general formula are those in which R represents chLorine, bromine, cyano, or represents a group of the formula -NR 4
R
5
-CUR
6 -(CH2)a-X, -0-(CH2)a-X or -CH=CH-(CH 2 )b-X, wherein R denotes hydrogen, 5 7 8 R denotes a group of the formula -COR or -S0 2 R wherein 30 R 7 represents hydrogen, or represents an -NHR group, or represents methoxy or ethoxy, R represents trifluoromethyl, phenyl, tolyL, or represents an -NR 10
R
1 1 group, wherein R 0 and R 1 1 are identical or different and denote Le A 24 869 15 hydrogen, methyl or ethyl, and
R
9 represents hydrogen, or represents methyl, ethyl, propyl, isopropyL or butyl, or represents phenyL,
R
6 denotes hydrogen, hydroxyl, amino, methoxy or ethoxy, a denotes a number 1 to 4, b denotes a number 0 to 2, and X denotes a group of the formula -NR 12
R
13
-COR
4 -S0 2
R
15 or -OR 16 where
R
12 and R 13 are identical or different and represent hydrogen, methyl, ethyl or propyL, or represent a -COR 14 -02R 15 or ,S02 r
-(CH
2
-N
a *a a a. a a a a 4o a a a 0 a group, 0 14 R denotes hydrogen, or denotes an -NHR 14 group, or 20 denotes methyl, ethyl, propyl, methoxy or ethoxy, R15 denotes trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl or isobutyl, or dpnotes phenyl or naphthyl which are optionally monosubstituted or polysubstituted by methyl or chlorine, or denotes an -NR 10
R
1 1 group, where
R
0 and R 1 have the abovementioned meaning,
R
16 denotes hydrogen, methyl, ethyl or propyl, 30 R 17 denotes hydrogen, or denotes methyl, ethyl, propyl, isopropyl, butyl or isobutyl, or denotes phenyl, and c denotes a number 2 to 4, and R and R 3 represent propyL, and the salts thereof.
The following 8-substituted 2-aminotetralins may be Le A 24 869 16 9* 9 9.
99..
99*9 9. 9.
9 9 9 99 9 9 9 *9 999999 9. 9 9 99 *9 9 9 9 mentioned as examples: 2-dipropyLamino-8-chLoro-1,2,3,4-tetrahydronaphthaLene, 2-dipropyL amino-8-bromo-1 ,2,3,4-tetrahydr’onaph thaLene, 2 -dipropyLamino– 8 -cyano-1,2,3,4-tetrahydronaphthaLene, 2-dipi-opyL amino-8-(3-butyL-ureido)-1 ,2,3,4-tetrahydronaphthaLene, 2 -dipropyLamino-8-formamido-1,2,3,4-tetrahydronaphthaLene, 2 -dipropyLamino-8-carbamoyL-1,2,3,4-tetrahydronaphthaLene, 2-dipropyLamino-1,2,3,4-tetrahydronaphthaLene-8-carboxyLic ac id 2 -dipropyLamino-8-ethoxycarbonyL-1,2,3,4-tetrahydronaphthaLene, 2 -dipropyLamino-8-formyL-1,2,3,4-tetrahydronaphthaLene, 2-dipropyL amino-8-hydroxymethyL-1,2,3,4-tetrahydronaphthaLene, 2 -dipropyLamino-8-aminomethyL-1,2,3,4-tetrahydronaphtha- I e ne 2 -dipropyLamino-8-aminomethyL–1,2,3,4-tetrahydronaphtha- Lene hydroch Lor ide, 20 2-dipropyLamino-8-suLphonami domethyL-1 ,2,3,4-tet rahydronaphthaLene, 2 -dipropyLamino-8-butyLsuLphonamidomethyL-1,2,3,4-tetrahydronaphthaLene, 2-dipropyLamino-8-ethoxycarbonyLamidomethyL-1,2,3,4-tetra- 25 hydr-onaphthaLene, 2-d ip ropyL am ino-8-ethoxyc arbonyL am idomethyL-1,2,3, 4-tetr ahydroxynaphthaLene hydrochLoride, 2 -dipropyLamino-8-C3,3-diethytureido)methyL-1,2,3,4-tetrahydronaphthaLene, 30 2-dipropyL am ino-8-ure idomethyL-1 ,2,3,4-tetrahydronaph tha- Le ne 2 -dipropyLamino-8-(3-methyLureido)methyL-1,2,3,4-tetrahydronaphthaLene, 2 -dipropyLamino-8-for-mamidoethyL-1,2,3,4-tetrahydronaphthaLene, 2 -dipropyLamino-8-(2-‘-hydroxyethoxy)-1,2,3,4-tetrahydro- Le A 24 869 17 MINIMENIMEMENEwnaphthaLene hydrochLoride, 2-dipropyiamino-8-carbamoyLethoxy-1,2,3,4-tetrahydronaphthaiene, 2-dipropyLamino-8-C2-aminoethoxy)-1,2,3,4-tetrahydr-onaphthaiene, 2-dipropyLaminco-8-(2-methanesutphonamido-methoxy)-1 ,2,3,4tetrahydronaphthai ene, 2-dipropyLamino-8-(2,-buityLsuLphonam ido-ethoxy)–1,2,3,4tetv-ahydronaphthaLene, 2-dIipropyLamino-8–(2-prop ionyLamido-ethoxy)-1,2,3,4,-tetrahydronaph thai ene, 2-dipropyLamino-8-(2-ethoxycarbonyL amido-ethoxy)–1,2,3,4tetrahydrorraphthaLene, 2-dipropyLamino-8-E2-C3,3-diethyiureido)ethoxyJ-1,2,3,4tetrahydronaphthaLene, 2-dipropyiamino-8-ureidoethoxy–1,2,3,4-tetrahydtronaphtha- I enie 2-dipropyLamino-.8-E2-(3-‘-methyLureido)ethoxyJ-1,2,3,4-tetrahydronaphthaLene, .:20 2-dipropyLamino-8–E2-(3-butyLure ido )ethoxy]-1 ,2,3,4-tetra hydronaph thai ene, 2-dipropyL amino-8-(2-formy amido-ethoxy)- 1,2,3,4-tet rahydronaphthaLene, 2-dipropyiamino-8-[2-(N,N-diethyiaminosuLphonyi )ethenyi 1 ,2,3,4-tetrahydronaphthaiene, 2-dipropyiamino-8-[2-(N,N-dimethyiaminosuiphonyiL)ethyLJ- 1 ,2,3,4-tet rahydronaph thai ene, 2-dipropyiamino-8-(2-nitro-ethenyi )-1,2,3,4-tetrahydro- J 30 naphthaiene, 302-dipropyiamino-8-(2-amino-ethyi )-1,2,3,4-tetrahydronaphthaLene, 2-dipropyiamino-8-C2-metharesutlphonamido-ethyi tetrahydronaphthai ene hydrochloride, 2-dipropyiLamino-8-(2-butanesuiphonamido-ethyi tetrahydrconaphthai ene, 2-dipropyiamino-8-[2-(p-chiorobenzenesuiphonamido)ethyiJ- Le A 869 18r- 1,2,3,4-tetrahydronaphthaLene, 2-dipropyLamino-8-(2-ethoxycarbonyLamido-ethyL)-1,2,3,4tet rahydronaphthaL ene, 2-dli p ropy Lam ino-8- (2-benzyLoxyc a rony L F. idal-e thy L 4tetrahydronaphthaLene, 2-dipropyLamino-8-(2-ureido–ethyL)-1,2,3,4-tetrahydronaph tha Lene, 2-di piropyL am ino-8-E2-(3-me thytLure i do) ethyL J-1,2,3,4-tet rahydronaphthaLene, 2-dipropyLamino-8-(2-formyLamido-ethyL )-1,2,3,4-tetrahydronaphthaLene.
In the context of the present invention, the 8haLogeno-aniinotetraLins CIa) correspond to the generaL formuL a (Is3a)
Y
i in wh ic h 2 2 R and Rhave the specified meaning and Y represents haLogen or cyano.
In the context of the present invention, the dliaminotetraLins (Ib) correspond to the generaL formula 2 z i n wh ic h Z represents a group of the formuLa -NR 4 R wherein R4 and R 5are identicaL or different and denote hydrogen or a group of the formuLa -COR 7 or -SO 2
R,
R 71 represents hydrogen,. or Le A 24 869 19
*I
1 1 represents aLkoxy, or represents aryL, aryLoxy, araLkoxy, aralkyL or heteroaryL, where the radicals mentioned may be up to trisubstituted, identicalLy or differentLy, by alkyL, alkoxy, alkyltnio, halogen, cyano, trifLuoromethyl, trifLuoromethoxy, trifLuoromethylthio, amino, aLkylamino or dialkylamino, and
R
8 has the .specified meaning and
R
2 and R 3 have the specified meaning.
In the context of the present invention, the 8ureido-aminotetralins (Ic) correspond to the general formula
NHCONHR
9 (Ic) 2 25 in which
R
2
R
3 and R have the specified meaning.
In the context of the present invention, the 8acyl-aminotetralins (Id) correspond to the general formula NR3
COR
6 (Id) in which R represents hydroxyl, amino, alkoxy, aryloxy or aralkoxy, and R2 and R 3 have the specified meaning.
In the context of the present invention, the 8formyl-aminotetralins (le) correspond to the general formula (Ie) Le A 24 869 20
I
CHO
e) in which
R
2 and R 3 have the specified meaning.
In the context of the present invention, the 8methyLene-aminotetraLins (If) correspond to the general formula (If) y~N~ 3
CH
2
X
(If) 10 0 0 1 *15 .00.
:0
S
*5 in which R R and X have the abovementioned meaning.
In the context of the present invention, the 8alkyLene-aminotetralins (Ig) correspond to the general formula w 2 w (Ig) in which W represents a group of the formula -(CH2)a’-X or
-CH=CH-(CH
2 )b-X, R R 3 X and b have the abovementioned meaning, and a’ denotes a number 2 to In the context of the present invention, the Le A 24 869 -21 8-ethylene-aminotetralins (Ih) correspond to the general formula €C 2 3 (Ih)
X
in which R R and X have the specified meaning.
A process has been found for the preparation of the 8-haLogeno-aminotetralins, according to the invention, Sof the general formula (Ia) S(Ia)
Y
in which Y represents halogen or cyano, 2 R represents hydrogen or alkyl, and 3 R represents alkyL, and the salts thereof, i which is characterized in that 8-aminotetralins of the general formula (II) *-2
(II)
NH
2 in which 2 3 R and R have the specified meaning, are reacted with nitrites in inert solvents in the presence of acids, Le A 24 869 22
I;
i» the diazonium salts obtained are then reacted with copper salts of the general formula (III) CuY
(III)
in which Y has the specified meaning, if appropriate in the presence of auxiliaries, and, in the case of the preparation of the salts, are reacted with the appropriate acids, or in that tetraLones of the general formula (IV)
CIV)
18 in which S18
R
18 represents chlorine or bromine, are initially reacted with amines of the general formula (V)
HN
a 3 in which
R
2 and R have the specified meaning, in inert solvents, if appropriate in the presence of 20 auxiliaries, then the intermediates are reduced in inert solvents, then, if appropriate, halogen is exchanged for cyano, and then, in the case of the preparation of the salts, the products are reacted with the appropriate acids.
25 The process according to the invention may be illustrated by the following equation: Le A 24 869 23 2
-~~-UIIIIC(
Process version A: NI 3 2 NH2 diazotization
HCL
/I2 N2+
C
2 1 R 3 C1 Cl decomposition using CuCL Process version 8: reductive am i nation
(C
3
H
7 2 S* o.
S. 4 4 0 f bromine/cyano
I
exchange (C 3
H
7 2
CN
Process version A: When carrying out process A according to the 10 invention, the diazonium salts are generaLLy produced as intermediates which can be isolated. However, it has proven expedient to carry out the process without isolating the intermediates.
Suitable inert solvents here are water or alcohols, 15 such as methanol, ethanol, propanol or isopropanol, or amides, such as formamide or dimethylformamide, or acids, such as mineral acids or carboxylic acids. Water and/or acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid or acetic acid, are preferred.
Le A 24 869 24 7 It is likewise possible to employ mixtures of the solvents mentioned.
In general, mineral acids are employed as acids.
Hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid, or mixtures of the acids mentioned, are preferred here.
In general, alkali metal nitrites, such as sodium or potassium nitrite, are used as nitrites. Sodium nitrite is preferably used.
In general, alkali metal or alkaline earth metal halides or cyanides are employed as auxiliaries. Sodium chloride, sodium bromide or sodium cyanide are preferred.
The reaction is generally carried out in a temperature range from -10 0 C to +150 0 C, preferably from 0 C to +100 0
C.
0 .0 0 *0 00* 0*
S
*0 The reaction is generally carried out at atmospheric pressure. It is likewise possible to carry out the reaction at increased or reduced pressure (for example from 0.5 to 5 bar).
The process according to the invention is generally carried out in a fashion such that a solution of nitrite in water is initially added to the i-aminotetralin in concentrated aqueous acids, and the reaction solution is subsequently treated with copper(I) halides or copper(I) cyanide, if appropriate dissolved in water. In general, the diazonium salt is not isolated. Hydrochloric acid and copper(I) chloride are preferably used for the introduction of the chlorine atom (Y Cl), hydrobromic acid and copper(I) bromide for the introduction of the bromine atom (Y Br), and sulphuric acid and copper(I) cyanide for the introduction of the nitrile function (Y CN), if appropriate in the presence of sodium cyanide.
In general, work-up is effected by neutralization of the reaction mixture using alkali metal hydroxides or carbonates, and also extraction, crystallization and/or chromatography of the free bases thus obtained, from which Le A 24 869 25
-J
9*99 *9 4 9 the saLts thereof are obtained by reaction with the appropriate acids.
The 8-aminotetraLins employed as starting compounds are known EEP-A1 41,488].
The foLLowing 8-aminotetraLins may be mentioned as exampLtes: 8-amino-2-dimethyLamino-1,2,,4-tetrahydronaphthaLene, 8-amino-2-diethyLamino-1,2,3,4-tetrahydronaphthaLene, 8-amino-2-dipropyLamino-1,2,3,4-tetrahydronaphthaLene, 8-amino-2-(N-ethyL-N-methyl)amino-1,2,3,4-tetrahydronaph thaLere, 8-amino-2-(N-methy-N-propy)amino-1,2,3,4-tetrahydronaphthaLene, 8-amino-2-(N-ethyL-N-propy)amino-1,2,3,4-tetrahydronaphthaLene.
Process version B: The intermediates are prepared by reacting the tetralones (IV) with amines in inert organic soLvents, if appropriace in the presence of a cataLyst and if appropriate in the presence of a dehydrating agent.
In the case of the reaction with primary amines, the intermediates are Schiff bases, and in the case of the reaction with secondary amines, the intermediates are enamines or immonium salts.
The process according to the invention may be carried out in two steps, that is to say with isoLation of the intermediates. It is likewise possible to carry out the process according to the’ invention as a one-pot process.
Suitable inert solvents here are those convention- 30 at organic solvents which do not change under the reaction conditions. These preferably include alcohols s.uch as methanol, ethanol, propano 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 tetrachoride, or Le A 24 869 26 9.
4* 9 4 0 9.
99 I_
I
hydrocarbons such as benzene, toluene, xylen or petroleum fractions, or amides such as dimethylformamide or hexamethyLphosphoric triamide, or acetic acid.
In addition, it is possible to use mixtures of the solvents mentioned.
In general, protonic acids are used as catalysts.
These preferably include inorganic acids such as, for example, hydrochloric acid or sulphuric acid, or organic carboxylic acids having 1 to 6 C atoms, optionally substituted by fluorine, chlorine and/or bromine, such as, for example, acetic acid, trifluoroacetic acid, trichloroacetic acid or propionic acid, or sulphonic acids having
C
1
-C
4 -alkyl radicals or having aryl radicals, such as, for example, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid or toluenesulphonic acid.
The water formed during the reaction may be removed, if appropriate, during or after the reaction as a mixture with the solvent used, for example by distillation or O by addition of dehydrating agents, such as, for example, 20 phosphorus pentoxide, or preferably by molecular sieve.
In general, the reaction is carried out in a temt» perature range from 00C to +2000C, preferably from +200C to +1500C.
In the case of removal of the water formed during the reaction by azeotropic distillation with the solvents used, the reaction is preferably carried out at the boilinq temperature of the azeotrope.
The reaction can be carried out at atmospheric, elevated or reduced pressure (for example 0.5 5 bar).
S 30 In general, the reaction is carried out at atmospheric pressure.
When carrying out the reaction, the starting materials are generally employed in a tetralone (IV) to amine S(V) molar ratio of 0.5 2 to 1 2. Molar amounts of the reactants are preferably used.
The enamines are reduced either by hydrogen in Le A 24 869 27 water or inert organic solvents such as alcohols, ethers or halogenated hydrocarbons, or mixtures thereof, using catalysts such as Raney nickel, palladium, palladium on animal charcoal, or platinum, or using hydrides in inert solvents, if appropriate in the presence of a catalyst.
The reaction is preferably carried out using hydrides, such as complex borohydrides or aluminium hydrides. Sodium borohydride, lithium aluminium hydride or sodium cyanoborohydride are particularly preferably employed here.
Suitable solvents in this reaction are all those O 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 likewise possible to use mixtures of the solvents mentioned.
20 In general, protonic acids are used as catalysts in the reduction. These preferably include inorganic acids such as, for example, hydrochloric acid or sulphuric acid, or organic carboxylic acids having 1-6 C atoms, optionally substituted by fluorine, chlorine and/or bromine, such as, for example, acetic acid, trifluoroacetic acid, trichloroacetic acid or propionic acid, or sulphonic acids having C 1
-C
4 -alkyl radicals or having aryl radicals, such as, for example, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid or toluenesulphonic acid.
30 When carrying out the process according to the invention, it has proven favourable to carry out the reaction of the tetralones (IV) with the amines as a one-pot process in an inert solvent, preferably in ethyl acetate or in alcohols such as, for example, methanol, ethanol, propanol or isopropanol, or mixtures thereof, in the presence of inorganic or organic acids, such as, for example, Le A 24 869 28
I
7 0064
S
6 ft 4 *5 *4* 5
S..
4
S
S.
0 hydrochloric acid or acetic acid, and in the presence of a reducing agent, preferably complex hydrides such as, for example, sodium borohydride or sodium cyanoborohydride, if appropriate in the presence of a dehydrating agent, preferably a molecular sieve.
In this case, the reaction is carried out in a temperature range from 0 0 C to +150 0 C, preferably from 0 C to +1000C, at atmospheric pressure. It is likewise possible to carry out the reaction at reduced pressure or at increased pressure (for example in a Carius tube).
If the process according to the invention is carried out as a one-pot reaction, it has proven favourable to employ the amine in an excess of up to 10-fold, preferably up to 5-fold, compared to the tetralone.
The substitution of cyano for halogen, particularly bromine, is generally carried out using 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 to +1500C, at atmospheric pressure.
The amines employed as starting materials are known or can be prepared by known processes (Houben-Weyl’s «Methoden der organischen Chemie» [Methods of Organic Chemistry] XI/1 and XI/2).
25 The following amines may be mentioned as examples: methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, methyl-propylamine, ethylmethylamine and ethyl-propylamine.
Some of the tetralones employed as starting mate- 30 rials are new and can be prepared by methods, known per se, of Friedel-Crafts acylation from 2-halogeno-phenylacetyl chlorides or bromides, aluminium chloride and ethers (Houben-Weyl’s «Methoden der organischen Chemie» [Methods of Organic Chemistry] VII/2a, 141; G.P. Johnson, Org.
Synth., Coll. Vol. IV, 900 (1963)).
The following tetralones may be mentioned as Le A 24 869 29 examples: 8-chLoro-2-tetraLone and 8-bromo-2-tetraLone.
In addition, a process has been found for the preparation of the diaminotetralins, according to the invention, of the general formula (Ib) 2 N,4R 3 wherein Z represents a group of the formula -NR R wherein R and R 5 are identical or different and denote hydrogen, or a group of the formula -COR 7 or -SO 2
R
8 where R represents hydrogen, or (Ib) 20 25 30 S represents alkoxy, or represents aryl, aryloxy, aralkyL, aralkoxy or heteroaryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyL, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkyLamino, and P represents cycloalkyL, or represents alkyL which may be substituted by cyano, halogen, trifLuoromethyL, trifluoromethoxy or aLkoxycarbonyL, or represents aryl, aralkyL or heteroaryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyL, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifLuoromethyLthio, amino, aLkylamino or diaLkyLamino, or Le A 24 869 30 I_ represents an -NR10R 11 group, wherein R and R are identical or different and denote hydrogen, aLkyl, aryL or araLkyL, R represents hydrogen or alkyL, and R represents alkyl, but where R does not denote NH 2 when
R
2 and R 3 denote propyl and the salts thereof, which is characterized in that 8-aminotetraLins of the generaL formuLa (II)
I-R
(II)
in which
NH
2 R and R have the abovementioned meaning, are reacted with acylating or sulphonating agents of the generaL formula (VI) *i V-R19 (VI) in which 19 7 8
R
19 represents a group of the formula -COR or -S0 2 R and V represents halogen, or represents the -OR 2 0 radicaL, wherein
R
2 0 has the same meaning as R 19 and can be identical to or different from the Latter, in inert solvents, if appropriate in the presence of bases, and then, in the case of the preparation of the salts, the products are reacted with the appropriate acids.
The process according to the invention may be illustrated by the following equation: Le A 24 869 31 30 a)
II
-N3(CH 2
CH
2
CH
3 2
NH
2
H
3
CSO
2 C1 Ycx(CH 2
CH
2
CH
3 2
NHSO
2
CH
3 b) 0 L-N2 (CH 2
CH
2
CH
3 2
NH
2 j(H 3
(CH
2
CH
2
CH
3 2
NHCOCH
3 *9 99 Suitable inert solvents here are those conventionaL organic solvents which do not change under the reaction conditions. These preferabLy incLude ethers such as diethyL ether, butyl methyl ether, dioxane, tetrahydrofuran, glycoL dimethyl ether or die:hylene glycol dimethyl ether, or halogenated hydrocarbons such as, for example, methyto** Lene chloride, chLoroform, carbon tetrachoride, dichloroethane, dichloroethyene or trichloroethyene, or hydro- 10 carbons such as benzene, toluene, xylene, or petroleum fractions, or alcohols such as methanol, ethanol, propano or isopropanol, or carboxylic acids such as formic acid, acetic acid or propionic acid, or carboxylic acid anhydrides such as propionic anhydride or acetic anhydride, or acetone, ethyl acetate or acetonitrile. It is likewise possible to employ mixtures of the solvents mentioned.
Le A 24 869 32 I j The conventionaL basic compounds may be employed as bases for basic reactions. These preferably include alkali metal or alkaline earth metal hydroxides, or aLkali metal or alkaline earth metal carbonates, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate, or alkali metal alcoholates such as, for example, sodium methanolate, sodium ethanolate, potassium methanolate or potassium ethanoLate, 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 00C to +800C.
The reaction is generally carried out at atmospheric pressure. It is Likewise possible to carry out the reaction at increased or reduced pressure (for example 20 from 0.5 to 5 bar).
In general, carboxylic acid halides or anhydrides, preferably carboxylic acid chlorides or bromides or symmetrical or asymmetrical carboxylic acid anhydrides, are 19 used as acylating agents (general formula VI with R COR mixed anhydrides with formic acid, acetic acid or propionic acid preferably being used in the case of the asymmetrical anhydrides.
In general, sulphonyl halides or sulphonic anhydrides, preferably sulphonyl chlorides or bromides, or 0 30 symmetrical or asymmetrical sulphonic anhydrides, are employed as sulphonating agents (general formula VI with
R
19
SO
2 R mixed anhydrides with methanesulphonic, ethanesulphonic, benzenesulphonic or toluenesulphonic acid preferably being used in the case of asymmetrical anhydrides.
WhP carrying out the process according to the Le A 24 869 33 invention, the acyLating or suLphonating agents are generally employed in an amount from 1 to 10 moles, preferably from 1 to 5 moles, relative to 1 mole of the 8-aminotetra- Lin. The base is generally employed in an amount from 1 to 5, preferably from 1 to 2 moLes, reLative to 1 moLe of the acylating or suLphonating agent.
In addition, a process has been found for the preparation of the 8-ureido-aminotetralins, according to the invention, of the general formula (Ic)
~/R
2 (Ic) in which
NHCONHR
9 R represents hydrogen or aLkyL, R represents alkyl and R represents hydrogen, or represents cycloalkyl, or represents alkyL which is optionally substituted by cyano, halogen, trifluoromethyl or trifluoromethoxy, or represents aryl, aralkyl or heteroaryl, where the radi- 20 cals mentioned may be up to trisubstituted, identically or differently, by alkyl, aLkoxy, alkylthio, halogen, cyano, trifLuoromethyl, trifLuoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino, and the salts thereof, 25 which is characterized in that 8-aminotetralins of the general formula (II)
(II)
NH2 in which 2 3
R
2 and R 3 have the specified meaning, are reacted with isocyanates of the general formula (VII) Le A 24 869 34 S-
J
T I- e R9N=C=O (VII) in which R has the specified meaning, in inert solvents, if appropriate in the presence of bases, and then, in the case of the preparation of the salts, the products are reacted with the appropriate acids.
The process according to the invention may be illustrated by the following equation: N (CH 2
CH
2
CH
3 2
NH
2 N+ (CH 2
CC
H
2CCH 3 )2
H
3 C-N=C=O
NHCONHCH
3 Suitable inert solvents are those conventional organic solvents which do not change under the reaction con- S» ditions. These preferably include ethers such as diethyl ether, butyl methyl ether, dioxane, tetrahydrofuran or gLycol dimethyl ether, or haLogenated hydrocarbons such 15 as, for example, methyLene chloride, chloroform, carbon tetrachloride, dichloroethane, dichLoroethylene or trichloroethylene, or hydrocarbons such as benzene, toluene, xylene or petroleum fractions, or amides such as dimethylformamide or hexamethylphosphoric triamide, or acetic 20 acid, acetonitrile or pyridine. It is likewise possible to employ mixtures of the solvents mentioned.
Suitable bases here are the conventional organic amines. These preferably include trialkylamines such as, for example, triethylamine or tripropylamine, or tertiary 25 organic bases such as, for example, pyridine, N,N-dimethylaminopyridine, picoline, piperidine, morpholine or azabicycloE4,3,03non-5-ene or 1,5-diazabicycLo[5,4,03undec- Le A 24 869 35 The reaction is generaLLy carried out in a temperaj| ture range from -30 0 C to +100 0 C, preferabLy from 0°C to +80 0
C.
The reaction is generaLLy carried out at atmospheric pressure. It is Likewise possible to carry out the reaction at increased or reduced pressure (for example from 0.5 to 5 bar).
When carrying out the process according to the invention, the isocyanates are generaLLy empLoyed in an amount from 1 to 3, preferably from 1 to 2 moLes, reLative to 1 moLe of the 8-aminotetraLin. The base is generally empLoyed in an amount from 0.01 to 1 mole, preferably from 0.1 to 0.5 mole, relative to 1 mole of the isocyanate.
The process can be carried out, for exampLe, by mixing the 8-aminotetralin with isocyanate and base in an ‘ert solvent, and warming, if appropriate. Work-up is effected by extraction, chromatography and/or crystallization.
In the case of the preparation of the unsubstituted 8-ureido-aminotetralins (R 9 alkali metaL cyanates, preferably sodium or potassium cyanate, are empLoyed in 20 water and/or acids such as hydrochloric acid, hydrobromic .acid or suLphuric acid.
In addition, a process has been found for the preparation of the 8-acyL-aminotetraLins, according to the invention, of the generaL formula (Id) (Id) It 25 3 COR6 2 1 in which R represents hydrogen or alkyl,
R
3 represents alkyl and 60’ 30 R represents hydroxyl, amino, alkoxy, aryloxy or araLkoxy, and the saLts thereof, which is characterized in that Le A 24 869 36 C 1 i I 8-cyanotetralins of the general formuLa (VIII) N
(VIII)
@3
CN
in which R and R 3 have the abovementioned meaning, are hydroLized, and, in the case of the preparation of the carboxyLates, the carboxylic acids obtained are.esterified and, in the case of the preparation of the salts, reacted with the appropriate acids.
The process according to the invention may be il- Lustrated by the following equation:
N(CH
2
CH
2
CH
3 )2
CN
-N(CH
2
CH
2
CH
3 2
CONH
2 lN (CH2H2CH3) 2
C..OOH
o9o
‘(CH
2
CH
2
CH
3 2 Vee
COOCH
3 During the hydroLysis when carrying out the process according to the invention, the amides are generally produced first and then the carboxylic acids. The Le A 24 869 37
_I
‘r
I
i ii 0* 0* 0* 0
I
carboxyLic acids can also be prepared without isolating the amides. The esters according to the invention are obtained by esterifying the carboxyLic acids. This reaction can aL.. be carried out without isolating the amides or the carboxylic acids. The carboxyLic acids are preferably prepared in one step without isolating the amides, but, in contrast, the carboxyLates are prepared from the istlated carboxyLic acids.
The hydrolysis to form the amides or carboxylic acids according to the invention is generally carried out using water in inert solvents in the presence of bases.
Suitable inert solvents here are water or alcohols such as methanol, ethanol, propaneo isopropanol or butanol or glycol, or amides such as dimethylformamide or hexamethylphosphoric triamide, or ethers such as dioxane, tetrahydrofuran, glycol monomethyl ether, glycol dimethyl ether or diethyl glycol dimethyl ether. It is likewise possible to employ mixtures of the solvents mentioned.
Suitable bases for the hydrolysis are the conven- 20 tional basic compounds. These preferably include alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as, for example, sodium carbonate, sodium bicarbonate or potassium carbonate, or aLksi metal alcoholates such as, for example, sodium methanolate, sodium ethanolate, potassium methanolate, potassium ethanuoate or potassium tert.butanolate.
The hydrolysis is generally carried out in a temperature range from 0°C to +200 0 C, preferably from +20 0
C
30 to +1500C.
The hydrolysis is generally carried out at atmospheric pressure. It is likewise possible to carry out the reaction at increased or at reduced pre.ssure (for example from 0.5 to 5 bar).
When carrying out the hydrolysis according to the invention, the bases are generally employed in an amount Le A 24 869 38 7 S I IS 0 0* 0 0* 0 *0 0 4 4 4T 54 4 44 I, 4 4 from 1 to 10, preferably from 1 to 5 moLes, relative to 1 mole of the 8-cyano-aminotetraLins.
The esterification of the carboxyLic acids according to the invention to form the carboxyLates according to the invention is generally carried out using tne appropriate alcohols in the presence of acids in inert solvents.
Suitable inert solvents here are those conventional 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 Likewise possible to employ mixtures of the solvents mentioned.
Suitable acids for the esterification are the conventional inorganic acids. These preferably include mineral acids such as hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid.
The esterification is generally carried out in a 20 temperature range from +10 0 C to +150 0 C, preferably from +20°C to +1000C.
The esterification is generally carried out at atmospheric pressure. It is likewise possible to carry out the esterification at increased or reduced pressure (for 25 example at 0.5 to 5 bar).
When carrying out the esterification, the acids are generally employed in an amount from 1 to 50, preferably from 1 to 20 moles, relative to 1 mole of the carboxy- Lic acid. The alcohols are generally employed in excess.
30 It has proven favourable here to simultaneously employ the alcohols with which the esterification is carried out as solvents.
An etherial or alcoholic hydrogen chloride solution is preferably used as acid, the alcohol with which the carboxyLic acid is esterified itself being used as alcohol.
Le A 24 869 39 The process according to the invention may be carried out, for example, in the foLLowing fashion: the 8-cyano-aminotetralin is warmed in an inert s rlnt together with a base, the Length of the reaction o the temperature level being dependent on whether the carboxy- Lic acid amide or the carboxylic acid is to be prepared.
For the esterification, the appropriate carboxyLic acid is warmed in an inert solvent in the presence of an acid, during which the resultant water of reaction can be removed, together with the solvent, by distillation, if appropriate.
The 8-cyano-aminotetralins employed as starting materials are new and can be prepared by the process described above.
The following may be used, for example, according to the invention as 8-cyano-aminotetralins: 8-cyano-2-dimethyLamino-1,2,3,4-tetrahydronaphthalene, 8-cyano-2-diethylamino-1,2,3,4-tetrahydronaphthaLene, 8-cyano-2-dipropylamino-1,2,3,4-tetrahydronaphthalene, S* 20 8-cyano-2-(N-ethyl-N-methyL)amino-1,2,3,4-tetrahydronaphir thalene, t* 8-cyano-2-(N-ethyl-N-propyL)amino-1,2,3,4-tetrahydronaph- I thalene, 2. 8-cyano-2-(N-methyl-N-propyL)amino-1,2,3,4-tetrahydronaphthalene.
In addition, a process has been found for the preparation of the 8-formyl-aminotetraLins, according to the invention, of the general formula (Ie)
R
2 (le)
R
3 30 in which CHO *2 R represents hydrogen or alkyL, and
R
3 represents alkyl, and the salts thereof, Le A 24 869 40 which is characterized in that 8-halogen-substituted 2-aminotetralins of the general formula (IX) 2 OO ,,NR 2
(IX)
T\
3 in which Hal R and R 3 have the abovementioned meaning and HaL represents fluorine, chlorine, bromine, iodine, preferably chlorine or bromine, are reacted with magnesium and formamides of the general formula (X)
R
2 1 N-CHO
(X)
R22/ in which
R
2 1 and R 2 2 are identical or different and 15 represent methyl, ethyl, propyl, phenyl or pyridyl, or SR2 and R together with the nitrogen atom, form a piperidine ring, in inert solv.ents, if appropriate in the presence of auxi- Liaries, and then, in the case of the preparation of the salts, the products are reacted with the appropriate acids.
The process according to the invention may be iL- Lustrated by the following equation: 0 0.: Le A 24 869 41 I~l~r~Y
‘-N(CH
2
CH
2
CH
3 2 l (CH 2
CH
2
CH
3 2 N-formyLpiperidine
(CH
2
CH
2 CH3.) 2 MgBr
CHO
Suitable inert solvents here are those conventional organic solvents which do not change under the reaction conditions. These preferably include ethers such as di- 5 ethyl ether, butyl methyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene or xylene, or amides such as dimethylformamide or hexame-thylphosphoric triamide. It is likewise possible to employ mixtures of the solvents mentioned.
In general, substances are employed as auxiliaries as are conventional for the activation of a Grignard reaction. These preferably include iodine or organoiodine compounds, or anthracene, preferably iodine or iodoethane.
The reaction is generally carried CJt in a temperature range from -30°C to +1000C, preferably from 0°C to +500C.
20 The reaction is generally carried out at atmospheric pressure. It is likewise possible to carry out the reaction at increased or reduced pressure (for example from 0.5 to 5 bar).
When carrying out the process according to the invention, the formamides are generally employed in an amount from 1 to 5 moles, preferably from 1 to 2 moles, Le A 24 869 42
S.
S
S.
*5
S
reLative to 1 moLe of the starting compound.
The process according to the invention may be carried out, for exampLe, in the, foLLowing fashion: magnesium powder or magnesium turnings are initiaLLy introduced into a suitabLe soLvent, a soLution of the 8-haLogensubstituted 2-aminotetraLin in a suitabLe soLvent is added dropwise, and the appropriate formamide, if appropriate dissoLved in an inert soLvent, is subsequently added to the reaction mixture. After hydroLysis of the reaction mixture, work-up is effected by extraction, chromatography and/or crystaL Lization.
The 8-haLogen-substituted 2-aminotetraLins empLoyed as starting materiaLs are new and can be prepared by the process aLready described above.
The foLlowing may be used, for exampLe, according to the invention as 8-haLogen-substituted 2-aminotetraLins: 8-bromo-2-dimethyLamino-1,2,3,4-tetrahydronaphtnaLene, 8-bromo-2-diethyLamino-1,2,3,4-tetrahydronaphthaLene, 8-br om 0-2-dip rop yLam ino-i, 2,3,4 -te t rah y dron aph tha L ‘n e, 20 8-chLoro-2-dimethyLamino-1 ,2,3,4-tetrahydronaphthaLene, 8-chLoro-2-diethyLamino-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-tetrahydronaphthaLene, 25 8-bromo-2-(N-ethyL-N-propyL )amino-i1,2,3,4-tetrahydronaphthaLene, 8-Lr- mo-2-(N-methyL-N-propyL)amino-1,2,3,4-tetrahydronaphthaLene, 8-chLoro-2-CN-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-CN-methyL-propyL)amino-1,2,3,4-tetrahydronaphthaLene.
In addition, a process has been found for the preparation of the 8-methyLene-aminotetraL ins, according to Le A 24 869 43 N .4 5 5* 5* 5 5 5
S
5 5 SS the invention, of the general formula (If) 3 (If)
CH
2 x in which
R
2 represents hydrogen or alkyL,
R
3 represents alkyL and X denotes a group of the formula -NR 1 R -COR 15 16 -S0 2 R or -OR 16 wherein
R
1 2 and R 1 3 are identical 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
1 15 or -(CH2)c-NR 12
R
1 14 R denotes hydrogen, or e17 denotes an -NHR group, or denotes aLkyL or aLkoxy, or denotes aryL, aryloxy, araLkyL, aralkoxy or heteroaryL, where the radicals mentioned may be up to trisubstituted, identicaLLy or differently, by aLkyL, aLkoxy, aLkyLthio, halogen, cyano, trifluoromethyL, trifLuoromethoxy, trifLuoromethylthio, amino, aLkyLamino or diaLkyLamino, 25 R 15 denotes cycloalkyL, or denotes aLkyL which may be substituted by cyano, halogen, trifLuoromethyl, trifLuoromethoxy or aLkoxycarbonyL, or denotes aryl, araLkyL or heteroaryL, where the radicaLs mentioned may be up to trisubstituted, identicaLLy or differentLy, by aLkyL, aLkoxy, aLkylthio, haLogen, cyano, trifLuoromethyL, trifLuoromethoxy, trifluoromethyLthio, amino, alkyLamino or Le A 24 869 44
L
diaLkylamino, or denotes an -NR 10
R
1 1 group, where
R
10 and R 1 1 are identicaL or different and represent hydrogen, aLkyL, aryL or araLkyL,
R
16 denotes hydrogen, aLkyL, aryl, araLkyl or a group 171 of the formuLa -COR 10
R
11
R
17 denotes hydrogen, or denotes cycoalky or denotes aLkyL which is optionaLLy substituted by cyano, haLogen, trifluoromethyL or trifLuoromethoxy, or denotes aryl, araLkyl or heteroaryl, where the aryL radicaL may be up to trisubstituted, identicaLLy or iffereentLy, by alky ak y, aikyLthio, halogen, cyano, trifluoromethyL, trifLuoromethoxy, trifLuoromethyLthio, amino, aLkyLamino or dialkyLamino, and c denotes a number to 8, or where
R
12 and R 1 together with the nitrogen atom, form a ring from the series comprisingrome tfH 0 and Sc denotes a number 1 to 8, or wher rj
H
2
C
C
2 C H 0. Le A 24 869 or -N N=A Le A 24 869 45 61..
wherein n denotes a number 1 or 2, and A represents hydrogen or cycLoalkyl, A. A
A
9 A A 9 represents aLkyl which may be substituted by halogen, hydroxyl, amino, alkylamino, dialkylamino, carbamoyl or sulphamoyL, or represents aryL, heteroaryL, aralkyl, aLkoxycarbonyl, aLkyLsuLphonyL, phenyLsulphonyL, tolyLsulphonyl, benzylsuLphonyL, formyl, carbamoyL or sulphamoyL,
R
2 represents hydrogen or alkyl, and
R
3 represents aLkyL, but where
R
I does not denotes NH 2 when
R
2 and R 3 denote propyL, and the salts thereof, which is characterized in that tetraLins of the general formula (XI) YN 2
R
2 3
(XI)
in which
R
2 represents hydrogen or alkyL,
R
3 represents aLkyL, and
R
2 represents a group of the formuLa -COR 2 or -CN, wherein
R
2 4 denote.s hydrogen, hydroxyL, aLkoxy or amino, are reduced in inert solvents, then, if appropriate, functional groups are converted into other functional groups by reduction, hydroLysis, oxidation Le A 24 869 46 or reaction with eLectrophiLic reagents, and then’, in the case of the preparation of the saLts, the products are reacted with the appropriate acid.
The process according to the invention may be iL- Lustrated, for exampLe, by the following equation:
(CH
2
CH
2
CH
3 )2 reduction
.NCCH
2
CH
2
CH
3 2 I H 3
CSO
2 C1 a.
0* a a *aa a.
-N(CH
2
CHCH
3 2 0 2
CH
CH
2
CH
2
CH
3 )2 c t io n l(CH 2
CH
2
CH
3 2 *aa a a.
I1 (H 3
CCO)
2 0 a. a a a a. a a a.
CH
2
CH
2
CH
3 )2
CH
2
OCOCH
3 Le A 24 869 47 I i The reduction is carried out either by means of hydrogen in water or inert organic solvents such as aLcohols, ethers or haLogenated hydrocarbons, or mixtures thereof, using catalysts such as metals or noble metals or salts thereof, such as, for example, Raney. nickel, paLLadium, palladium on animal charcoal, platinum or platinum oxide, or using hydrides in inert solvents, if appropriate in the presence of a catalyst.
The reduction is preferably carried out using metal hydrides or complex metal hydrides, such as aluminium hydrides or complex borohydrides or aluminium hydrides.
Sodium borohydride, lithium aluminium hydride, sodium aluminium hydride, aluminium hydride, sodium cyanoborohydride or lithium trimethoxy-hydrido-aluminate, if appropriate in the presence of aluminium chloride, are particularly preferably employed here.
Suitable solvents are all those inert organic sol- S vents which do not change under the reaction conditions.
These preferably include alcohols such as methanol, etha- .20 nol, propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or I» diethylene glycol dimethyl ether, or amides such as hexamethylphosphoric triamide or dimethylformamide, or acetic acid, trichloroacetic acid or trifluoroacetic acid, or haLogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride. It is likewise possible to use mixtures of the solvents mentioned.
In general, acids are used as catalysts in the reduction. These preferably include inorganic acids such as 30 hydrochloric acid, hydrobromic acid or sulphuric acid, or organic carboxylic acids having 1 to 4 carbon atoms, or sulphonic acids having 1 to 4 carbon atoms, such as, for example, formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, methanesulphonic acid, ethanesulphonic acid, benzenesuLphonic acid or toluenesulphonic acid.
Le A 24 869 48 The reduction is particuLarly preferably carried out in inert solvents, preferably in ethyl acetate or in alcohols such as, for example, methanoL, ethanol, propanol or isopropanol, or mixtures thereof, in the presence of inorganic or organic acids, such as, for example, hydrochloric acid or acetic acid, and in the presence of a reducing agent, preferably complex hydrides such as, for exampLe, sodium borohydride, Lithium aluminium hydride or sodium cyanoborohydride.
The reduction is generally carried out in a temperature range from -20 0 C to +100 0 C, preferably from 0 C Sto +800C.
The reduction is generally carried out at atmospheric pressure. It is likewise possible to carry out the reaction at reduced or increased pressure (for example from 0.5 to 5 bar).
When carrying out the reduction, the reducing Sagerit is generally employed in an amount from 1 to 6, preferably from 1 to 3 moles, relative to 1 mole of the start- 20 ing compound.
The process according to the invention can be carried out, for example, by adding the tetralins, if appropriate in an inert solvent, to the reducing agent in an inert solvent, and, if appropriate, warming. Work-up is effected in a conventional fashion by extraction, chroma- S tography and/or crystallization.
In addition, a process has been found for Lhe preparation of the 8-alkylene-aminotetralins, according to S. the invention, of the general formula (Ig) 2 R (Ig) •N ,R3 in which
R
2 represents hydrogen or alkyl,
R
3 represents alkyl, and Le A 24 869 49 V
S
0 0* *5 0.
*5*
S
W represents a group of !he formula -(CH2)a’-X or
-CH=CH-(CH
2 )b-X, wherein X denotes a group of the formuLa–NR12R 1 3
-COR
1 4
-SO
2
R
15 or -OR 16 wherein R12 and R 13 are identical or different and represent hydrogen, aLkyL, aryL or aralkyl, where the aryl radicals may be substituted by halogen, cyano, alkyL, alkoxy or trifluoromethyL, or 14 represent a group of the formula -COR -SO 2
R
1 or -(CH2)c-NR 12 R 13 R denotes hydrogen, or 17 denotes an -NHR17 group, or denotes aLkyl or alkoxy, or denotes aryL, aryloxy, aralkyl, araLkoxy or heteroaryL, where the radicaLs mentioned may be up to trisubstituted, identically or different- Ly, by alkyL, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino,
R
15 denotes cycloalkyL, or denotes alkyL which may be substituted by cyano, halogen, trifluoromethyl, trifluoromethoxy or alkoxycarbonyl, or denotes aryL, aralkyl or heteroaryl, where the radicals mentioned may be up to trisubstituted, identicaLLy or differently, by alkyl, aLkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino, or denotes an -NR1OR 1 1 group, where R and R 11 have the abovementioned meaning,
R
16 denotes hydrogen, alkyl, aryl, aralkyl or a group of the formula -CONR 10
R
1 1 Le A 24 869 50
S
S.
S
*S
I
R
17 denotes hydrogen, or denotes cycloalkyL, or denotes aLkyL which is optionaLLy substituted by cyano, halogen, trifLuoromethyL or trifLuoromethoxy, or denotes aryL, araLkyL or heteroaryL, where the radicals mentioned may be up to trisubstituted, identically or differently, by aLkyL, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifLuoromethylthio, amino, alkylamino or dialkyLamino, and O c denotes a number 1 to 8, or where
R
12 and R 13 together with the nitrogen atom, form a ring from the series comprising
H
2
&-(CH
2 n i 0 0 02 or -N N-A wherein n denotes a number 1 or 2, Le A 24 869 51 and A represents hydrogen or cycloaLkyL, or represents alkyL which may be substituted by halogen, hydroxyL, amino, aLkylamino, dialkylamino, carbamoyL or sulphamoyL, or represents aryL, heteroaryL, aralkyL, alkoxycarbonyL, alkylsulphonyl, phenyLsuLphonyL, toLyLsulphonyL, benzylsuLphonyL, -JrmyL, carbamoyL or sulphamoyl, and a’ denotes a number 2 to and b denotes a number 0 to 8, and the salts thereof, which is characterized in that 8-formyl-aminotetralins of the general formula (le) 2 (le) I3 in which
CHO
20 R 2 and R 3 have the specified meaning, are reacted with phosphorus compounds of the general formula (XII)
U-(CH
2 )at-1-X’ (XII) 9*t* in which X’ has the meaning given for X, or represents nitro, a’ has the abovementioned meaning and U represents a group of the formula Le A 24 869 52 11 I
III
0 0 where 25 26
R
25 and R are identicaL or different and denote alkyL or phenyL, and T denotes a haLid anion, preferabLy chloride, bromide or iodide, in inert solvents in the presence of bases, then, if appropriate, functionaL groups are converted into other functionaL groups by reduction, hydroLysis, oxidation or reaction with eLectrophiLic reagents, and then, in the case of the preparation of the saLts, the products are reacted with the appropriate acids.
The process according to the invention may be il- Lustrated by the following equation: 0
I
9. II
(CHCH
2
CH
3 2
(H
5
C
2 0) 2
P-CH
2
CH
2
CH
2
N(CH
3 2 9 I (CH 2
CH
2
CH
3 2 N(CH3)2 9CH2CH2CH32 2 2 3)23) 53
S..
S..
H(CH
3 2 H2H3) Le A 24 869 14(CH 32 -53- T u 9O 0
S
*5
S
*5S
S
S
S. S S
S
A
S*
S
S
S
S
Suitable inert solvents here are those conventional organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, butyl methyl ether, dioxane, tetrahydrofuran,, glycol dimethyl ether or diethylene glycol dimethyl ether, 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 sulphoxide. It is likewise possible to use mixtures of the solvents mentioned.
Suitable bases are the conventional basic compounds for basic reactions. These preferably include alkali metal or alkaline earth metal hydroxides, s’uch as, for example, 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 sodium methanolate, sodium ethanolate, potassium methanolate, potassium ethanolate or potassium tert.butylate, or amides such as sodium amide or lithium diisopropylamide, or organolithium compounds such as phenyLLithium or butyllithium.
The choice of solvent or base depends on the stability, sensitivity to hydrolysis or CH acidity of the 25 appropriate phosphorus compound. Ethers such as diethyl ether, tetrahydrofuran or dioxane, or hydrocarbons such as benzene, toluene or xylene, or dimethylforma ide are particularly preferably used as solvent. Alkali metal alcoholates such as sodium methanolate, sodium ethanolate, 30 potassium methanolate, potassium ethanolate or potassium tert.butylate, or organolithium compounds such as phenyllithium or butyllithium are particularly preferably used as bases.
The reaction is generally carried out in the temperature range from -30 0 C to +150 0 C, preferably from 0 0 C to +100 0
C.
Le A 24 869 -54 The reaction may be carried out at atmospheric, increased or at reduced pressure (for example 0.5 to bar). In general, the reaction is carried out at atmospheric pressure.
When carrying out the reaction, the phosphorus compounds are generally employed in an amount from 1 to 2 moles, preferably in molar amounts, relative to 1 mole of the 8-formyl-aminotetralins. The bases are generaLly employed in an amount from 1 to 5, preferably from 1 to 2 moles, relative to 1 mole of the phosphorus compound.
The process according to the invention can be carried out, for example, by adding the base and then the 8formyl-aminotetralins, if appropriate in a suitable solvent, to the phosphorus compounds, dissolved or suspended in a suitable solvent, and, if appropriate, warming. The work-up is effected in a conventional fashion by extraction, chromatography and/or crystallization.
When carrying out the process according to the invention, it is likewise possible to employ the appropriate 20 phosphoranes E(R25) 3
P=CH-(CH
2 2 which have previously been prepared from the appropriate phosphonium salts and bases in a separate reaction, directly in place of the phosphonium salts IU -P(R 2 5 However, it has proven favourable 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 may aLso be carried out, depending on the stability nf the phosphorus compounds, in the form of a phase transfercatalyzed reaction, where ether, hydrocarbons and halo- 30 genated hydrocarbons may be used as solvents and aqueous sodium hydroxide or potassium hydroxide solutions may be employed as bases.
The phosphorus compounds of the general formula (XII) employed as starting materials are known or can be prepared by known methods (Houben-Weyl’s «Methoden der organischen Chemie» [Methods of Organic Chemistry] Vol.
Le A 24 869 55
L,
i I XII/1, 33, 167).
In addition, a process version has been found for the preparation of the 8-ethyLene-aminotetraLins, according to the invention, of the general formula (Ih) 2 (Ih) a 9 a.
a.
ac a.
a a a a.
*9 a a a in which
R
2 represents hydrogen or alkyL, R represents hydrogen or alkyL and X denotes a group of the formula -NR 12
R
13
-COR
14 -S0 2
R
15 or -OR 16 wherein 12 13 R and R are identical 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 -S0 2 R or -(CH2)c-NR 12
R
13
R
14 denotes hydrogen, or 20 denotes an -NHR 1 group, or denotes alkyL or alkoxy, or denotes aryl, aryloxy, aralkyL, aralkoxy or heteroaryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by 25 alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino, R15 denotes cycloalkyl, or denotes alkyl which may be substituted by cyano, halogen, trifLuoromethyL, trifluoromethoxy or alkoxycarbonyl, or Le A 24 869 56 denotes aryL, araLkyL or heteroaryL, where the radicals mentioned may be up to trisubstituted, identicaLLy or differently, by alkyl, aLkoxy, aLkylthio, halogen, cyano, trifluoromethyl, trifLuoromethoxy, trifluoromethyLthio, amino, aLkyLamino or diaLkyL.amino, or denotes an -NR 1
R
1 1 group, where
R
10 and R 1 have the abovementioned meaning,
R
16 denotes hydrogen, aLkyl, aryL, araLkyL or a group of the formula -CONR 1
R
1 1 R denotes hydrogen, or denotes cycLoaLkyL, or denotes aLkyl which is optionaLLy substituted by cyano, halogen, trifluoromethyL or trifLuoromethoxy, or denotes aryL, araLkyL or heteroaryL, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyL, alkoxy, alkyL- 20 thio, halogen, cyano, trifLuoromethyL, trifluoro-
S.
methoxy, trifluoromethyLthio, amino, alkylamino or dialkylamino, and c denotes a number 1 to 8, Sor where 12 13 25 R and R together with the nitrogen atom, form a ring from the series comprising 2 2
X
H
2 S 0 Le A 24 869 57 021 1
(CH
2 )C 2) o r -N -A w h er ein n denotes a number 1 or 2, and A represents hydrogen or cycLoaLkyL, or represents aLkyL which may be substituted by halogen, hydroxyL, amino, aLkyLamino, diaLkyLamino, carbamoyl or suiphamoyL, or represents aryL, heteroaryL, araLkyL, aLkoxycar- .bonyL, aLkyL~uLphonyL, phenyLsuLphonyL, toLyLsuL phonyL, benzenesuLphonyL, formyL, carbamoyL or *suiphamoyLI and the saLts thereof, O 15 which is cha’racterized in that 8-formyL-aminotetraL ins of the generaL formuLa (Ie) 34 e
CHO
i n wh ic h *R 2 and R3have the abovementioned meaning, are reacted with CH-acidic compounds of the generaL formu- L a XI I I
H
3 C-X’ (XIII) Le A 24 869 58 in which X’ has the meaning given for X, or represents nitro, in inert solvents, if appropriate in the presence of condensation agents, then, if appropriate, functional groups are converted into other functional groups by reduction, hydrolysis, oxidation or reaction with electrophilic reagents, and then, in the case of the preparation of the salts, the products are reacted with the appropriate acid.
The process according to the invention may be il- Lustrated, for example, by the following equation: a) (CH2CH 2
CH
3 2
H
3
C-NO
2
CHO
C
aj condensation
(CH
2
CH
2
CH
3 2 s a€ NO2 reduction C (CH 2
CH
2
CH
3 2
PS
NH
2 94 k.
Le A 24 869 59
-I
-I
(CH
2
CHZCH
3 2
CHO
H
3
CSO
2
N(CH
3 2 I condensation
(CH
2
CH
2
CH
3 2 Sreduction
N(CH
2
CH
2
CH
3 2
SO
2
N(CH
3 2 Os..
30 *::gs 0 a* 5 *0as Sa a 6 0 0 C a.
OS
sO
C
em Suitable inert solvents here are those conventional solvents which do not change under the reaction conditions. These preferably include water alcohols, such 5 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, for example, 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 sulphoxide or acetic acid. It is Likewise possible to use mixtures of the solvents mentioned.
In general, bases are used as condensation agents.
These preferably include 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 alcoholates such as sodium methanolate, sodium Le A 24 869 60 T I rl ethanolate, potassium methanoLate, potassium ethanoLate or potassium tert.butanoLate, or ammonia, or ammonium acetate, or organic amines such as diethylamine, triethylamine, diisopropylamine, tripropyLamine, pyridine, piperidine, morpholine or N,N-dimethyLaminopyridine or picoLine.
The reaction is generaLLy carried out in a temperature range from 0 C to +150 0 C, preferably from +20 0 C to +1000C.
The reaction can be carried out at atmospheric, increased or reduced pressure (for example 0.5 to 5 bar).
In general, the reaction is carried out at atmospheric Spressure.
When carrying out the reaction, the CH-acidic compounds are generally employed in an amount from 0.1 to 100, preferably 0.5 to 50, particularly preferably 1 to moles, relative to 1 mole of the 8-formyl-aminotetralin.
The process according to the invention may be carried out, for example, by mixing and, if appropriate, Swarming the 8-formyl-aminotetralin with the CH-acidic com- 20 pound, if appropriate in an inert solvent and if appropri- S ate with bases. The work-up is effected in a conventional fashion by extraction, chromatography and/or crystallization. It is also possible here to carry out the process according to the invention by a phase transfer-catalyzed version.
The conversion of functional groups into other functional groups in the preparation process described above is carried out, depending on the type of functional group, by oxidation, reduction, hydrolysis or by reaction with electrophilic reagents and is intended to be described in detail below.
1. In general, the nitrile group is reduced to the amino group using metal hydrides, preferably using lithium aluminium hydride, aluminium hydride (prepared, for example, by reaction of Lithium aluminium hydride with 100% strength sulphuric acid or with aluminium c.hloride), Le A 24 869 61 i or mixtures thereof, in inert solvents such as ethers or chlorinated hydrocarbons, preferably in ethers such as, for example, tetrahydrofuran,.diethyl ether or dioxane, in a temperature range from -20°C to +100 0 C, preferabLy from 0 C to +500C, at atmospheric pressure.
In addition, the reduction is possible by hydrogenation of the nitriles in inert solvents such as aLcohols, for example methanol, ethanol, propanol or isopropanol, in the presence of a noble metal catalyst such as platinum, palladium, palladium on animal charcoal, or Raney nickel, in a temperature range from 0 C to +1500C, preferably from room temperature to +1000C, at atmospheric pressure or at increased pressure.
The reaction may be illustrated by the following equation: 2 -CH CH 3 I
(CH
2
CH
2
CH
3 2 l i N(CH 2
CH
2
CH
3 2 reduction P
N
CN
SCN
H
2
N
2. In general, carbamates are converted to N-methylamines by reduction using hydrides, preferably using L* ithium aluminium hydride, in inert solvents such as g:sers, hydrocarbons or chlorinated hydrocarbons, preferably in ethers, such as, for example, diethyl ether, tetrahydrofuran or dicA&ne, in a temperature range from 0°C to +1500C, preferably from +20 C to +100 0 C, at atmospheric pressure.
The reaction may be illustrated by the following 25 equation:
(CH
2
CH
2
CH
3 2
O
reduction
NHCOOC
2
H
Le A 24 869 -62
(CH
2 CHZCp ,2 0
HHCH
3 3. In general, aLkoxycarbonyL groups are reduced to aLcohoL groups using hydrides, preferably using Lithium aluminium hydride, in inert solvents such as ethers, hydrocarbons or halogenated hydrocarbons, or mixtures thereof, preferably in ethers, such as, for example, diethyl ether, tetrahydrofuran or dioxane, in a temperature range from 0°C to +150 0 C, preferabLy from +20 0 C to +100 0 C, at atmospheric pressure.
The reaction may be illustrated by the following equation *E 9 A
S
S. S
S
(CH
2
CH
2
CH
3 2 reduction 7
CHZOH
(CH
2
CH
2
CH
3 )2
COOC
2
H
4. In general, the nitrile group is hydrolysed to the carboxamide group using strong mineral acids, preferably using hydrochloric acid, in inert solvents such as water and/or alcohols, such as, for example, methanol, ethanol, propanol or isopropanol, in a temperature range from 0 C to +150 0 C, preferably from +20 0 C to +100 0
C,
at atmospheric pressure.
20 The reaction may be described by the following equation:
(CH
2
CH
2
CH
3 )2
(CH
2
CH
2
H
3 )2
O
CN
Le A 24 869 hydrolysis
CONH
2 63 i_ A Large number of further compounds according to the invention are obtained by reacting NH- or OH-acidic compounds with eLectrophilic reagents: a) In generaL, amines are converted to carboxamides by reaction with carboxyLates in inert solvents such as ethers or hydrocarbons, or their mixtures, preferably in ethers such as, for example, diethyl ether, tetrahydrofuran or dioxane, if appropriate in the presence of bases such as alkali metals, alkali metal hydrides, alkali metal alcoholates or organoLithium compounds, preferably in the presence of alkali metals such as, for example, sodium, or alkali metal hydrides such as sodium hydride or potasslum hydride, in a temperature range from +20 0 C to +150 0
C,
preferably at the boiling temperature of the solvent used, at atmospheric pressure.
In addition, it is possible to prepare the amides using carboxylic acid halides or anhydrides, preferably using carboxylic acid chlorides, in inert solvents such as ethers, hydrocarbons or halogenated hydrocarbons, or 20 mixtures thereof, preferably in ethers such as, for example, diethyl ether or tetrahydrofuran, or halogenated hydrocarbons such as methylene chloride or chloroform, if appropriate in the presence of bases such as alkali metal carbonates, for example sodium carbonate or potassium carbonate, or organic amires such as, for example, triethylamine or pyridine, in a temperature range from -20 C to +100 0 C, preferably from 0’C to +60 0 C, at atmospheric pressure.
The reaction may be illustrated by the foLLowing 30 equation: Le A 24 869 64 7 NN~~NuCH 3
(CH
2
CH
2
CH
3 2
NH
2
CH
2
CH
2
CH
3 2 Ic -C b) In generaL, amines are converted to carbamates using carbonates, preferably using asymmetricaL carbonates, particularly preferabLy using carbonates which carry one phenyL ester radlical, in inert soLvents such as ethers, hydrocarbons or halogenated hydrocarbons, or mixtures thereof, preferably in ethers such as, for example, diethyl ether, tetrahydrofuran or dlioxane, in a temperature range from +20 0 C to +150 0 C, preferabLy from +20 0 C to o +100 0 C, at atmospheric pressure.
The reaction may be described by the following equation: aOCOOC 2
H
(CH
2
CH
2
CH
3 2
NH
2
I
(CH
2
CH
2
CH
3 2 41 S S* 55 55 5 S S 55 5 S S
S.
NHCOOC
2
H
Le A 24 869 65
I
c) In general, amines are converted to ureas by reaction with isocyanates in inert solvents such as ethers, hydrocarbons or haLogenated hydrocarbons or mixtures thereof, preferably in ethers such as, for example, diethyl ether or tetrahydrofuran, or in halogenated hydrocarbons such as, for example, methylene chloride or chloroform, in a temperature range from -20 0 C to +150 0 C, preferably from 0°C to +1000C, at atmospheric pressure.
The reaction may be described by the following equation: CO=C=0 CH 2
CH
2
CH
3 2
NH
2 4*
A.
(CH
2
CH
2
CH
3 2
NHCONHC
6
H
d) In general, amides are converted to sulphonamides or aminosulphamoyl derivatives using sulphonyl halides or using amidosulphonyl halides, preferably using the corresponding chlorides, in inert solvents such as ethers, hydrocarbons or halogenated hydrocarbons, or mixtures thereof, preferably in halogenated hydrocarbons such as, for example, methylene chloride or chloroform, if appropriate in the presence of bases such’ as alkali metal hydroxides, alkali metal carbonates, alkali metal alcoholates or organic amines, preferably using alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal carbonates such as, for example, sodium carbonate or potassium carbonate, or organic amines such as triethylamine or pyridine, in a temperature range from Le A 24 869 66 to +100 0 C, preferably from 0°C to +50 0 C, at atmospheric pressure The reaction may be iLLustrated by the foLLowing equation:
‘(CH
2
CH
2
CH
3 2
*(H
3 2 NS0 2 C1
(CH
2
CH
2
CH
3 )2
NHSO
2 N(CH3)2 9 a 9a *9a* In general, the hydroxyL group is converted to a carbonate by reaction with halogenoformates, 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, if appropriate in the presence of bases such as alkali metal hydroxides, alkali metal carbonates or organic amines, preferably 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 atmospheric pressure.
:2 0 :zo The reaction may be illustrated by the following equation: Le A 24 869 67
__I
Y(CH
2
CH
2
CH
3 2 C1COOC 2
H
OH
(CH
2
CH
2
CH
3 2
OCOOC
2
H
f) In general, cyclic suLphonamides are prepared by reaction of intramolecular electrophiLes in inert dipoLar aprotic solvents, preferably in dimethylformamide, hexamethyLphosphoric triamide or dimethyl suLphoxide, if appropriate in the presence of bases such as alkali metals, alkali metal hydrides, alkali metal amides, alkali metal alcoholates or organolithium compounds, preferably in the S* presence of alkali metal hydrides such as sodium hydride 10 or potassium hydride, or alkali metal amides such as so- S* dium amide or lithium diisopropylamide, if appropriate in the presence of catalytic amounts of an alkali metal iodide, for example sodium iodide or potassium iodide, in Sa temperature range from -20 0 C to +100 0 C, preferably 15 from 0 C to +50°C, at atmospheric pressure.
The reaction may be illustrated by the following equation:
S
N(CH
2
CH
2
CH
3 2 cyclization Le A 24 869 68
I
(CH
2
CH
2
CH
3 2 02 6. A further variation of the process according to the invention with respect to the functional groups in R is given by the reduction of the double bond in R 1 nitro groups NO 2 which are present simultaneously being reduced to amino groups. The reduction is generally carried out using metal hydrides, preferably using lithium aluminium hydride, aluminium hydride (prepared, for example, by reaction of lithium aluminium hydride with sulphuric acid and aluminium chloride), sodium borohydride, lithium borohydride, or mixtures thereof, in inert solvents such as ethers or chlorinated hydrocarbons, preferably in ethers such as, for example, tetrahydrofuran, dioxane or diethyl ether, in a temperature range from -200C to +1000C, 15 preferably from 0 C to +80°C, at atmospheric pressure.
It is likewise possible to carry out this reduction by hydrogenation in inert solvents such as alcohols, for example methanol, ethanol or isopropanol, in the presence of catalysts such as platinum, platinum oxide, pal- Ladium, palladium on animal charcoal, or Raney nickel, if appropriate in the presence of acids such as hydrochloric acid, acetic acid, trichloroacetic acid or trifLL. roacetic acid, in a temperature range from 0 C to +200 0 C, preferably from +200C to +1000C, at atmospheric pressure or 25 superatmospheric pressure.
The reaction may be illustrated by the following equation: Le A 24 869 69 i i I i- I
(CH
2
CH
2
CH
3 )2
‘H
2
CH
3 2 reduction
NH
2
NO
2 Compounds formula with R=O (CH2) X (in which a and X have the specified meaning) can be obtained from the corresponding 8-hydroxy-2-alkylamino-tetralins. The 8-hydroxy-2-alkylamino-tetralins are known (EP-A 41 488) or can be prepared from the corresponding halogen-compounds of Formula The 8-hydroxy-2-alkylamino-tetralins are reacted under alkylation conditions (which are known per se) with compounds of the formula Y (CH 2
X
in which Y represents -Cl, -Br or -OS0 2 -alkyl (C 1 to C and X and a have the above meaning.
a.
.at a a 4 a a a. ar 130 The substances of the general formula according to the invention have a high affinity for cerebral 5-hydroxytryptamine receptors of the type. Agonistic, partially agonistic or antagonistic actions on the serotonin receptor are connected with this, against which the known substances have purely agonistic properties.
The high-affinity ligands, described in the present invention, for the serotonin-1 receptor thus represent better active compounds for combating diseases which are charachterized by disturbances to the serotoninergic system, particularly when involvine receptors which have a high affinity to 5-hydroxyt’ryptamine (5-HT 1 type). They are therefore suitable for the treatment of diseases of the central nervous system, such as anxiety, tension and depression, sexual dysfunctions caused by the central nervous system, and insomnia. In addition, they are suitable for eliminating congnitive deficits, for improving learing and memory performance and for treatment of Alzheimer’s disease. In addition, these active compounds are also suitable for modulation of the cardiovascular system. They alos engage in the regulation of the cerebral blood supply, and thus represent effective agents for combating migraine. The compounds according to the invention can likewise be employed for combating pain. They are also suitable for combating diseases of the intestinal tract, which are characterized by disturbances of the serotoninergic system.
Le A 24 869 70 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. The therapeutically active compound should in each case be present here in a concentration of about 0.5 to 90% by weight of the total mixture, that is to say in amounts which suffice to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, optionally with the use of emulsifiers and/or dispersing agents, and, for example, when using water as a diluent, organic solvents can optionally be used as auxiliary solvents.
Examples of auxiliary substances which may be mentioned are: water, non-toxic organic solvents, such as paraffins (for example petroleum fractions), vegetable ois (for example groundnut oil/sesame oil), alcohols (for example ethyl alcohol and glycerol), excipients, such as, for example, ground natural minerals (for example kaolins, clays, talc and chalk), ground synthetic minerals (for example highly disperse silica and silicates) and sugars (for example sucrose, lactose and glucose), emulsifiers (for example polyoxyethylene fatty acid esters), polyoxyethylene fatty alcohol ethers (fnr exam- O pie Lignin-sulphite waste liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (for example magnesium stearate, talc, stearic acid and sodium sulphate).
Administration is effected in the customary manner, preferably orally or parenterally, particularly perlingually or intravenously. In the case of oral use, the tahbl ts can, of course, also contain, in addit n to the 35 excipients mentioned, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additional substances, such as starch, preferably Le A 24 869 71 4 -7 potato starch, gelatine and the like. Furthermore, Lubricants, such as magnesium stearate, sodium Lauryl sulphate and talc, can be used concomitantly when making tablets. In the case of aqueous suspensions, the active compounds can be mixed with various flavour-improving agents or colourants in addition to the abovementioned auxiliary substances.
In the case of parenteral use, solutions of the active compounds, using suitable Liquid excipients, .can be empLoyed.
In general, it has proved advantageous, in the case of intravenous administration, to administer amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to mg/kg, of body weight to achieve effective results, and in the case of 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, under certain circumstances, to deviate from the amounts mentioned, and in particular to do so as a function of the body weight 20 or of the nature of the administration method, of the individuaL behaviour towards the medicament, the nature of its formulation, and the time or interval over which the administration takes place. Thus, it can in some cases be sufficient to manage with less than the abovementioned minimum amount, whereas in other cases the upper Limit V. mentioned must be exceeded. In the case of administration ,of larger amounts, it may be advisable to divide these into several individual administrations over the course of the day.
0* 0 0 00 0 S S 0 Le A 24 869 72 Preparation examples Example 1 2-DipropyLamino-8-chLoro-1,2,3,4-tetrahydronaphthaLene
«N(CH
2
CH
2
CH
3 2 Cl 700 mg (2.8 mmol) of 2-dipropyLamino-8-amino- 1,2,3,4-tetrahydronaphthalene were dissolved in 2.5 mL of water and 1.14 ml (13.7 mmoL) of 37% strength hydrochloric acid. A solution of 195 mg of sodium nitrite and 0.45 ml 10 of water were added dropwise to this solution at an internal temperature of 0°C. The solution was subsequently stirred for 15 minutes at 0°C.
In the meantime, 396 mg (4 mmol) of copper(I) chloride were dissolved in 1.6 ml of water, and the solution was cooled to 0 0 C. The reaction solution above was carefully added dropwise to this solution, and the batch was warmed for 30 minutes at +95°C until the evolution of S 4.
nitrogen had ceased.
The reaction mixture was neutralized using aqueous S 20 potassium bicarbonate solution and extracted with dichloro- Smethane. The organic phase was dried over sodium sulphate and the solvent was separated off. The residue was purified by means of column chromatography on silica gel. Di- 04.
chloromethane/methaiul, 20:2, was used as eLuent.
Yield: 74% of theory (oily product) Rf 0.64.
4 d The base was precipitated as the hydrochloride from a solution of petroleum ether using ethereal hydrogen chloride solution. The hydrochloride was a very hygroscopic, 30 colourless, crystalline product.
ii *I Le A 24 869 73 T Example 2 Process version A: 2-Dipropylamino-8-bromo-1,2,3,4-tetrahydronaphtha- Lene (C Q (CH 2
CH
2
CH
3 2 The reaction couLd be carried out analogously to the reaction for 2-dipropyLamino-8-chLoro-1,2,3,4-tetrahydronaphthaLene (Example employing copper(I) bromide and 47% strength hydrobromic acid.
Yield: 32% of cheory (oily product) Rf 0..73 (dichloromethane/methanoL 20:2).
The base was precipitated as the hydrochLoride from a solution of petroleum ether using ethereal hydrogen chloride solution. The hydrochloride was a very hygroscopic, colourless, crystalline product.
Process version B: 1. 8-Bromo-2-tetralone Br 83.5 g of aluminium chloride (0.63 mmol) were introduced into 1.8 litres of methylene chloride at 0 +5 0
C.
105 g (0.49 moL) of 2-bromophenyl-acetyl chloride (dissolved in 200 ml of methylene chloride) were added dropwise at 0 +5 0 C over 30 minutes. After stirring for 30 minutes at 0 +50C, 50 g of ethylene were passed in at such 25 a rate that the reaction temperature did not exceed +10 C.
The mixture was stirred for a further 2 hours at 20 +25 0
C.
4 The aluminium complex was decomposed by careful addition of 0 500 ml of ice water, the phases were separated, and the aqueous phase was extracted with 250 ml of methylene chloride.
The title compound was obtained from the dried methylene chloride phase in a yield of 109 g as a yellow oil (content according to GC 97%) and employ.ed without further purification.
Le A 24 869 74 2. 8-Bromo-2-dipropylamino-1,2,3,4-tetrahydronaphtha- Lene a) Enamine synthesis: 385 g (1.71 mot) of 8-bromo-2tetraLone and 165 g of propylamine (2.8 mol) were stirred under reflux for 2 hours on a water separator in 700 mL of benzene, in the presence of 1.5 g of AmberLyst 15 ion exchange resin. The ion exchange resin was filtered off and the filtrate was concentrated under reduced pressure.
The residue (437 g) which remained was employed as a crude product in the reductive alkylation.
b) Reductive alkylation: 437 g of crude enamine (a) Swere initially introduced into 3 litres of propionic acid at 0 +5 0 C. 310 g of sodium borohydride were added in portions at 0 +10 0 C. When the addition was complete, the reaction temperature was increased slowly to +50 0 C and maintained for 2 hours. The reaction temperature was subsequently increased to +1200C and maintained for 3 hours.
The cooled reaction solution was diluted with 10 litres of ice water and rendered weakly alkaline by addition of sodium hydroxide solution (45% strength). 320 g of the fin- S al product (boiling point 128 1350C; 0.07 mm) were obtained by means of extraction with chloroform and fractional distillation (GC 90% pure).
The secondary amine 8-bromo-2-propylamino-tetrahydronaphthalene is obtained if the reaction is interrupted after stirring for 2 hours at +50 0 C and worked-up as described.
94 Example 3 Process version A: 30 2-Dipropylamino–cyano-8-cyao-1,2,3,4-tetrahydronaphtha- Lene *4 e S*
(CH
2
CH
2
CH
3 2
CN
Le A 24 869 75 I i- g (24 mmol) of 2-dipropyLamino-8-amino-1,2,3,4tetrahydronaphthalene were dissolved in 36 g (120 mmol) of 33% strength sulphuric acid under nitrogen. A solution of 1.7 g (24 mmol) of sodium nitrite in 5 ml of water was then added dropwise at 0°C to a maximum of +5 0 C. The reaction solution was subsequently stirred for a further minutes at the same temperature and then added dropwise to a solution, warmed to 50 0 C, of 2.9 g (32 mmoL) of copper(I) cyanide, 8.7 g (177 mmoL) of sodium cyanide and 39 mL of water. The batch was then stirred for a further 1 hour at 0 C until the evolution of nitrogen had ceased.
The batch was subsequentLy stirred in 500 mL of Sice water and the mixture was adjusted to pH 10 using 2N sodium hydroxide solution. The mixture was then extracted with dichloromethane and the organic phase was washed with water until neutral. The solution was dried over sodium sulphate and the solvent was removed by distillation. The residue was purified by column chromatography on silica gel. Toluene/methanoL, 85:15, was used as eluent.
20 Yield: 48% of theory (oil) Rf 0.63 (toluene/methanol 83:17) Process version B: 152 g of 8-bromo-2-dipropyLamino-1,2,3,4-tetra- 0* hydronaphthalene (Example 2) (0.49 mol) and 66 g of cop- 25 per(I) cyanide were stirred for 6 hours a 1500C in 450 ml of dimethylformamide. The cooled reaction batch was in- °troduced into a mixture of 150 ml of ethylenediamine and 450 ml of H 2 0, and stirred for 1 hour at room temperature.
S, The crude product, obtained by extraction with ethyl ace- S30 tate, was subjected to fractional distillation. The product was obtained as a colourless oil (boiling point 140 150 0 C; 0.1 mm) in a yield of 73 g (GC Example 4 2-Dipropylamino-8-(3-butyl-ureido)-1,2,3,4-tetrahydronaphthaLene Le A 24 869 76
«(CH
2
CH
2
CH
3 2
NH
CONHCCH
2
CH
2
CH
3 0.7 g (2.8 mmol) of 2-dipropylamino-8-amino-1,2,3,4tetrahydronaphthaLene were dissolved in 3 ml of toLuene.
0.34 g (3.4 mmol) of butyl isocyanate were added to the solution and the mixture was stirred for 17 hours at room temperature.
The solvent was subsequently removed by distillation in vacuo and the residue was purified by column chromatography on silica gel. Ethyl acetate/methanol/triethyla ne, 20:1:0.1, was used as eluent.
Yield: 51% of theory (oily substance) Rf 0.51 After dissolving in petroleum ether, it was possible to convert the base into the hydrochloride by dropwise ad- 15 dition of ethereal hydrogen chloride solution. The hydrochloride was a colourless, slightly hygroscopic, crystalline substance.
Example **2-Dipropylamino-8-formamido-1,2,3,4-tetrahydro- 20 naphthalene N(CH2CH2CH3) 2
NHCHC
1.06 g (10.4 mmol) of acetic anhydride and 0.48 g (10.4 mmol) of formic acid were combined and warmed for 3.5 hours at 500C. After cooling, a 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 batch was stirred for 17 hours at room temperature.
The solvent was subsequently removed by distillation Le A 24 869 77 in vacuo and the residue was dissolved in dichloromethane.
The solution was then washed with aqueous potassium bicarbonate solution and dried over sodium sulphate. The solvent was subsequently removed by distillation.
The residue was purified by column chromatography on aluminium oxide 90 (aluminium oxide from Merck, activity II-III). CycLohexane/methanol/triethylamine, 20:0.5:0.1, was used as eluent.
Yield: 42% of theory (crystalline substance) Rf 0.62 After dissolving in diethyl ether, the base could be converted into the hydrochloride by dropwise addition of an ethereal hydrogen chloride solution. The hydrochloride was a colourless, very hygroscopic, crystalline substance.
Example 6 2-Dipropylamino-8-carbamoyL-1,2,3,4-tetrahydronaphthalene
(CH
2
CH
2
CH
3 2
CONH
2 20 1.0 g (4 mmol) of 2-dipropyLamino-8-cyano-1,2,3,4tetrahydronaphthalene and 0.5 g (8 mmol) of potassium hydroxide in 10 ml of tert.butanol were refluxed for 6 hours under nitrogen. After cooling, the reaction solution was diluted wit:, 20 ml of saturated sodium chloride solution 25 and extracted with dichloromethane. The organic phase was dried using sodium sulphate and the solvent was removed by distillation in vacuo. The residue was crystallized from 10 ml of diisopropyl ether.
Yield 56% of theory (beige powder) S 30 Boiling point 105 1060C Rf 0.25 (silica gel; dichloromethane/methanol 75:25) Le A 24 869 78 I ExampLe 7 2-DipropyLamino-1,2,3,4-tetrahydronaphthaLene-8carboxyLic acid
,(%CH
2
CH
2
CH
3 2
COOH
256 mg (1 mmoL) of 2-dipropyLamino-8-cyaRio-1,2,3,4tetrahydronaphthalene, 132 mg (2 mmoL) of potassium hydroxide and 36 mg (2 mmoL) of water’in 1 mL of ethylene glycol were stirred for 20 hours at +150 0 C under nitrogen.
After cooling, the reaction solution was diluted with 6 mL of water and extracted with dichloromethane. The aqueous phase was adjusted to pH 1-2 using 2.75 mL of 1N hydrochLoric acid, and was then extracted again with dichloromethane. The aqueous phase was subsequently adjusted to pH 5 using 25% strength ammonia solution. The water was then removed by distillation in vacuo and the residue was dried at +50 0 C and a vacuum of 0.05 mbar until the weight remained constant. The residue was then dissolved in absolute tetrahydrofuran. After the insoluble salts had been filtered off, the solution was freed of solvent in 20 vacuo. The reaction product remained as a residue, as a S virtually colourless oil.
Yield: 44% of theory V. Rf 0.67 (silica gel; strength ammonia solution 67:27:6) 25 Example 8 2-Dipropylamino-8-ethoxycarbony-1,2,3,4-tetra- **hydronaphthaene
(CH
2
CH
2
CH
3 2
COOC
2
H
Le A 24 869 79
I.
300 mg (1.1 mmoL) of 2-dipropylamino-1,2,3,4-tetrahydronaphthalene-8-carboxylic acid were stirred at room temperature in 30 mL of absolute ethanol and 3 mL of a solution of hydrogen chloride in diethyl ether (190 mg/ml), until the reaction was complete. The solvent was subsequently removed by distillation in vacuo and the residue was dissolved in 10 ml of dichloromethane. The solution was washed once with 0.1N sodium hydroxide solution and twice with water, and dried over sodium sulphate. The solvent was then removed by distillation in vacuo. The reaction product remained as a virtually colourless oil.
O Yield: 64% of theory Rf 0.97 (silica gel; strength ammonia solution 67:27:6) Example 9 2-DipropyLamino-8-formyl-1,2,3,4-tetrahydronaphthalene ,k
(CH
2
CH
2
CH
3 2
CHO
3.75 g (154.4 mmol) of magnesium powder were initially introduced into 100 mL of dry tetrahydrofuran under S argon. Several drops of iodoethane were added, and a solution of 31.9 g (103 mmol) of 2-dipropyLamino-8-bromo- 1, 2 ,3,4-tetrahydronaphthalene and 20 ml of absolutely dry tetrahydrofuran were then added dropwise at 0 0 C. The mix- 25 ture was stirred for 3 hours at +600C. Cooling to room temperature was then effected, and 12.8 g (113.3 mmol) of No formylpiperidine were then added dropwise at this temperature. The mixture was stirred for a further 30 minutes at S room temperature and then hydrolyzed using 3N hydrochloric •’30 acid. The mixture was then adjusted to pH 12 and extracted with ethyl acetate. Chromatography was carried out using cyclohexane/ethyl acetate/triethyLamine, 80:19:1, over Le A 24 869 80 n.lrhsilica’gel 60, 63 200 im.
Yield: 65.5% of theory (oiL) Rf 0.342 (diisopropyl ether/triethyLamine 99:1) Example 2-Dipropylamino-8-hydroxymethyl-1,2,3,4-tetrahydronaphthaLene Y
W(CH
2
CH
2
CH
3 2
CH
2
OH
mg (0.4 mmol) of lithium aluminium hydride were suspended in 2 ml of diethyl ether under nitrogen. A solution of 210 mg (0.7 mmol) of 2-dipropylamino-8-ethoxycarbonyL-1,2,3,4-tetrahydronaphthalene in 1 mL of diethyl ether was carefully added dropwise to the suspension. The batch was subsequently stirred for a further 5 hours at room temperature.
Firstly 5 mg (0.05 mmol) of ethyl acetate, then 15 mg of water, subsequently 20 mg of 15% strength sodium S hydroxide solution and finally a further 50 mg of water were then added dropwise and stirred for 0.5 hours in each case. The batch was then diluted with 3 ml of diethyl 20 ether. The precipitate was filtered off and the filtrate was washed with water and freed of solvent. The oily residue was dried in a vacuum of 0.05 mbar and at a temperature of 50 0 C until the weight remained constant.
Yield: 71% of theory 25 Rf 0.28 (silica gel; toluene/methanol 85:15) Example 11 8-Acetylamino-2–dipropylamino-1,2,3,4-tetrahydronaphthalene
(CH
2
CHCH
3 2
NHCOCH
3 Le A 24 869 81 24 g (0.094 mol) of 8-cyano-2-dipropylamino-1,2,3,4tetrahydronaphthalene were initially introduced into 100 mL tetrahydrofuran (absolute); 4.5 g of Lithium aluminium hydride (0.12 mol) were added in portions at +20 +309C.
After stirring for 2 hours under reflux, the excess Lithium aluminium hydride was decomposed by addition of water and sodium hydroxide. The precipitated inorganic solid was filtered off under suction and washed with 50 mL of tetrahydrofuran. The crude product (25 g) remaining after drying and concentrating the filtrate was dissolved in 200 ml of methylene chloride, and 10 g of triethylamine were added. After addition of 0.2 g of dimethylaminopyridine as acylation catalyst, 1 g of acetic anhydride was added dropwise at +20 +25°C. After a stirring for further twelve hours at +20 +25 0 C, the reaction solution was washed with sodium bicarbonate and water, dried and concentrated. The resultant crude product (30 g) was recrystallized from hexane/ethyl acetate The product was isolated as a solid in a yield of 75% of 20 theory.
Melting point: 99 100 0
C
Example 12 2-Dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene *9 9*9* 99 9* 9
CH
2
CH
2
CH
3 2
CH
2
NH
2 1 9 *9 9 99 9 9 .9 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 were heated to a gentle reflux for 24 h at 900C under nitrogen. The 30 batch was subsequently stirred into 1 litre of ice water and the mixture was extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulphate. The solvent was removed by distillation in Le A 24 869 82 vacuo. The reaction product, remaining as a residue, was purified by column chromatography on siLica gel using methanoL/triethyLamine, 95:5,. as eluent.
YieLd: 59% of theory (oiL) Rf 0.62 ExampLe 13 2-Dipropylamino-8-aminomethyL-1,2,3,4-tetrahydronaphthalene hydrochLoride The compound.of ExampLe 12 was dissolved in ether.
By dropwise addition of ethereal hydrogen chloride solution, the hydrochloride was precipitated and was then filtered off under suction and dried in vacuo at room temperature.
Yield 3.6 g Melting point: 97 100 0
C
Example 14 2-Dipropyamino-8-methysuphonamido-methyL-1,2,3,4tetrahydronaphthalene P #N
(CH
2
CH
2
CH
3 2
CH
NH-SO
2
-CH
3 1.6 g (6 mmol) of 2-dipropyLamino-8-aminomethyL- 1,2,3,4-tetrahydronaphthaLene were dissolved in 16 mL of dichioromethane under nitrogen. 0.7 g (6 mmoL) of methanesuLpiornyl chloride was then added dropwlse at a maximum of +25 0 C. The reaction solution was then stirred for 18 hours at room temperature. 16 mL of water were then added. The mixture was adjusted to pH 10 using 1N sodium hydroxide solution. The organic phase was separated off and washed with water. After drying over sodium sulphate, the solvent was removed by distillation in vacuo. The residue was purified by column chromatography on siLica gel using diisopropyL ether/isopropanol/triethylamine, 65:70:5, as eIuent.
Le A 24 869 83 YieLd: 76% of theory (oiL) Rf 0.55 ExampLe 2-Dipropylamino-8-butyLsuLphonamidomethyL-1,2,3,4tetrahydronaphthaLene
(CH
2
CH
2
CH
3 2
CH
2
I
NH-SO
2
-C
4
H
9 1.6 g (6 mmoL) of 2-dipropyLamino-8-aminomethyL- 1,2,3,4-tetrahydronaphthaLene were dissolved in 16 ml of dichloromethane under nitrogen. 0.9 g (6 mmoL) of butanesulphonyl chloride was then added dropwise at a maximum of +25 0 C. The reaction solution was then stirred for 18 hours at room temperature. 16 mL of water were then added.
The mixture was adjusted to pH 10 using 1N sodium hydroxide solution. The organic phase was separated off and washed with water. After drying over sodium sulphate, the solvent was removed by distillation in vacuo. The residue was purified by column chromatography on siLica gel using Sdiisopropyl ether/triethyLamine, 99.5:0.5, as eLuent.
S Further purification was achieved by dissolving the base .’20 in ether and converting to the hydrochloride by dropwise addition to an ethereal hydrogen chLoride solution. After addition of water and separation of the organic phase, the base was liberated again by addition of sodium hydroxide solution and isolated by extraction with ether.
0..25 Yield: 49% of theory (oil) Rf 0.10 (silica gel; diisopropyL ether/triethylamine 99.5:0.5) Example 16 2-DipropyLamino-8-ethoxycarbonyLamido-methyL- «30 1,2,3,4-tetrahydronaphthaLene Le A 24 869 84
NXCOOC
2
H
CG
S
1.6 g (6 mmol) of 2-dipropylamino-8-aminomethyL- 1,2,3,4-tetrahydronaphthalene were dissolved in 16 ml of diethyL ether under nitrogen. 0.58 mL of ethyl chloroformate was added dropwise, with cooling, at a maximum of +5 0 C. The batch was subsequently stirred for a further 1 h at +50C and then stirred into ice water. The aqueous phase w.as adjusted to pH 10 using 1N sodium hydroxide solution and then extracted with ether. The organic phase now obtained was washed with water and dried over sodium sulphate. The solvent was removed by distillation and the remaining residue was purified by column chromatography on silica gel. Diisopropyl ether/triethylamine, 99.5:0.5, was used as eluent.
15 Rf 0.20 Example 17 2-Dipropylamino-8-ethoxycarbonyLamido-methyl- 1,2,3,4-tetrahydronaphthalene hydrochloride The free base of the compound of Example 16 was converted into the hydrogen chloride, after dissolving in diisopropyl ether, using ethereal hydrogen chloride solution.. The very hygroscopic hydrochloride was filtered off under suction and dried in vacuo.
Yield: 18% of theory Example 18 2-Dipropylamino-8-(3,3-diethyLureido)methyl-1,2,3,4tetrahydronaphthalene ,(CH 9S D^N (CH 2
CH
2
CH
3 2
CH
2
I
NHCON(C
2
H
5 2 Le A 24 869 85 Ge
C
S. C 9 C 7- 1.6 g (6 mmoL) of 2-dipropylamino-8-aminomethyl- 1,2,3,4-tetrahydronaphthalene wer» dissolved in 16 ml of dichloromethane under nitrogen. 6.B1 g (6 mmol) of diethyLcarbamoyl chloride was then added dropwise at a maximum of +250C. The batch was then stirred for 26 h at room temperature. The batch was then stirred into 160 ml of ice water. The mixture was adjusted to pH 9 using 1N sodium hydroxide solution and extracted with dichLoromethane. The organic phase was washed with water and dried over sodium sulphate. The solvent was subsequently removed by distillation. The residue was purified by column chromatography. DiisopropyL ether/isopropanol/triethyLamine, 80:19.5:0.5, was used as eluent. The final product could be crystallized from petroleum ether 30-50 and was dried at +40 0 C in vacuo.
Yield 64% of theory Melting point: 86 870C Rf 0.42 ExampLe 19 20 2-Dipropylamino-8-ureidomethyL-1,2,3,4,-tetrahydronaphthalene I 2
NHCONH
2 2.6 g (10 mmoL) of 2-dipropylamino-8-aminomethyl- 1,2,3,4-tetrahydronaphthalene were dissolved in 22 ml of 25 1N hydrochloric acid under nitrogen. A solution of 0.81 g (10 mmoL) of potassium cyanate and 6 ml of water was sub- S sequently added dropwise at a maximum of +25 0 C, and the batch was allowed to react for 4 h at room temperature.
mL of diethyl ether were then added. The aqueous phase 30 was separated off and adjusted to pH 9 using 1N sodium hydroxide solution. The precipitated reaction product was filtered off under suction and dried at +40 0 C in vacuo. The Le A 24 869 86 product was purified by recrystaLLization from methanoL.
Yield :33% of theory MeLting point: 182.5 183.5 0
C
R f 05 ExampLe 2-D ipropyL am ino-8-C3-methyL ure ido) me thyL-1,2,3, 4te trahydronaph tha Lene
(CH
2
CH
2
CH
3 )2
CH
2 NHCONHCH 3 4 1.6 g (6 mmoL) of 2-dipropyLamino–8-aminomethyL- 1,2,3,4-tetrahydronaphthaLene were diss’oLved in 16 mL of toLuene under nitrogen. 0.34 g (6 mmoL) of methyl isocyanate was added dropwise at a maximum of +25 0 C. The batch was subsequentLy stirred for a further 1.5 h at room temperature. The reaction product which crystallized out was then fiLtered off under suction and dried at +400C in v’acuo.
Yield: 65% of theory Rf 0 Example 21_ *sl Z-DipropyLamino-8-formamidomethyL-1,2,3,4,-tetrahydronaphthaLene _.N(CH 2
CH
2
CH
3 )2 C H.
see
NHCHO
J 2.04 ml (21.5 mmoL) of acetic anhydride and 0.86 ml (22.8 mmoL) of formic acid were stirred for 2 h at +-60 0
C
under nitrogen. After cooling to ropm temperature, 2.6 g (10 mmoL) of 2 -dipropyLamino-8-aminomethyL-1,2,3,4-‘tetraage 0 hydronaphthaLene were added dropwise at a maximum of +25 0
C.
After 15 minutes post-reaction, 5 ml of ether were added.
The batch was subsequentLy stirred for a further 18 h at Le A 24 869 87 room temperature and then diluted with 20 mL of ether and mL of water. The aqueous phase was adjusted to pH 9 using 1N sodium hydroxide solution and extracted with ether. The organic phase now obtained was wa.shed with water and dried over sodium sulphate, and the solvent was removed by distillation. The residue was recrystallized from petroleum ether 60-80.
Yield: 46% of theory Melting point: 74.5 75.50C Example 22 2-Dipropylamino-8-(2-hydroxyethoxy)-1,2,3,4-tetrahydronaphthalene hydrochloride N (CH 2
CH
2 CH3 2 O x HC1
OH
0.7 g (23 mmol) of sodium hydride (80% in paraf- 15 fin) was initially introduced into 5 ml of diethylene gly- .col dimethyl ether. A solution of 4.9 g (20 mmoL) of 2dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthaLene and 20 mL of diethylene glycol dimethyl ether was then added dropwise at +25 0 C. The mixture was stirred for 30 minutes S 20 at +500C. After cooling to +250C, 2.5 g (20 mmol) of 2bromoethanol were added dropwise. The mixture was stirred for 2 h at +1000C. The cooled batch was ooured into water and extracted twice with ethyl acetate. The organic phase was dried over sodium sulphate and evaporated. Unreacted 25 starting material was removed by chromatography using chloroform over basic aluminium oxide, activity I. 700 mg of a viscous oil were subsequently obtained by chromatography over silica gel 60, 40-63 pm, using diisopropyl ether/ethanol 3:2. The oil was dissolved in ether and the hydrochloride was precipitated using ethereal hydrochloric acid. The product was extracted with water and washed Le A 24 869 88 once more with ether. Methylene chloride was subsequently added and the pH adjusted to 11 using ammonia. The organic phase was separated off, dried using sodium sulphate and filtered. The hydrochloride was again precipitated using ethereal hydrochloric acid. The hydrochloride was evaporated to dryness, and a glassy residue was obtained.
Yield: 6% of theory Rf 0.392 (diisopropyl ether ethanol 3:2) Example 23 2-Dipropylamino-8-carbamoylmethoxy-1,2,3,4-tetrahydronaphthalene y 0%N
(CH
2
CH
2
CH
3 2
OCH
2
CONH
2 0.35 g (11 mmol) of an 80% dispersion of sodium hydride in oil was washed with petroleum ether and then suspended in diglyme under nitrogen. A solution of 2.50 g 15 (10 mmol) of 2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene and 5.9 ml of diglyme was added dropwise within 30 minutes at +20 +25 0 C with gentle cooling. The batch was subsequently stirred for a further 30 minutes Sand then warmed at +50 0 C for 15 min. 0.94 g (10 mmol) of chloroacetamide was then added in portions at +20 +25 0
C.
The batch was then warmed at +135 0 C for 1 h and, after cooling, stirred into 100 ml of ice water. The precipi- 0 tate was filtered off under suction and dried at +40 0 C in vacuo. The crude substance was purified by recrystalliz- 25 ing twice from isopropanol.
Yield 50% of theory Melting point: 132-132.5 C Rf 0.43 (silica gel; toluene/methanol 70:30) Le A 24 869 89
I
r Example 24 2-DipropyLamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthaLene 0
NH
2 12.5 g (0.328 moL) of Lithium aluminium hydride were initiaLLy introduced into 200 ml of absolute ether under nitrogen. A suspension of 25 g (0.082 mol) of 2dipropyLamino-8-(carbonamido-methoxy)-1,2,3,4-tetrahydronaphthaLene in 500 mL of absolute ether was added to this in small portions. The mixture was stirred for 4 h at 0 C and then carefully decomposed using water. The mixture was filtered under suction and the residue was washed thoroughly 3 times with ether. The ether phase was separated off, dried over sodium sulphate and then evaporated 15 to dryness. Chromatography was then effected over silica gel 60, 40 -63 pm, using isopropanol/triethylamine 95:5.
Yield: 73.6% of theory Rf 0.208 Example 20 2-DipropyLamino-8-(2-methanesulphonamido-ethoxy)- 1,2,3,4-tetrahydronaphthal ene T
S
S
S
S
S
*S
(CH
2
CH
2
CH
3 2
I
1
NHSO
2
CH
3 1.45 g (5 mmol) of 2-dipropyLamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphtha ene and 1.38 g (10 mmol) :25 of potassium carbonate were initially introduced into ml of toluene. 0.63 g (5.5 mmol) of methanesuLphonyl chloride was then added dropwise, and the mixture was subsequently stirred for 3 h at room temperature. The mixture Le A 24 869 90 _I I 1 was then filtered and evaporated. The residue obtained was stirred with petroleum ether and filtered off under suction. The product, obtained by chromatography over silica gel 60, 40 63 pm, using diisopropyL ether/ethanoL, 3:2, was recrystallized from petroleum ether with activated charcoal.
Yield L 30% of theory Melting point: 76 0
C
ExampLe 26 2-DipropyLamino-8-(2-butanesuLphonamidoethoxy)- 1,2,3,4-tetrahydronaphthalene O (CH 2
CH
2
CH
3 2 0
NHSO
2
C
4
H
9 g (8.6 mmol) of 2-dipropyLamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthalene and 2.4 g (17.2 mmol) of potassium carbonate were initially introduced into s ml of toluene. 1.5 g (9.5 mmol) of butanesuLphonyL chloride were added dropwise, and the mixture was then stirred for a further 2 h at room temperature. The mixture was then filtered and evaporated in a rotary evaporator. Af- 20 ter chromatography on silica gel 60, 40 63 pm, using diisopropy.L ether/ethanol, 3:2, the product was recrystal- O Lized from petroleum ether.
Yield: 27% of theory Rf 0.517 Example 27 2 -Dipropylamino-8-(2-propionylamido-ethoxy)-1,2,3,4tetrahydronaphthalene
(CH
2
CH
2
CH
3 2
I
NHCOC
2
H
Le A 24 869 91 1.459g (5 mmoL) of 2 -dipropyLamino’-8-(2-aminoethoxy)-l,2,3,4-tetrahydronaphthaLe’ne and 1.38 g (10 mmoL) of potassium carbonate were initialLy introduced into 20 mL of toLuene. 0.5 g (5.5 mmoL) of propionyL chLoridle was then added dropwise, Aind the mixture was subsequentLy stirred for 30 min under refLux. The mixture was then filtered and evaporated. The residue was stirred with Nhexane, and the product was filtered off under suction.
Yield 75% of theory MeLting point: 67 680 C ExampLe 28 2 -DipropyLamino-8-(2-ethoxycarbonyLamido-ethoxy)- 1,2,3,4-tetrahydronaphthaL ene
‘(CH
2
CH
2
CH
3 2 0Y
NHCOOC
2
H
S
a *5
S
S.
-A
S
S *5
S
S 15 1.459g (5 mmoL) of 2 -dipror,/Lamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthaLene and 1.389g (10 mmoL) of potassium carbonate were initialLy introduced into 20 mL of toLuene. 0.53 niL (5.5 nimoL) of ethyl chioroformate was then added dropwise, and the mixture was stirred for 20 a further 20 min at +25 0 C. The mixture was then filtered and evaporated. The product ;.as obtained by chromatography over silica gel 60, 40 -63 g~m, using diisopropyL ether/ethanol, 3:2.
YieLd: 71.8% of theory Rf 0.492 Example 29 2 -DipropyLamino-3-E2-(3,3-diethyLureido)-ethoxyJ- 1 ,2,3,4-tetrahydronaphthaLene Le A 24 869 92
I
T~ *N (CH2CH2CH3)2 0
NHCON(C
2 H5) 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 introduced into mL of toluene. 0.77 g (5.5 mmol) of diethylcarbamoyL chloride was then added dropwise, and the mixture was stirred for 2 h at +1000C. The mixture was then filtered and evaporated. The product was obtained by chromatography over silica gel 60, 40 63 um, using diisopropyL ether/ethanol, 3:2.
Yield: 56.4% of theory Rf 0.408 Example 2-DipropyLamino-8-ureidoethoxy-1,2,3,4-tetrahy- 15 dronaphthalene S. K.N (CH 2
CH
2
CH
3 2
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. A solution of 4.1 g (50 mmol) of potassium cyanate and 20 ml of water was then added dropwise at a temperature of +60 0 C. The :mixture was stirred for 3 h at +600C, the reaction product precipitating. This was filtered off under suction, and the residue was stirred with hot petroleum ether. After cooling, the product was filtered off under suction.
Le A 24 869 93
I-
Yield :83.8% of theory Melting point: 107 1080 C Example 31 2-DipropyLamino-8-EZ-(3–methyLureido)ethoxyj- 1 ,2,3,4-tetrahydronaphthaLene C CH 2
CH
2
CH
3 )~2
NHONHCH
3 1.45 g (5 mmoL) of 2-dipropyLamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthaLene were initially introduced into 20 ml of toLuene. The reaction was catalyzed using 3 drops of triethyLamine, and 0.325 ml (5.5 mmoL) of methyl isocyanate was then added dropwise. The mixture was stirred for 1 h at +250 C. The mixture was evaporated, and the residue obtained was stirred with hot diisopropyL ether. The mixture was cooled, and the product was fiLtered off under suction.
00 Y ieLd :l 80.5% of theory Melting point: 104 1050 C Example 32 2-D ipropyLamino-8-E2-C3–butyLureido)ethoxy]-1,2,3,4- 20 tetrahydronaphthaLene 9 0 (CH 2
CH
2
CH
3 2 0
NHCONHC
4
H
9 1.45 g (5 mmoL) of 2-dipropyLamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthaLene were itiaL I> introduced into 25 ml of toLuene. The reaction was catalyzed Le A 24 869 94 T using 3 drops of triethylamine, and 0.63 mL (5.5 mmoL) of butyl isocyanate was then added dropwise. The mixture wa stirred for 2 h at room temperature. The mixture was evaporated to dryness, and the-residue was crystaLLized from petroleum ether/diisopropyL ether.
Yield 82% of theory Melting point: 90 91 0
C
Example 33 2-DipropyLamino-8-(2-formylamido-ethoxy)-1, 2 3 4 tetrahydronaphthaLene 9 0
N(CH
2
CH
2
CH
3 )2 0
NHCHO
1.02 mL (10.8 mmoL) of acetic anhydride and 0.86 mL (22.8 mmoL) of formic acid were heated at +60 0 C for 4 h.
The mixture was then cooled to room temperature, and 1.45 g 15 (5 mmoL) of 2-dipropyLamino-8-(2-amino-ethoxy)-1,2, 3 4 tetrahydronaphthaLene were added dropwise. After the exothermic reaction had subsided, the mixture was then stir- Sred for a further 2 h at room temperature. EthyL acetate was then added, and the batch was adjusted to pH 11 using 20 1 molar sodium hydroxide solution. The aqueous phase was extracLed a further time with ethyL acetate. The organic phases were combined, dried over sodium sulphate and evaporated. The residue was recrystaLLized from petroleum ether with activated charcoal.
Yield 58.4% of theory Melting point: 93°C Example 34 2-Dipropylamino-8-C2-(N,N-dimethyLaminosuLphonyL)ethenyl]-1,2,3,4-tetrahydronaphthalene Le A 24 869 95
N(CH
2
CH
2
C»
3 2
HC=CH
S0 2
-N(CH
3 2 1.23 g (10 mmoL) of dimethyL-methanesuLphonamide and 150 mg (1 inmoL) of benzyttriethyLammonium chLoridle were stirred vigorousLy for i5 min at room temperature with 20 mL of 50% strength sodium hydroxide soLution in ml of methyLene chLoridle. A soLution of 7.8 g (30 rnmoL) of 2-dipropyL am ino-8-formyL-1 ,2,3,4-tetrahydronaph tha Lerie in 5 mL of meth,Lene chloridle was subsequently added dropwise at room temperature, and the mixture was stirred overnight. The mixture was then diluted with pLenty of water and extracted repeatedly with methylene chloridle. The organic phase was dried over sodium sulphate and then evaporated. The product was obtained by chromatography over silica gel 60, 63 200 pim, using a) 15 0y~ h x n t y c t t rity a ie 0 1 a d b 15 cycLohexane/ethyL acetate/triethyLamine, 80:19:1,.ndb Yiel: 50.7% of theory *0 Rf 0.617 (diisopropyL ether: ethanol 3:2) Example 2-DipropyLamino-8-E2-(N,N-dimethyLamigiosuLphonyL ethyl ,2,3,4-tetrahydronaphthaLene N(4CH 2
CH
2 CH3) 2 S0 2
N(CH
3 2 .:320 mg (8 mmoL) of Lithium aluminium hydridle were initiaLLy introduced into 20 ml of absolute dliethyL ether under argon. A soLution of 1.46 g (4 mmoL) of 2-diisopropyLamino-8-E2-(N,N-dimethyLaminosuLphonyL)ethenyLj-1,2,3,4tetrahydronaphthaLene in 10 ml of absolute dliethyL ether Le A 24 869 96 was then added dropwise. The mixture was stirred for h under reflux. Decomposition was then carefully effected with water, and the residue was filtered off under suction and washed thoroughly with ethyl acetate. The phases were then separated and the organic phase was dried over sodium sulphate and then evaporated. The product was recrystallized from isopropanol/water, filtered off under suction and dried at +50°C in a high vacuum.
Yield 55.2% of theory Melting point: 84°C Example 36 2 -DipropyLamino-8-(2-nitro-ethenyl)-1,2,3,4-tetrahydronaphthaLene
CHN(CH
2
CH
2
CH
3 2
CH=CH-NO
2 9999 4 99 4 9 9.
*9 9 9 9 9* 99 9 9* 15 14 g (54 mmol) of 2-dipropyLamino-8-formyl-1,2,3,4tetrahydronaphthalene, 14 ml of nitromethane and 5.6 g (73 mmol) of ammonium acetate were stirred for 2 h under reflux in 56 ml of glacial acetic acid. After cooling, the mixture was adjusted to pH 12 using 5 molar sodium hydroxide solution and extracted 3 times with ethyl acetate. The organic phase was dried using sodium sulphate and then evaporated. The product was obtained by chromatography over silica gel 60, 63 200 im, using diisopropyl ether/triethylamine, 99.5:0.5.
Yield: 52.1% of theory H-NMR (300 MHz, CDCL 3 protons of the nitroethylene radical: 6= 7.38 ppm; J 15 Hz, 1H, 6= 8.25 ppm; J 15 Hz, 1H Example 37 2-Dipropylamino-8-(2-amino-ethyl)-1,2, 3 ,4,-tetrahydronaphthalene Le A 24 869 97
I
CH2
‘(CH
2
CH
2
CH
3 2 NH2 820 mg (20.4 mmoL) of sodium borohydride were initially introduced into 30 ml of absolute tetrahydrofuran at 0 C under nitrogen. 3.24 ml (25.8 mmol) of boron trifluoride diethyL ether complex were added dropw4 e at this temperature, and the mixture was subsequently stirred for 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 then stirred for 5.5 h under reflux. After cooling to room temperature, 55 ml of ice water were carefully added dropwise, and the mixture was then acidified using 55 ml of 1N hydrochloric acid. The mixture was subsequently stirred for 2 15 h at +800 +85 0 C. The cooled aqueous phase was washed twice with 35 ml of ether, then adjusted to pH 12 using 5 molar sodium hydroxide solution, and the product was extracted with methylene chloride. The extract was dried over sodium sulphate and evaporated. The product was obtained by 20 subsequent chromatography over silica gel 60, 40 63 um, Susing isopropanol/triethylamine.- 95:5.
Yield: 50.8% of theory Rf 0.192 Example 38 25 2-Dipropylamino-8-(2-methanesulphonamido-ethyl)- S* 1,2,3,4-tetrahydronaphthalene hydrochloride
(CH
2
CH
2
CH
3 )2 x 1.5 HC1
NHSO
2 CH3 1.2 g (4.4 mmol) of 2-dipropylamino-8-.(2-amino- Le A 24 869 98 ethyl)-1,2,3,4-tetrahydronaphthalene and 1.21 g (8.8 mmoL) of potassium carbonate were initiaLLy introduced into mL of methylene chloride. 550 mg (4.8 mmoL) of methanesuLphonyL chloride were then added dropwise at 25 0 C. The mixture was stirred overnight at room temperature. The mixture was then filtered, and the filtrate was washed once with water, dried over sodium sulphate and evaporated.
Diethyl ether was added to the residue, methylene chloride was added until everything was dissolved, and the hydrochloride was precipitated using ethereal hydrochloric acid.
The product was filtered off under suction and dried at 0 C in a high vacuum.
Yield 56.2% of theory Melting point:212 0 C (decomp.) Example 39 2-Dipropylamino-8-(2-butanesulphonamido-ethyL)- 1,2,3,4-tetrahydronaphthaLene
S
S
*5*5 S.
S
S
*5 .5 5 S 5 5 *S
S
S.
S
CH
2
CH
2
CH
3 )2
NHSO
2
C
4 H9I 1.1 g (4 mmol) o» 2-dipropylamino-8-(2-amino-ethyl)- 1,2,3,4-tetrahydronaphth3Lene and 1.1 g (8 mmol) of potassium carbonate were initially introduced into 20 mL of methylene chloride. 690 mg (4.4 mmoL) of butanesulphonyL chloride were then added dropwise, and the mixture was stirred for 5.5 h at room temperature. 20 ml of water 25 were then added, and the mixture was stirred vigorously for 10 min. The phases were separated, and the aqueous phases were extracted once more with methylene chloride.
The organic phases were combined, dried over sodium sulphate and then evaporated. The product was obtained by chromatography over silica gel 60, 40 63 pm, using ethyl acetate.
Le A 24 869 -99 Yield: 72.9% of theory Rf 0.592 (diisopropyL ether ethanol 3:2) Example 2 -DipropyLamino-8-C2-(p-chlorobenzenesulphonamido)ethyl]-1,2,3,4-tetrahydronaphthalene O’ a N (CH 2
CH
2
CH
3 2 1.1 g (4 mmolr of 2-dipropylamino-8-(2-amino-ethyl)- 1,2,3,4-tetrahydronaphthalene were initially introduced into 15 ml of methylene chloride with 2 ml of 50% strength potassium carbonate solution. A solution of 930 mg (4.4 mmol) of p-chlorobenzenesulphonyL chloride in 15 mL of methylene chloride was then added dropwise with vigorous stirring. -The mixture was stirred for 1 h at room temperature. 20 mL of water were added, and the mixture as stirred vigorously. The phases were separated, and the aqueous phase was extracted once more with methyLene 9.
chloride. The organic phases were combined, dried over sodium sulphate and evaporated. The product was obtained by chromatography over silica gel 60, 40 63 pm, using 20 othyl acetate.
Yield: 97.4% of theory Rf 0.650 (diisopropyl ether ethanol 3:2) Example 41 25 bo a 2-Dipropylamino-8-(2-ethoxycarbonylamido-ethyL)- 1,2,3,4-tetrahydronaphthalene Le A 24 869 100 C I N(CH 2
CH
2
CH
3 2
NHCOOC
2
H
1.1 g (4 mmol) of 2-dipropyLamino-8-(2-amino-ethyL)- 1,2,3,4-tetrahydronaphthalene and 1.1 g (8 mmol) of potassium carbonate were initiaLLy introduced into 20 mL of methyLene chloride. 0.45 mL (4.4 mmol) of ethyL chloroformate was then added dropwise at +25 0 C, and the mixture was stirred for a further 1 h at room temperature. 20 ml of water were then added, and the mixture was stirred vi- Sgorously for 10 min. The phases were separated, and the aqueous phase was extracted once more with methyLene chloride. The organic phases were combined, dried over sodium sulphate and then evaporated. The residue was then dissolved in 30 ml of 3N hydrochloric acid, extracted 3 times with diethyl ether, and again adjusted to pH 12, and 15 the product was extracted with ethyl acetate, dried over sodium sulphate and evaporated.
Yield: 85.8% of theory S. Rf 0.598 (diisopropyL ether ethanol 3:2) Example 42 20 2-Dipropylamino-8-(2-benzyloxycarbonylamido-ethyL)- 1,2,3,4-tetrahydronaphthalenc
(CH
2
CH
2
CHI)-
K
NHCOOCH
2
C
6
H
0 g (12.75 mmol) of 2-dipropylamino-8-(2-aminoethyl)-1,2,3,4-tetrahydronaphtha ene and 3.5 g (25.5 mmol) 25 of potassium carbonate ‘ere initially introduced into ml of methylene chloride. 4.7 mL (14 mmol) of benzyl chloroformate (50% strength solution in toluene) were then added dropwise at 250C, and the mixture was stirred for a Le A 24 869 101 i i further 2 h at room temperature. 50 mL of water were subsequently added, and the mixture was stirred vigorously for 10 min. The phases were separated, and the aqueous phase was extracted once more with methylene chloride.
The organic phases were combined, dried over sodium sulphate and then evaporated. The product was obtained by chromatography over silica gel 60, 40 63 im, using ethyl acetate.
Yield: 92.1% of theory Rf 0.567 (diisopropyl ether ethanol 3:2) Example 43 2 -Dipropylamino-8-(2-ureido-ethyl)-1,2,3,4-tetrahydronaphthalene
‘(CH
2
CH
2
CH
3 2
NHCONH
2 *333 a
WI
B
3 0 3 0* 3d Ia 3 3 a. 3 4 15 1.1 g (4 mmol) of 2 -dipropylamino-8-(2-aminoethy 1, 2 ,3,4-tetrahydronaphthalene were dissolved in 8 ml of water and 8 ml of 1N hydrochloric acid, and heated to +600C.
A solution of 3.24 g (40 mmol) of potassium cyanate and 15 ml of water was added dropwise at this temperatUre.
20 The mixture was stirred for 1 h at +60 0 C. The mixture was then cooled and filtered under suction. The product was recrystallized from petroleum ether/diisopropyl ether with activated charcoal.
Yield 43.4% of theory 25 Melting point: 123 124°C Example 44 2 -Dipropylamino-8-C2-(3-methylureido)ethyl]- 1,2,3,4-tetrahydronaphthalene Le A 24 869 102
(CH
2
CH
2
H
3 )2
NHCONHCH
3 1.3 g (4.7 mmol) of 2-dipropyLamino-8-(2-aminoethyl)-1,2,3,4-tetrahydronaphthalene were initially introduced into 20 ml of toLuene. The reaction was catalyzed using 3 drops of triethyLamine, and 0.31 mL (5.17 mmoL) of methyl isocyanate were then added dropwise. The mix- Sture was stirred overnight at room temperature, and then evaporated. After subsequent chromatography over siLica gel 60, 40 63 pm, using diisopropyl ether/ethanol/triethylamine, the product was stirred with petroleum ether and a little diisopropyl ether, and filtered off under suction.
Yield 21.1% of theory Melting point: 700C 15 Example 2-DipropyLamino-8-(2-formyLamido-ethyl)-1,2,3,4tetrahydronaphthalene
SN(CH
2
CH
2 CH3 2
NHCHO
S1.02 ml (10.8 mmol) of acetic anhydride and 0.86 ml S 20 (22.8 mmol) of formic acid were heated at +50 +600C for 4 h. The mixture was cooled to room temperature, and 1.4 g (5 mmol) of 2-dipropylamino-8-(2-amino-ethyL)-1,2,3,4tetrahydronaphthalene were then added dropwise, the temperature being maintained below +40 0 C during this addition.
25 The mixture was subsequently stirred for 2 h at room terrperature. The mixture was then adjusted to pH 12 using 5 molar sodium hydroxide solution and extracted with methylene Le A 24 869 103 chloride. The extract was dried over sodium sulphate and then evaporated. The product was obtained by chromatography over siLica gel 6, 40 63 pm, using diisopropyL ether/ethanol 3:2.
YieLd: 56.3% of theory Rf 0.242 (ALL TLCs were carried out on TLC’aluminium foils, silica gel 60, F254, 5 x 7.5 cm, run height 6 cm).
Example 46 2 -DipropyLamino-8-8 2-(N-methylaminosuLphonyL)ethenyL]- 1,2,3,4-tetrahydronaphthaLene
SN(CH
2
CH
2
CH
3 2
HC=CH
I
S0 2
-NHCH
3 This compound was prepared anaLogously to ExampLe 34. N-methyl-methane suLphonamide was employed as the 15 starting materiaL.
Yield: 49.6% of theory R 0.383 (diisopropyl ether: ethanol 3:2) Example 47 S «2-DipropyLamino-8-C2-(N-methyLaminosuLphonyL)ethyl]- 20 1,2,3,4-tetrahydronaphthaLene
N(CH
2
CH
2 CH3)2 A S02NHCH 3 0 This compound was prepared analogously to ExampLe 35 by reduction of the compound of Example 47 using Lithium aluminium hydride.
YieLd: 33% of theory R 0.492 (diisopropyl ether: ethanol 3:2) Le A 24 869 104 Example 48 2-DipropyLamino-8-[2-C2-naphthyL )suLphonamidoet-,’vL -1,2,3,4-tetrahydronaphthaLene :H 2 CH 2 -NH -So 2
CH
2
-CH
2
-CH
3 961 mg (3.5 mmol.) of 2-dipropyLamino-8-(2-aminoethyl )-1,2,3,4-tetrahydronaphlhaLene were introduced into mL of methyLene chloridle containing 1.75 rnL of strength potassium carbonate solution. A soLuti6n of 873 mg (3.85 mmoL) of naphthaLene-2-sulphonyL chloride and 5 mL of methyLene chloride are added dropwise and the mixture was stirred at room temperature for a further hours. The mixture was then diluted with water and methylene chloride. The organic phase was separated off, dried over sodium sulphate and concentrated. The residue 15 was subsequently chromatographed using cycLohexane/ethyL acetate 1:1 over silica gel 60, 40-63 pim.
6 Yiel: T.32 g 81.2% of theory *Rf 0.117 (cycLohexane: ethyl acetate 1:1) Example 49 2-DipropyLamino-8-[2-(3,4-dichLorophenyL )-suLphonamido-ethyL>-1,2,3,4-tetrahydronaphthaene
H
2 -CH-NH-S0 2 l
CH
2
-CH
2
-CH
3 (1.82 mmoL) of 2-dipropyLamino-8-(2-aminoethyl )-1,2,3,4*-tetrahydronaphthaLene were introduced into ml of methyLene chloridle containing 1 ml of 50% strength Le A 24 869, 105 potassium carbonate solution. A solution of 491 mg mmol) of 3,4-dichLorobenzenesulphonyl chloride and 5 mL of methylene chloride was added dropwise, and the mixture was stirred at room temperature for a further 2 hours.
The mixture was then diluted with water and methylene chloride. The organic phase was separated off, dried over sodium sulphate and concentrated. The residue was subsequently chromatographed using cyclohexane/ethyl acetate 1:1 over silica gel 60, 40-63 pm.
Yield: 3.82 mg 43.4% of theory Rf 0.121 (cyclohexane:ethyl acetate 1:1) Example 2-Dipropylamino-8-[2-N-(4-N-saccharinyl)-nbutylaminoethyL]-1,2,3,4-tetrahydronaphthalene hydrochloride
S
H2-CH2-NH-CH2-CH2-CH2-CH2-N I
II
0-
C
8 CH 2
-CH
2
-CH
3
O
N» x HC1
CH
2
-CH
2
-CH
3 1.3g (4.7 mmol) of 2-dipropylamino-8-(2-aminoethyL)-1,?,3,4-tetrahydronaphthaLene and 1.38 g (10 mmoL) of potassium carbonate were introduced into 10 ml of di- S 20 methylformanide. A solution of 1.49 g (4.7 mmol) of 4- N-saccharinyl-n-butyI bromide and 5 ml of dimethylformamide was added dropwise, and the mixture was stirred at 800C for a further 5 hours. The mixture was subsequently poured into water and extracted with ethyl ace- S» 25 tate. The extracts were chromatographed twice with ethyl acetate and once with cycLohexane:ethyl acetate:triethylamine 50:49:1 over silica gel, 40-63 um. The viscous oil was dissolved in ether, etherial hydrochloric acid was added, and the mixture was concentrated and dried at 50 0
C
in a high vacuum.
Yield: 300 mg 11.6% of theory Rf 0.612 (methanoL:triethylamine 95+5) Le A 24 869 106 Use examples Example 51 A) Affinity to the 5-HTI receptor In Table 1, as an example, the high affinity of the compounds according to the invention to tamine receptors of the sub-type 1 is shown. The values specified are data which were determined from receptor binding studies using calf hippocampus membrane preparations. 3H-serotonin was used for this purpose as radioactively labelled ligand.
Table 1 Compound of Ki (nmol/l) Example No.
1 2 13 6 7 13 26 17 28 4 30 33 19 42 Cmparison In this test model, the compounds described in EP-Al- 41 488 with R OCH 3 R R nC 3
H
7 and 1 OH, R 2 S R 1 OH R 2
R
3 nC 3
H
7 exhibit Ki values of 3 and 2 nmoL/L respectively.
Investigations of the serotonin-agonistic/antagonistic action.
To this purpose, the action on the contraction, caused by serotonin, of the arteria basilaris of the dog is investigated Ccf. Peroutka et al., Brain Research 259, 5 327 (1983)].
Le A 24 869 107 Table 2 Compound of Fxamnie No.
Effect Antagonistic Examn-e No.
Comparison from EP-AI- 41 488: R OH, R 2 nC 3
H
7
R
3 nC 3
H
7
S
*5 *5
S
S
It will be understood that the specification and examples are illustrative but not limitative of the present invention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.
Le A 24 869 108

Claims (3)

8-Substituted 2-aminotetralins of the general 1. formula 9aC S. S in which R represents halogen, cyano or represents a group of the formula -NR 4 R 5 -COR 6 -(CH2)a-X, -O-(CH 2 )a-X or -CH=CH-(CH 2 )b-X, wherein R and R are identical or different and denote hydrogen or 7 8 a group of the formula -COR or -SO 2 R, where R represents hydrogen, or represents an -NHR group, or represents alkoxy, or represents aryl, aryloxy, aralkyl, aralkoxy or heteroaryL, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyl, alkoxy, alkylthio, halogen, cyano, tri- fluoromethyl, trifluoromethoxy, trifluoromethyl- thio, amino, alkylamino or dialkylamino, R represents cycloalkyl, or represents alkyl which may be substituted by cyano, halogen, trifluoromethyl, trifluoromethoxy Le A 24 869 109 9 ~I ti it’ i i i i a. a a. or alkyLoxycarbonyl, or represents aryl, aralkyL or heteroaryl, where the radicals mentioned may be up to trisubstituted, identicaLLy or differentLy, by aLkyL, alkoxy, aLkyLthio, halogen, cyano, trifluoromethyL, tri- fluoromethoxy, trifLuoromethyLthio, amino, aLkyL- amino or diaLkyLamino, or represents an -NR 10 R 1 1 group, wherein R i and R 1 1 are identical or different and denote hydrogen, alkyl, aryL or araLkyL, and R 9 represents hydrogen, or represents cycLoaLkyL, or represents aLkyL which is optionally substituted by cyano, haLogen, trifLuoromethyL or trifluoro– methoxy, or represents aryL, araLkyL or heteroaryL, where the radicals mentioned may be up to trisubstituted, identicaLLy or differentLy, by aLkyl, aLkoxy, aLkyLthio, haLogen, cyano, trifLuoromethyL, tri- fLuoromethoxy, trifLuoromethylthio, amino, aLkyL- amino or diaLkylamino, R 6 denotes hydrogen, hydroxyL, amino, aLkoxy, aryLoxy or araLkoxy, a denotes a number 1 to b denotes a number 0 to 8, and X denotes a group of the formuLa -NR 12 R 1 3 -COR 14 16 -SO 2 R 15 or -OR 16 wherein R 1 and R 13 are identicaL or different and represent hydrogen, alkyL, aryL or araLkyL, where the aryL radicals may be substituted by haLogen, cyano, aLkyL, aLkoxy or trifluoromethyL, or Le A 24 869 110 __I represent a group of the formula -COR14, -S0 2 R 1 or -(CH2)c-NR 12 R 13 14 R denotes hydrogen, or denotes an -NHR 17 group, or denotes alkyl or alkoxy, or denotes aryL, aryloxy, aralkyl, aralkoxy or heteroaryL, where the radicals mentioned may be up to t.risubstituted, identically or differently, by aLkyl, alkoxy, alkyLthio, halogen, cyano, tri- fluoromethyl, trifluoromethoxy, trifluoromethyL- thio, amino, aLkylamino or dialkylamino, R denotes cycloaLkyL, or denotes alkyl which may be substituted by cyano, halogen, trifluoromethyl, trifluoromethoxy or alkoxycarbonyl, or denotes aryl, aralkyL or heteroaryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, tri- fluoromethoxy, trifluoromethylthio, amino, alkyl- amino or dialkylamino, or denotes an -NR 10 R 11 group, where R and R have the abovementioned meaning, R 16 denotes hydrogen, alkyl, aryl, aralkyl, or a group of the formula -COR 10 R 11 17 R denotes hydrogen, or denotes cycloalkyl, or denotes alkyl which is optionally substituted by cyano, halogen, trifluoromethyl or trifluoro- methoxy, or denotes aryl, aralkyl or heteroaryL, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyL, trifluoromethoxy, trifLuoromethylthio, amino, Le A 24 869 111 a a. a a *t a. a. a a a aLkyLamino or diaLkyLarnino, and c denotes a number 1 to 8, or where R 12and R 13 together with the nitrogen atom, form a ring from the series comprising H 2 CH 2 n I I 02~ 0 o r -N 770 5 1

9- %O2 (CH2KnCH2)n I-so2 D 0 00 0 0 0 wh er e in n denotes a number 1 or 2, and A represents hydrogen or cycLoaLkyL, o r represents aLkyL which may be substituted by haLogen, hydroxyl, amino, aLkyLamino, diaLkyL- amino, carbamoyL or suiphamoyL, o r represents aryl, heteroaryL, aralkyL, alkoxycar- bonyL, aLkyLsuiphonyL, phenyLsuLp)honyL, toLyLsuL- phonyL, benzyLsuLphonyL, formyL, carbamoyL or suiphamoyL, Le A 24 869 112 i i S *6 6 I 6* I *I 6I 6 .6 *6 R 2 represents hydrogen or alkyl, and R 3 represents alkyL, but where R does not denote NH 2 when R2 and R 3 denote propyl, and the salts thereof. 2. 8-Substituted 2-aminotetraLins according to Claim 1 wherein R represents fluorine, chlorine, bromine or cyano, or represents a group of the formula -NR 4 R 5 -COR 6 -(CH2)a-X, -0-(CH2)a-X or -CH=CH-(CH2)b-X, wherein 4 5 R and R are identical or different and denote hydrogen, or 7 8 a group of the formula -COR or -S0 2 R where R 7 represents hydrogen, or 9 represents an -NHR group, or represents lower alkoxy, or represents phenyl, benzyl, benzyloxy, thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyL or isothiazolyl which are optisnally substituted by lower alkyl, lower alkoxy, fluo- rine, chlorine, bromine, trifluoronethyl, dime- thylamino or diethylamino, R 8 represents cyclopropyl, cyclopentyl or cyclohexyl, or represents Lower alkyl which is optionally sub- stituted by cyano, fluorine, chlorine, bromine, trifluoromethyl or Lower alkoxycarbonyl, or represents phenyL, benzyl, thienyl, furyl, pyri- midyl, pyridyl, quinolyl, isoquinolyl, benzothia- zolyl, benzoxazolyl, thiazolyl, oxazolyl, isox- Le A 24 869 113 e 0 a 0 *0 a Oa a a. a a a S.. A a a. azolyL or isothiazoLyL which are opti’onaLLy sub- stituted by Lower alkyL, lower alkoxy, fLuorine, chlorine, bromine, trifLuoromethyL, dimethylamino or diethylamino, or represents a group of the formuLa -NR10R 1 wherein R and R are identical or different and denote hydrogen, lower aLkyL or phenyL and R represents hydrogen, or represents Lower aLkyL which is optionaLLy sub- stituted by cyano, fLuorine, chLorine or bromine, or represents phenyl, benzyL, thienyL, furyL, pyri- dyL, pyrimidyL, quinoLyL, isoquinoLyL, benzothia- zoLyL, benzoxazoLyL, thiazolyl, oxazoLyL, isoox- azolyl or isothiazoLyL which are optionaLLy sub- stituted by Lower alkyl, Lower aLkoxy, fLuorine, chLorine, bromine, trifLuoromethyL, dimethylamino or diethylamino, R denotes hydrogen, hydroxyl, amino, Lower aLkoxy or benzyLoxy, a denotes a number 1 to 8, b denotes a number 0 to 6, and X denotes a group of the formuLa -NR 12 R 13 -COR 14 15 16 -S 2 R 15 or -OR 16 where R and R 13 are identicaL or different and represent hydrogen, Lower aLkyL, phenyL or benzyL, where the radicaLs mentioned may be substituted by fLuorine, chLorine, bromine, Lower aLkyl, Low- er aLkoxy or trifLuoromethyL, or represent a group of the formuLa -COR 14 -S0 2 R 1 5 or -(CH2)c-NR 12 R 13 14 17 R 14 denotes an -NHR group, or Le A 24 869 114 denotes Lower aLkyL or ‘ower aLkoxy, or denotes phenyL, benzyL, benzyLoxy, thienyL, furyL, pyridyl, pyrimidyl, quinoLyl, isoquinoLyL, benzo- thiazoLyL, benzoxazoLyL, thiazoLyl, oxazolyL, isoxazoLyL.or isothiazoLyL, which are optionaLLy substituted by Lower alkyL, Lower alkoxy, fLuo- rine, chlorine bromine, trifLuoronethyL, di- methyLamino or diethyLamino, 15 R denotes cycLopropyL, cycLopentyl, cycLohexyL, or Lower aLkyL which is optionalLy substituted by cyano, fLuorine, chLorine, bromine, trifLuoro- methyL or Lower aLkoxycarbonyl., or denotes phenyL, naphthyL, benzyL, thienyL, furyL, pyriridyl, pyridyL, quinoLyL, isoquinoLyL, benzo- thiazoLyL, berzoxazoLyL, thiazotyL, oxazoLyL, isoxazoLyL or isothiazoLyL, which are optionally monosubstituted or poLysubstituted by Lower aLkyL, Lower aLkoxy, fLuorine, chlorine, bromine, trifluoromethyl, dimethyLamino or diethyLamino, the substituents being identicaL or different or denotes an -NR R 11group, where 10 11 R and R have the abovementioned meaning, R 16denotes hydrogen, lower aLkyl, phenyL or benzyl, R 17 denotes hydrogen, or Lower aLkyl which is optionalLy substituted by cyano, fLuorine, chLorine or bromine, or phenyl, benzyL, thienyL, furyL, pyridyL, pyrimi- dyL, quinoLyL, isoquinoLyL, benzothiazoLyL, benz- oxazolyl, thiazoLyL, oxazoLyl, isoxazolyL or iso- thiazolyL which are optionaLLy substituted by Lower aLkyL, Lower aLkoxy, fLuorine, chLorine, bromine, trifluoromethyL, dimethylamino or diethylamino, and c denotes number 1 to 6, Le A 24 869 -115- -1 or where R 12 and R1,together with the nitrogen atom, form a ring from the series comprising I2 IH 0 o r I .100 -(CH 2 )n S~ Oa a a. 4 a.. a a4 a* S a a a a’ a a at 8 I 4 a, *a a A a a. a a a a. a a~ *5 9* I a wh er e in n denotes a number 1 or 2, R 2 represents hydrogen or Lower aLkyL and Rrepresents Lower aLkyL, but where Rdoes not represent NH 2 whc-n R 2 and R3denote propyL, and the salts thereof. 3. 8-Substituted 2-aminotetraLins according to CLaims 1 and 2 wh er e in Rrepresents chLorine, bromine, cyano or represents a grou Ip of the formulai -NR 4 R 5 -COR 6 (CH2)a-X, OC-CH2)a-X or -CH=CH-(CH2)b-X, R4 and R5 are identicaL or different and denote hydrogen or Le A 24 869 116 i I_ e *a a *a a. a.. a. *i eae. a group of the formula -COR 7 or -S0 2 R 8 wherein 7 R represents hydrogen, or represents an -NHR 9 gr-oup, or represents methoxy, ethoxy, propoxy or isopropoxy, or represents phenyL, benzyl, benzyloxy, thienyL, furyl, pyridyL, pyrimidyL, quinolyL or isoquinoL- yL which are optionally substituted by methyl, methoxy, fluorine or chlorine, R 8 represents ethyl, propyl, isopropyl, butyl or isobutyl which are optionally substituted by fluorine, chLorine, methoxycarbonyl, ethoxycar- bonyl, propoxycarbonyL, isopropoxycarbonyl, but- oxycarbonyl or isobutoxycarbonyl, or represents phenyl, thienyl, furyl, pyridyl, pyri- midyl, quinolyl or isoquinolyl which are option- ally substituted by methyl, ethyl, propyl, iso- propyl, methoxy, ethoxy, propoxy or isopropoxy, fLuorine or chlorine or represents an -NR 10 R 1 1 group, wherein 10 11 R and R are identicaL or different and denote hydrogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl, and 9 R represents hydrogen, or represents methyl, ethyl, propyL, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl or isohexyl which are optionally substituted by fluorine or chLorine, or represents phenyl which may be substituted by fluorine, chlorine, methyl or methoxy, R 6 denotes hydrogen, hydroxyl, amino, methoxy, eth- oxy, propoxy, butoxy, isopropoxy or isobutoxy, a denotes a number 1 to 6, Le A 24 869 117 I_ b denotes a number 0 to 4, and X denotes a group of the formula -NR R 13 -COR 14 15 16 -SO 2 R or -OR, where 12 13 R 12 and R 13 are identical or different and represent hydrogen, methyl, ethyl, propyL, isopropyL, butyl, isobu;, or represent phenyl which is optionally substitu- ted by fluorine, chlorine, methyl or methoxy, or represent a -COR 1 4 -S0 2 R 15 or -(CH 2 s group R14 denotes hydrogen, or denotes an -NHR 17 group, or denotes methyL, ethyl, propyl, isopropyL, methoxy, ethoxy, propoxy, isopropoxy, or denotes phenyl, benzyl, benzyloxy, thienyl, furyl, pyridyl, pyrimidyl, quinolyl or iso- quinolyl which are optionally substituted by Smethyl, methoxy, fluorine or chlorine, R denotes methyl, ethyl, propyl, isopropyl, butyl or isobutyl which are optionally substi- tuted by fluorine, chlorine, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy- carbonyl, butoxycarbonyl or isobutoxycarbonyl, *or denotes phenyl, naphthyL, thienyl, furyl, pyridyl, pyrimidyl, quinolyl or isoquinolyl which are optionally monosubstituted or poly- I substituted by methyl, ethyl, propyl, isopropyl methoxy, fluorine or chlorine, the substituents being identical or different, or where 10 11 R and R have the abovementioned meaning, R 16 denotes hydrogen, methyl, ethyl, propyl, isopropyl, phenyl or benzyl, Le A 24 869 118 R 17 denotes hydrogen, or denotes methyl, ethyl, propyl, isopropyL, butyl, isobutyl, pentyl, isopentyl, hexyl or isohexyl which are optionally substituted by fluorine or chlorine, or denotes phenyl which may be substituted by fluorine, chlorine, methyl or methoxy, and n denotes a number 1 to 4, R 2 represents hydrogen, methyl, ethyl, propyl or isopropyL, and R 3 represents methyl, ethyl, propyL or isopropyl, Sbut where R does not denote NH 2 when R 2 and R 3 denote propyl, and the salts thereof. 4. 8-Substituted 2-aminotetralins according to Claims 1, 2 and 3, in which R represents chlorine, bromine, cyano, or represents a group of the formula -NR R -COR6 -(CH2)a-X, -0-(CH2)a-X or -CH=CH-(CH 2 )b-X, wherein R denotes hydrogen, R denotes a group of the formula -COR or -S0 2 R wherein 7 V. R represents hydrogen, or epresents an -NHR group, or represents methoxy or ethoxy, 8 R represents trifluoromethyl, phenyl, tolyl, or Srepresents an -NRO R 1 1 group, Swherein R 10 and R 1 are identical or different and denote hydrogen, methyl or ethyl, and 9 R represents hydrogen, or represents methyl, ethyl, propyl, isopropyl or butyl, or Le A 24 869 119 represents phenyL, R denotes hydrogen, hydrox;yl, amino, methoxy or ethoxy, a denotes a number 1 to 4, b denotes a number 0 to 2, and X denotes a group of the formula -NR12R13 -COR -S0 2 R 15 or -OR 1 6 where R and R are identical or different and represent hydrogen, methyl, ethyl or propyL, or 14 15 SD, o represent a -COR -S0 2 R 15 or -CHi2)cN 2 grOUp, 0 o R denotes hydrogen, or denotes an -NHR group, or denotes methyl, ethyl, propyL, methoxy or ethoxy, R 15 denotes trifLuoromethyl, methyl, ethyl, propyl, isopropyl, butyl or isobutyl, or denotes phenyl or naphthyl which are optionally monosubstituted or polysubstituted by methyl or chlorine, or denotes an -NR R 1 1 group, where 10 11 R i and R 1 1 have the abovementioned meaning, R 16 denotes hydrogen, methyl, ethyl or propyl, R 17 denotes hydrogen, or denotes methyl, ethyl, propyl, isoiropyL, butyl or isobutyl, or denotes phenyl, and c denotes a number 2 to 4, and R 2 and R 3 represent propyl, and the salts thereof. 5. 8-Substituted 2-aminotetralins of the formula (I) ^3 (I) R 1 Le A 24 869 120 S. S *5 S in which R represents halogen, cyano or represents a group of the formula -NR 4 R 5 -COR 6 -(CH2)a-X, -O-(CH 2 )a-X or -CH=CH-(CH 2 b-X, wherein R and R 5 are identical or different and denote hydrogen or a group of the formula -COR 7 or -SO 2 R where R represents hydrogen, or 9 represents an -NHR group, or represents aLkoxy, or represents aryL, aryLoxy, araLkyL, araLkoxy or heteroaryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyl, alkoxy, alkylthio, halogen, cyano, tri- fluoromethyl, trifluoromethoxy, trifLuoromethyl- thio, amino, alkylamin or dialkylamino, R represents cycloalkyL, or represents alkyL which may be substituted by cyano, halogen, trifluoromethyl, trifluoromethoxy or alkyloxycarbonyL, or represents aryl, aralkyL or heteroaryL, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyL, alkoxy, alkylthio, halnnen, cyano, trifLuoromethyl, tri- fluoromethoxy, trifluoromethyLthio, amino, alkyl- amino or dialkylamino, or represents an -NR 10 R 1 1 group, wherein R 10 and R 1 1 are identical or different and denote hydrogen, alkyL, aryl or aralkyl, and R represents hydrogen, or represents cycloalkyL, or represents alkyL which is optionally substituted Le A 24 869 121 S .0 0 4* 0 by cyano, halogen, trifluoromethyL or trifluoro- methoxy, or represents aryL, aralkyl or heteroaryL, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, tri- fluoromethoxy, trifluoromethylthio, amino, alkyL- amino or dialkylamino, R denotes hydrogen, hydroxyL, amino, alkoxy, aryloxy or aralkoxy, a denotes a number 1 to b denotes a number 0 to 8, and X denotes a group of the formuLa -NR 12 R 13 -COR 14 -SO 2 R15 or -OR 1 6 wherein 12 13 R 12 and R are identical 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 -SO 2 R 1 or -(CH2)c-NR12R 13 R denotes hydrogen, -r denotes an -NHR group, or denotes alkyL or alkoxy, or denotes aryL, aryloxy, aralkyl, aralkoxy or heteroaryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyl, alkoxy, alkylthi’o, halogen, cyano, tri- fluoromethyL, trifluoromethoxy, trifluoromethyl- thio, amind, alkyLamino or diaLkyLamino, 15 R denotes cycloalkyl, or denotes alkyl which may be substituted by cyano, halogen, trifLuoromethyl, trifluoromethoxy or alkoxycarbonyl, or Le A 24 869 122 denotes aryL, araky or heteroaryl, where the radicals mentioned may be up to trisubstituted, identicaLLy or differently, by aLkyL, aLkoxy, aLkyLthio, halogen, cyano, trifluoromethyl, tri- fluoromethoxy, trifluoromethyLthio, amino, aLkyL- amino or dialkylamino, or denotes an -NR1R 1 1 group, where R 10 and R 1 1 have the abovementioned meaning, R16 denotes hydrogen, alkyl, aryl, aralkyl, or a group of the formula -COR1OR11I 17 R 17 denotes hydrogen, or denotes cycloalkyl, or denotes alkyl which is optionaLLy substituted by cyano, halogen, trifluoromethyl or trifluoro- methoxy, or denotes aryL, araLkyL or heteroaryL, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyL, aLkoxy, aLkylthio, halogen, cyano, trifLuoromethyL, trifluoromethoxy, trifLuoromethyLthio, amino, aLkyLamino or dialkyLamino, and c denotes a number 1 to 8, or where R12 and R 13 together with the nitrogen atom, form V, a ring from the series comprising H2C-(CH H2C H2 I I 0 02 a. a 27J0. c~ 0so Le A 24 869 123 0=C -C 6 H o r -N N-A [:4CH2 In2n w h ere i n n denotes a number 1 or 2, and A represents hydrogen or cycLoaLkyL, o r represents aLkyL which may be substituted by halogen, hydroxyl, amino, aLkylamino, diaLkyL- amino, carbamoyL or suLphamoyL, o r represents aryl, heteroaryl, araLkyL, alkoxycar- bonyL, aLkyLsuLphonyL, phenyLsuiphonyL, toLyLsuL- phonyL, benzyLsuLphonyL, formyL, carbamoyl or s u I h;imoy 1, R 2 represents hydrogen or aLkyL, and R 3 represents aLkyL, but where Rdoes not denote NH 2 when Rand R3denote propyL, and the saLts thereof, for therapeutic use. 6. Process for the preparation of 8-haLogeno–amino- tetralins of the general formuLa .4 a a a. y2 Ia)I Le A 24 869 124 7 I I i I in which Y represents halogen or cyano, R2 represents hydrogen or alkyl, and R represents alkyL, and the saLts thereof, which is characterized in that 8-aminotetraLins of the general formula (II) I ,R2 S R3 (II) NH2 in which R and R 3 have the specified meaning, are reacted with nitrites in inert solvents in the presence of acids, ~e diazonium saLts obtained are then reacted with copper salts of the general formula (III) u CuY (III) 9 in which Y has the specified meaning, if appropriate in the presence of auxiliaries, and, in the case of the preparation of the salts, are re- acted with the appropriate acids, or in that CBJ tetralones of the general formula (IV) o. in which R 18 R 18 represents chlorine or bromine, Le A 24 869 125 I are initially reacted with amines of the general formula HN ,a3 a. a in which R 2 and R have the specified meaning, in inert solvents, if appropriate in the presence of auxiliaries, then the intermediates are reduced in inert solvents, then, if appropriate, halogen is exchanged for cyano, and then, in the case of the preparation of the salts, the products are reacted with the appropriate acids. 7. Proce’ss for the preparation of diaminotetralins of the general formula fR2 (Ib) T s 3 wherein 4 5 Z represents a group of the formula -NR R wherein R and R are identical or different and denote hydrogen, or a group of the formula -COR 7 or -S0 2 R 8 where 7′ R represents hydrogen, or represents alkoxy, or represents aryl, aryloxy, aralkyl, aralkoxy or heteroaryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyL, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoro- methoxy, trifluoromethylthio, amino, alkyl- amino or diaLkylamino, Le A 24 869 126 a. a a a a. a a. .a a w- I WIMMimm..0 and R represents cycLoalkyl, or represents aLkyL which may be substituted by cyano, halogen, trifLuoromethyL, trifluoro- methoxy or aLkoxycarbonyL, or represents aryL, araLkyL or heteroaryl, where the radicals mentioned may be up to trisubsti- tuted, identically or differently, by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoro- methyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino, or represents an -NR 10 R 1 1 group, wherein R and R 1 1 are identical or different a6d de- note hydrogen, alkyl, aryl or aralkyL, R represents hydrogen or alkyL, and R 3 represents alkyL, but where R does not denote NH 2 when 2 3 R and R denote propyL, and the salts thereof, which is characterized in that 8-aminotetraLins of the general formula S (II) .**NH in which R2 and R 3 have the abovementioned meaning, are reacted with acylating or sulphonating agents of the general formula 19 V-R (VI) in which Le A 24 869 -127 R 19 and represents a group of the formula -COR or -S0 2 R 8 V represents halogen, or represents the -OR 2 0 radical, wherein R has the same meaning as R 19 and can be identical to or different from the latter, in inert solvents, if appropriate in the presence of bases, and then, in the case of the preparation of the salts, the products are reacted with the appropriate acids. 8. Process for the preparation of 8-ureido-aminotetra- lins of the general formula NHCONHRS 9 (Ic) t. S S A in which R 2 represents hydrogen or alky!, R 3 represents alkyl and R 9 represents hydrogen, or represents cycloalkyl, or represents alkyl which is optionally substituted by cyano, halogen, trifluoromethyl cr trifluoromethoxy, or represents arfl, aralkyl or heteroaryl, where the radi- cals mentioned may be up to trisubstituted, identically or differently, by alkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoro- methylthio, amino, alkylamino or dialkylamino, and the salts thereof, which is characterized in that 8-aminotetralins of the general formula Le A 24 869 128 I Ii I IIX I Id 0- 1 .2 5 jjj .2 5 j j (II) NHz in which NH 2 R and R have the specified meaning, are reacted with isocyanates of the general formula R 9 N=C=O (VII) in which 9 R has the specified meaning, in inert solvents, if appropriate in the presence of bases, and then, in the case of the preparation of the salts, the products are reacted with the appropriate acids. 9. Process for the preparation of 8-acyL-aminotetra- Lins of the general formula 1 I2 COR 6 3 COR6′ (Id) 4* 4 I 4 0* in which 2 R represents hydrogen or alkyL, R represents alkyL and R 6 represents hydroxyl, amino, alkoxy, aryloxy or araLkoxy, and the salts thereof, which is characterized in that 8-cyanotetraLins of the general formula S 2 (VIII) PaC 3 in which CN R 2 and R have the abovementioned meaning, are hydrolized, and, in the case of the preparation of the carboxylates, the carboxylic acids obtained are esterified and, in the case of the preparation of the salts, reacted Le A 24 869 129 C I with the appropriate acids. Process for the preparation of 8-formyl-aminotetra- Lins of the general formula I ,eR2 e) in which w R represents hydrogen or aLkyL, and R represents alkyl, and the saLts thereof, which is characterized in tnat 8-halogen-substituted 2-aminotetraLins of the generaL for- mu La Hal (IX) S S 5** A S S. in which R and R 3 have the abovementioned meaning and Hal represents fLuorine, chLorine, bromine, iodine, pre- ferably chlorine or bromine, are reacted with magnesium and formamides of the generaL formula (X) R 2 1 N N-CHO R22, in which R21 and R 2 2 are identicaL or different and represent methyl, ethyl, propyL, phenyl or pyridyl, or 21 2 2 R and R together with the nitrogen atom, form a piperi- dine ring, in inert solvents, if appropriate in the presence of auxi- L i a r i e s, and then, in the case of the preparation of the salts, the products are reacted with the appropriate acids. Le A 24 869 130 I 0

97. 9* a 9* 49 0 0 9 0 11. Process for the preparation of 8-methylene-amino- tetralins of the general formuLa IR (If) N,,R3 CH 2 I in which X R2 represents hydrogen or aLkyL, R 3 represents aLkyl and X denotes a group of the formula -NR 12 R 13 -COR 14 -SO 2 R 15 or -OR 16 wherein R 12 and R 13 are identical 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 -S0 2 R 15 or -(CH2)c-NR 12 R 13 R 14 denotes hydrogen, or denotes an -NHR 17 group, or denotes aLkyl or alkoxy, or denotes aryl, aryloxy, araLkyL, aralkoxy or hetero- aryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyL, alkoxy, alkyLthio, halogen, cyano, trifLuoro- methyl, trifLuoromethoxy, trifluoromethyLthio, amino, alkylamino or dialkylamino, R denotes cycLoalkyL, or denotes alkyl which may be substituted by cyano, halogen, trifluoromethyL, trifLuoromethoxy or aLk- oxycarbonyl, or denotes aryL, aralkyL or heteroaryl, where the radicaLs mentioned may be up to trisubstituted, identicaLLy or differently, by aLkyL, aLkoxy, aLkyl- thio, halogen, cyano, trifLuoromethyL, trifLuoro- Le A 24 869 131 methoxy, trifLuoromethyLthio, amino, iLkyLamino or diaLkyLamino, or denotes an -NR 10 R 1 1 group, where R 10 and R 1 1 are identical or different and represent hydrogen, aLkyL, aryL or araLkyL, R16 denotes hydrogen, aLkyL, aryl, araLkyL or a group of the formuLa -COR 10 R 1 1 R 17 denotes hydrogen, or denotes cycLoaLkyL, or denotes aLkyL which is optionaLLy substituted by cyano, haLogen, trifluoromethyL or trifLuoromethoxy, Sor denotes aryL, araLkyL or heteroaryL, where the aryL radicaL may be up to trisubstituted, identicaL- Ly or differently, by alkyL, aLkoxy, aLkyLthio, haLogen, cyano, trifluoromethyL, trifLuoromethoxy, trifluoromethyLthio, amino, alkyLamino or dialkyL- amino, a m n and *4 ;n denotes a number 1 to 8, or where 12* 13 R and R 1 together with the nitrogen atom, form a ring from the series comprising 0 S0 0 O* -6H 5 I0 or -N N-A Le A 24 869 132 T wherein n denotes a number 1 or 2, and A represents hydrogen or cycloalkyL, or represents aLkyL which may be substituted by halo- gen, hydroxyL, amino, aLkyLamino, diaLkyLamino, carbamoyL or suLphamoyL, or represents aryL, heteroaryL, araLkyL, aLkoxycarbon- yL, aLkyLsuLphonyL, phenyLsulphonyL, toLyLsuLphonyl, benzyLsuLphonyL, formyL, carbamoyL or suLphamoyL, R 2 represents hydrogen or aLkyL, and R 3 represents aLkyL, but where R 1 does not denotes NH 2 when 2 3 R and R 3 denote propyL, and the salts thereof, which is characterized in that tetraLins of the generaL formula (XI) *9’r S S 0* S S. S S S S OS S. 0*S 9 5* 0 5 OS SS SI 0 5, S PS S S *0 S 1 0* 1 ~2~II\3 R23 (XI) in which R 2 represents hydrogen or aLkyL, R 3 represents aLkyL, and R represents a group of the formuLa -COR or -CN, wherein R 2 4 denotes hydrogen, hydroxyL, aLkoxy or amino, are reduced in inert soLvents, then, if appropriate, functionaL groups are converted into other functionaL groups by reduction, hydroLysis, oxidation Le A 24 869 133 -I I I 7 or reaction with electrophilic reagents, and then, in the case of the preparation of the salts, the products are re- acted with the appropriate acid. 12. Process for the prep.aration of 8-aLkyLene-amino- tetraLins of the general formula C’2 w3 (Ig) 9 *9 S 9 S *1 9 *9 S S S S. in which R 2 represents hydrogen or alkyL, R represents aLkyL, and W represents a group of the formuLa -(CH2)a’-X or -CH=CH-(CH 2 )b-X, wherein X denotes a group of the formuLa -NR 12 R 13 -COR 14 15 16 -S 2 R15 or -OR 16 wherein R12 and R 13 are identicaL 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 -COR14, -S0 2 R 1 or -(CH 2 )c-NR 2 R 13 R14 denotes hydrogen, or denotes an -NHR group, or denotes aLkyl or alkoxy, or denotes aryL, aryloxy, araLkyL, araLkoxy or heteroaryL, where the radicaLs mentioned may be up to trisubstituted, identicaLLy or different- Ly, by aLkyl, aLkoxy, aLkyLthio, haLogen, cyano, trifLuoromethyL, trifLuoromethoxy, trifluoro- methyLthio, amino, alkylamino or diaLkylamino, R denotes cycloalkyL, or Le A 24 869 134 denotes alkyl which may be substituted by cyano, halogen, trifluoromethyl, trifluoromethoxy or alkoxycarbonyl, or denotes aryl, araLkyL or heteroaryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyL, alkoxy, alkylthio, halogen, cyano, trifluoromethyl, tri- fluoromethoxy, trifluoromethylthio, amino, alkyl- amino or dialkylamino, or denotes an -NR 10 R 1 1 group, where R 10 and R 1 1 have the abovementioned meaning, R denotes hydrogen, alkyL, aryl, aralkyL or a 11 group of the formula -CONR1 R R denotes hydrogen, or denotes cycloalkyL, or denotes alkyl which is optionally substituted by cyano, halogen, trifluoromethyl or trifluoro- methoxy, or denotes aryl, aralkyL or heteroaryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyL, alkoxy, 0 alkylthio, halogen, cyano, trifluoromethyl, tri- «00» fluoromethoxy, trifluoromethylthio, amino, alkyl- amino or dialkylamino, and c denotes a number 1 to 8, or where 1 2 13 R and R together with the nitrogen atom, form a ring from the series comprising H 2 C-(CH 2 )n r H C It J C H 2 1* 0 0 0N 0 Le A 24 869 135 02 I-. ~-(CH 2 n ,H or -N N-A w he re i n n denotes a number 1 or 2, and A represents hydrogen or cycloaLkyL, o r represents alkyl which may be substituted by halogen, hydroxyl, amino, aLkyLamino, diaLkyL- amino, carbamoyl or suLphamoyL, or represents aryL, heteroaryl, araLkyL, aLkoxycar- bonyL, aLkyLsuLphonyL, phenyLsuLphonyL, tcLyL- suLphonyL, benzyLsuLphonyL, forn’yL, carbamoyl or suiphamoyL, and a’ denotes a number 2 to and b denotes a number 0 to 8, and the salts thereof, which is characterized in that 8-formyL–aminotetraLins of the general formula in which CHO R 2and R3have the specified meaning, Le A 24 869 -136 Ie ~T are reacted with phosphorus compounds of the general for- mula U-(CH 2 (XII) in which X’ has the meaning given for X, or represents nitro, a’ has the abovementioned meaning and U represents a group of the formula P(R 2 5 3 R 2 5 I 2 T- -P-R 2 6 II 0 OR 2 or -p-OR 2 6 II 0 0* i 4 where R 2 5 and R 2 6 are identical or different and denote alkyL or phenyl, and T denotes a halide anion, preferably chloride, bro- mide or iodide, in inert solvents in the presence of bases, then, if appropriate, functional groups are converted into other functional groups by reduction, hydrolysis, oxida- tion or reaction with electrophilic reagents, and then, in the case of the preparation of the salts, Lhe products are reacted with the appropriate acids. 13. Process for the preparation of 8-ethylene-amino- tetralins of the general formula ar Ih) Le A 24 869 137 in which R 2 represents hydrogen or aLkyL, R 3 represents hydrogen or alkyL and X denotes a group of the formuLa -NR 12 R 13 -COR 14 -S2 R 15 or -OR16 wherein R 1 2 and R 13 are identicaL or different and represent hydrogen, aLkyL, aryL o, araLkyL, where the aryL radicaLs may be substituted by haLogen, cyano, aLkyL, aLkoxy or trifLuoromethyL, or 14 represent a group of the formula -COR -S0 2 R or -(CH2)c-NR12R 3 R 14 denotes hydrogen, or denotes an -NHR 17 group, or denotes aLkyL or aLkoxy, or denotes aryL, aryloxy, araLkyL, aralkoxy or hetero- aryL, where the radicaLs mentioned may be up to trisubstituted, identicaLLy or differentLy, by aLkyL, aLkoxy, aLkyLthio, haLogen, cyano, trifluoro- methyL, trifLuoromethoxy, trifLuoromethylthio, Samino, aLkyLamino or diaLkylamino, R denotes cycLoaLkyL, or denotes aLkyL which may be substituted by cyano, halogen, trifLuoromethyL, trifluoromethoxy or alk- oxycarbonyL, or denotes aryL, araLkyl or heteroaryl, where the radi- caLs mentioned may be up to trisubstituted, identi- caLLy or differently, by aLkyl, alkoxy, aLkyLthio, halogen, cyano, trifLuoromethyL, trifluoromethoxy, trifLuoromethyLthio, amino, aLkylamino or dialkyl- amino, or denotes an -NR R 1 1 group, where 11 S* R 1 and R have the abovementioned meaning, 16 R 1 denotes hydrogen, alkyl, aryl, aralkyL or a group of the formuLa -CONR 10 R 1 1 Le A 24 869 138 I L, T R denotes hydrogen, or denotes cycloalkyL, or denotes alkyl which is optionally substituted by cyano, halogen, trifLuoromethyl or trifLuoromethoxy, or denotes aryl, araLkyL or heteroaryL, where the radicaLs mentioned may be up to trisubstituted, identicaLLy or differentLy, by aLkyL, aLkoxy, aLkyL- thio, halogen, cyano, trifluoromethyL, trifluoro- methoxy, trifLuoromethyLthio, amino, aLkyLamino or diaLkyLamino, and O c denotes a number 1 to 8, or where R 12 and R13, together with the nitrogen atom, form a ring from the series comprising H 2 C-(CH 2 )n 0 I I I o o o -N N-A Sdenotes a number 6 H or 2, oor 4 -N N-A wherein denotes a number 1 or 2, and Le A 24 869 139 A represents hydrogen or cycloalkyl, or represents aLkyL which may be substituted by halogen, hydroxyl, amino, aLkyLamino, diaLkyL- amino, carbamoyl or sulphamoyl, or represents aryl, heteroaryL, aralkyL, alkoxycar- bonyL, aLkylsuLphonyL, phenyLsulphonyl, tolylsul- phonyl, benzenesulphonyL, formyl, carbamoyl or suLphamoyL, and the salts thereof, which is characterized in that 8-formyL-aminotetraLins of the general formula (le) 2 3 (le) CHO in which R 2 and R have the abovementioned meaning, are reacted with CH-acidic compounds of the general formu- La (XIII) H 3 C-X’ (XIII) in which X’ has the meaning given for X, or represents nitro, in inert solvents, if appropriate ;n the presence of con- densation agents, S then, if appropriate, functional groups are converted into other functional groups by reduction, hydrolysis, oxida- tion or reaction with electrophilic reagents, and then, in the case of the preparation of the salts, the products are reacted with the appropriate acid. 14. Medicaments containing 8-substituted 2-aminotetra- Lins of the formuLa Le A 24 869 140 i I I I 9eR2 S S *5 S. S S S. S C in which R represents haLogen, cyano or represents a group of the formuLa -NR 4 R 5 -COR 6 -(CH2)a-X, -O-(CH2)a-X or -CH=CH-(CH 2 )b-X, wherein R and R 5 are identicaL or different and denote hydrogen or a group of the formuLa -COR 7 or -S0 2 R 8 where R represents hydrogen, or represents an -NHR 9 group, or represents aLkoxy, or represents aryL, aryloxy, aralkyL, araLkoxy or heteroaryL, where the radicaLs mentioned may be up to trisubstituted, identicaLLy or differentLy, by aLkyL, aLkoxy, aLkyLthio, halogen, cyano, tri- fLuoromethyL, trifluoromethoxy, trifLuoromethyL- thio, amino, aLkyLamino or diaLkyLamino, R 8 represents cycLoaLkyL, or represents aLkyL which may be substituted by cyano, haLogen, triftuoromethyL, trifLuoromethoxy or aLkyLoxycarbonyL, or represents aryL, araLkyL or heteroaryL, where the radicaLs mentioned may be up to trisubstituted, identicaLLy or differentLy, by aLkyL, alkoxy, aLkyLthio, haLogen, cyano, trifLuoromethyL, tri- fLuoromethoxy, trifLuoromethyLthio, amino, alkyL- amino or dialkyLamino, or Le A 24 869 141 _I represents an -NR10R11 group, wherein R and R 1 1 are identical or different and denote hydrogen, aLkyL, aryl or araLkyL, and R 9 represents hydrogen, or represents cycloalkyL, or represents alkyl which is optionally substituted by cyano, halogen, trifluoromethyl or trifluoro- methoxy, or represents aryl, aralkyl or heteroaryl, where the radicals mentioned may be up to trisubstituted, O identically or differently, by alkyL, alkoxy, alkylthio, halogen, cyano, trifLuoromethyl, tri- fLuoromethoxy, trifLuoromethyLthio, amino, alkyl- amino or dialkylamino, R 6 denotes hydrogen, hydroxyl, amino, alkoxy, aryloxy or aralkoxy, a denotes a number 1 to b denotes a number 0 to 8, and X denotes a group of the formula -NR 12 R 13 -COR 14 15 16 -SO 2 R5 or -OR 16 wherein ,12 13 «*12 and R are identical or different and represent hydrogen, alkyL, aryl or aralkyl, where 4 the aryl radicals may be substituted by halogen, cyano, alkyl, alkoxy or trifluoromethyl, or *14 represent a group of the formula -COR -S0 2 R or -(CH2)c-NR12R13 14 :R denotes hydrogen, or 17 denotes an -NHR group, or denotes alkyl or alkoxy, or g. denotes aryl, aryloxy, aralkyL, aralkoxy or heteroaryl, where the radicals mentioned may be Le A 24 869 142 up to trisubstituted, identicaLLy or differentLy, by aLkyl, alkoxy, alkyLthio, haLogen, cyano, tri- fLuoromethyl, trifLuoromethoxy, trifLuoromethyl- thio, amino, aLkyLamino or diaLkyLamino, R denotes cycLoaLkyL, or denotes alkyL which may be substituted by cyano, haLogen, trifLuoromethyL, trifLuoromethoxy or aLkoxycarbonyL, or denotes aryL, araLkyL or heteroaryL, where the radicals mentioned may be up to trisubstituted, identicaLLy or differently, by aLkyL, aLkoxy, aLkyLthio, halogen, cyano, trifLuoromethyL, tri- fLuoromethoxy, trifLuoromethyLthio, amino, aLkyL- amino or dialkyLamino, or d otes an -NR 10 R 1 1 group, where 10 11 R and R 1 1 have the abovementioned meaning, 16 R denotes hydrogen, alkyL, aryL, araLkyl, or a group of the formula -CONR 1 R 1 1 17 R denotes hydrogen, or denotes cycLoaLkyl, or denotes alkyl which is optionally substituted by cyano, halogen, trifluoromethyL or trifLuoro- methoxy, or denotes aryL, aralkyl or heteroaryL, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyl, alkoxy, alkyLthio, halogen, cy:no, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino, alkylamino or dialkylamino, and c denotes a number 1 to 8, or where 12 13 R and R together with the nitrogen atom, form a ring from the series comprising Le A 24 869 143 A 27 OIO £2XK H 2 -(cH 2 )n H 2 H 2 1 o 02 C 6 H i f;SCH2)n 1 jCH 2 )n or -N N-A S. S.. a. A S a a a wherein n denotes a number 1 or 2, and A represen-ts hydrogen or cycLoaLkyL, or represents aLkyL which may be substituted by haLogen, hydroxyL, amino, aLkyLamino, diaLkyL- amino, carbamoyL or suLphamoyL, or represents aryL, heteroaryL, araLkyl, alkoxycar- bonyL, aLkyLsuLphonyL, phenylsuiphonyL, toLyLsuL- phonyL, benzyLsuLphonyL, formyL, carbaroyl or suLphamoyL, R 2 represents hydrogen or alkyL, and R 3represents alkyL, but whore R 1doei not denote NH 2 when R 2 nd R denote propyL, and/or the saLts thereof. Medicaments according to CLaim 14 containing Le A 24 869 144 to 90% by weight of the 8-substituted 2-aminotetraLins and/or the salts thereof, relative to the total amount. 16. Use of 8-substituted 2-aminotetralins of the gene- ral formuLa 2 /R \R3 1 R *t44 S C. S. C C C.C4 S SC C C a. w C S C. a S *C S in which R represents halogen, cyano or represents a group of the formula -NR 4 R 5 -COR 6 -(CH2)a-X, (CH2)a-X or -CH=CH-(CH 2 )b-X, wherein R and R 5 are identical or different and denote hydrogen or 7 8 a group of the formula -COR or -SO 2 R where 7 R represents hydrogen, or 9 represents an -NHR group, or represents alkoxy, or represents aryL, aryloxy, aralkyl, aralkoxy or heteroaryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyL, alkoxy, alkylthio, halogen, cya tri- fluoromethyl, triiLuoromethoxy, trifluoromethyl- thio, amino, alkylamino or dialkylamino, 8 R represents cycloalkyL, or represents alkyL which may be substituted by cyano, halogen, trifluoromethyl, trifluoromethoxy or aLkyloxycarbonyL, or represents aryL, aralkyL or heteroaryl, where the radicals mentioned may be up to trisubstituted, identically or differently, by alkyL, alkoxy, alkylthio, halogen, cyano, trifluorometh.yl, tri- Le A 24 869 145 fluoromethoxy, trifLuoromethyLthio, amino, alkyL- amino or diaLkylamino, or represents an -NR10R 1 1 group, wherein R 10 and R 1 1 are identica or different and denote hydrogen, alkyl, aryL or araLkyL, and R represents hydrogen, or represents cycLoaLkyL, or represents aLkyl which is optionaLLy substituted by cyano, halogen, trifluoromethyl or trifLuoro- methoxy, or represents aryL, araLkyL or heteroaryL, where the radicaLs mentioned may be up to trisubstituted, identicaLLy or differentLy, by aLkyL, aLkoxy, aLkylthio, halogen, cyano, trifLuoromethyL, tri- fLuoromethoxy, trifLuoromethyLthio, amino, aLkyL- amino or diaLkyLamino, R 6 denotes hydrogen, hydroxyL, amino, alkoxy, aryLoxy or araLkoxy, a denotes a number 1 to b denotes a number 0 to 8, and X denotes a group of the formuLa -NR 1 R 13 -COR 14 -S0 2 R15 or -OR 16 g. wherein R 12 and R 13 are identicaL or different and represent hydrogen, aLkyL, aryL or araLkyL, where the aryL radicals may be substituted by haLogen, cyano, alkyl, aLkoxy or trifLuoromethyL, or 14 represent a group of the formula -COR -SO 2 R or -(CH2)c-NR 12 R 13 S °14 R denotes hydrogen, or *17 denotes an -NHR group, or denotes aLkyL or aLkoxy, or Le A 24 869 146 denotes aryL, aryLoxy, araLkyL, araLkoxy or heteroaryL, where the radicaLs mentioned may be up to trisubstituted, identicaLLy or differentLy, by aLkyL, aLkoxy, aLkyLthio, haLogen, cyano, tri- fLuoromethyL, trifLuoromethoxy, trifLuoromethyL- thio, amino, aLkyLamino or diaLkyLamino, R 15 denotes cycLoalkyL, or denotes aLkyL which may be substituted by cyano, halogen, trifluoromethyl, trifLuoromethoxy or aLkoxycarbonyL, or denotes aryL, araLkyL or heteroaryL, where the radicaLs mentioned may be up to trisubstituted, identicaLLy or differentLy, by aLkyL, aLkoxy, aLkyLthio, haLogen, cyano, trifLuoromethyL, tri- fluoromethoxy, trifLuoromethyLthio, amino, aLkyL- amino or diaLkyLamino, or denotes an -NR10R 11 group, where and R1 have the abovementioned meaning, R 16 denotes hydrogen, aLkyL, aryL, araLkyL, or 10 11 17 t’e group -COR R 1 1 R denotes hydrogen, or denotes cycLoaLkyL, or ~denotes aLkyL which is optionalty substituted by Y ,*cyano, haLogen, trifluofomethyL or trifLuoro- methoxy, or denotes aryl, araLkyL or heteroaryL, where the radicaLs mentioned may be up to trisubstituted, identicaLLy or differently, by aLkyL, aLkoxy, .4 aLkyLthio, haLogen, cyano, trifLuoromethyL, trifLuoromethoxy, trifLuoromethyLthio, amino, aLkyLamino or diaLkyLamino, and c denotes a number 1 to 8, or where 12 13 R1 and R1, together with the nitrogen atom, form a ring from the series comprising Le A 24 869 147 I H 2 CH 2 )nr I I 0 orl -N N-A @0 4 S S .5 0 0 50 4 @0 *be@ 0 0@ Sd 0 00 0* S 590 5* J 0B 0 00 *0 SB Be S S.. S 0@ 0 BO *S 05 0 S S S. w he re in n denotes a number 1 or 2, and A represents hydrogen or cycLoaLkyL, or represents aLkyt which may be substituted by haLogen, hydroxyL, amino, aLkyLamino, diaLkyL- amino, carbamoyL or suiphamoyL, or represents aryL, heteroaryL, araLkyL, aLkoxycar- bonyL, aLkyLsuiphonyL, phenyLsu~phonyL, toLyLsuL- phonyL, benzyLsuLphonyL, formyL, carbamoyL or suLphamoyL, R 2 represents hydrogen or aLkyL, and R 3represents aLkyL, but where Le A 24 869 148 i R does not denote NH 2 when R 2 and R denote propyL, and/or the salts thereof, for the preparation of medica- ments. 17. 8-substituted 2 -aminotetralins according to claim 1 substantially as herein described with reference to the Examples thereof. 18. A process for the preparation of 8-halogeno- aminotetralins according to claim 6 substantially as herein described with reference to the Examples thereof. DATED this 3rd day of June, 1991. S. S SSSS S S S. S BAYER AKTIENGESELLSCHAFT By Its Patent Attorneys ARTHUR S. CAVE CO. Le A 24 869 149

AU83029/87A
1986-12-22
1987-12-22
8-substituted 2-aminotetralins

Ceased

AU613884B2
(en)

Applications Claiming Priority (4)

Application Number
Priority Date
Filing Date
Title

DE3643899

1986-12-22

DE3643899

1986-12-22

DE3719924

1987-06-15

DE19873719924

DE3719924A1
(en)

1986-12-22
1987-06-15

8-SUBSTITUTED 2-AMINOTETRALINE

Publications (2)

Publication Number
Publication Date

AU8302987A

AU8302987A
(en)

1988-06-30

AU613884B2
true

AU613884B2
(en)

1991-08-15

Family
ID=25850693
Family Applications (1)

Application Number
Title
Priority Date
Filing Date

AU83029/87A
Ceased

AU613884B2
(en)

1986-12-22
1987-12-22
8-substituted 2-aminotetralins

Country Status (14)

Country
Link

US
(3)

US4873262A
(en)

EP
(1)

EP0272534A3
(en)

JP
(1)

JP2596956B2
(en)

KR
(1)

KR880007432A
(en)

CN
(1)

CN87101285A
(en)

AU
(1)

AU613884B2
(en)

DE
(1)

DE3719924A1
(en)

DK
(1)

DK675787A
(en)

FI
(1)

FI875598A
(en)

HU
(1)

HUT46653A
(en)

IL
(1)

IL84875A0
(en)

NO
(1)

NO167282C
(en)

NZ
(1)

NZ222977A
(en)

PT
(1)

PT86425B
(en)

Cited By (1)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

AU634366B2
(en)

*

1990-03-21
1993-02-18
Merrell Dow Pharmaceuticals Inc.
Novel 8-sulfamylmethylene-2-amino tetralins

Families Citing this family (52)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

US5177112A
(en)

*

1983-01-03
1993-01-05
Whitby Research, Inc.
Substituted 2-aminotetralins

DE3718317A1
(en)

*

1986-12-10
1988-06-16
Bayer Ag

SUBSTITUTED BASIC 2-AMINOTETRALINE

US4927955A
(en)

*

1987-08-12
1990-05-22
Sanofi
Process for the O-alkylation of N-(hydroxy)aralkylphenylethanolamines

DE3809155A1
(en)

*

1988-03-18
1989-09-28
Bayer Ag

1,3,4,5-TETRAHYDROBENZ- (C, D) indoles

CA1331191C
(en)

1988-03-25
1994-08-02
Bengt Ronny Andersson
Therapeutically useful tetralin derivatives

US5214156A
(en)

*

1988-03-25
1993-05-25
The Upjohn Company
Therapeutically useful tetralin derivatives

US5162375A
(en)

*

1988-05-06
1992-11-10
Beecham Group P.L.C.
Treatment of neuronal degeneration with 5HT1A agonists

GB8810748D0
(en)

*

1988-05-06
1988-06-08
Beecham Wuelfing Gmbh & Co Kg
Novel treatment

CA2026775C
(en)

*

1989-01-09
1998-04-07
Per Arvid Emil Carlsson
Halo substituted aminotetralins

US5225596A
(en)

*

1989-01-09
1993-07-06
The Upjohn Company
Halo substituted aminotetralins

IL109647A
(en)

*

1989-02-27
1997-04-15
Lilly Co Eli
Intermediate compounds for ring-substituted 2-amino-1, 2, 3, 4-tetra- hydronaphthalenes and 3-aminochromanes

CA1335106C
(en)

*

1989-02-27
1995-04-04
John Mehnert Schaus
Ring-substituted 2-amino-1,2,3,4-tetra-hydronaphthalenes

GB8907865D0
(en)

*

1989-04-07
1989-05-24
Wyeth John & Brother Ltd
Tetrahydroquinoline derivatives

SE8901889D0
(en)

*

1989-05-26
1989-05-26
Astra Ab

NOVEL 8-SUBSTITUTED-2-AMINOTETRALINES

DE69032725T2
(en)

*

1989-05-31
1999-04-08
Upjohn Co

CNS-active 8-heterocyclyl-2-aminotetralin derivatives

US5545755A
(en)

*

1989-05-31
1996-08-13
The Upjohn Company
Therapeutically useful 2-aminotetralin derivatives

DE3919624A1
(en)

*

1989-06-15
1990-12-20
Boehringer Ingelheim Kg

NEW 2,5-DIAMINOTETRALINE, METHOD FOR THE PRODUCTION THEREOF, AND ITS USE AS A MEDICAMENT

EP0482084B1
(en)

*

1989-07-13
1997-05-07
PHARMACIA & UPJOHN COMPANY
(1,2n) and (3,2n)-carbocyclic-2-amino tetralin derivatives

US5486611A
(en)

*

1989-07-13
1996-01-23
The Upjohn Company
Carboxamido-(1,2N)-carbocyclic-2-aminotetralin derivatives

DE3924365A1
(en)

*

1989-07-22
1991-01-24
Boehringer Ingelheim Kg

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

JPH05503517A
(en)

*

1989-12-18
1993-06-10
バージニア・コモンウェルス・ユニバーシティ

Sigma receptor ligand and its uses

US5420151A
(en)

*

1989-12-22
1995-05-30
Aktiebolaget Astra
Chroman derivatives

US5616610A
(en)

*

1989-12-22
1997-04-01
Astra Aktiebolag
(R)-5-carbamoyl-8-fluoro-3-N,N-disubstituted-amino-3,4-dihydro-2H-1-benzopyrans

US5194439A
(en)

*

1990-04-06
1993-03-16
John Wyeth & Brother Limited
N-(2,3-dihydro-1,4-benzodioxinyl)-N-substituted aminopyrido-fused cycloalkanes

US5258379A
(en)

*

1990-05-04
1993-11-02
Eli Lilly And Company
Method of inhibiting gastric acid secretion with n-arylpiperazines

US5096908A
(en)

*

1990-05-04
1992-03-17
Eli Lilly And Company
Method of inhibiting gastric acid secretion

US5340838A
(en)

*

1990-05-04
1994-08-23
Eli Lilly And Company
Method of inhibiting gastric acid secretion with 2-phenylcyclopropylamines

ATE149480T1
(en)

*

1990-08-15
1997-03-15
Lilly Co Eli

RING-SUBSTITUTED 2-AMINO-1,2,3,4-TETRA-HYDRONAPHTHALINES, 3-AMINOCHROMANES AND 3-AMINOTHIOCHROMANES

US5252586A
(en)

*

1990-09-28
1993-10-12
The Du Pont Merck Pharmaceutical Company
Ether derivatives of alkyl piperidines and pyrrolidines as antipsychotic agents

EP0712837B1
(en)

*

1991-02-08
2000-10-25
Eli Lilly And Company
Ring-substituted 2-amino-1,2,3,4-tetra-hydronaphthalenes and 3-aminochromanes

EP0586553A1
(en)

*

1991-05-20
1994-03-16
The Upjohn Company
Carboxamido-(3,2n)-carbocyclic-2-aminotetralin derivatives

WO1992020655A1
(en)

*

1991-05-20
1992-11-26
The Upjohn Company
Carboxamido-(1,2n)-carbocyclic-2-aminotetralin derivatives

CA2111957A1
(en)

*

1991-06-27
1993-01-07
Richard A. Glennon
Sigma receptor ligands and the use thereof

US5288749A
(en)

*

1991-12-20
1994-02-22
Abbott Laboratories
Tertiary and secondary amines as alpha-2 antagonists and serotonin uptake inhibitors

FR2686339B1
(en)

*

1992-01-22
1994-03-11
Adir Cie

NOVEL NAPHTHALENIC AMIDES AND SULFONAMIDES, PROCESSES FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.

US5194658A
(en)

*

1992-03-02
1993-03-16
The Dow Chemical Company
Process for making 2-amino-3-methyl-1-naphthalenecarbonitrile

EP0714292A4
(en)

*

1993-06-23
1996-10-09
Cambridge Neuroscience Inc
Sigma receptor ligands and the use thereof

GB9315566D0
(en)

*

1993-07-28
1993-09-08
Smithkline Beecham Plc
Medicaments

FR2711140B1
(en)

*

1993-10-12
1996-01-05
Sanofi Sa

1-Naphtylpyrazole-3-substituted carboxamides active on neurotensin, their preparation, pharmaceutical compositions containing them.

GB9420529D0
(en)

*

1994-10-12
1994-11-30
Pfizer Ltd
Indoles

US6025355A
(en)

*

1997-05-19
2000-02-15
Cambridge Neuroscience, Inc.
Pharmaceutically active compounds and methods of use

JP2000511529A
(en)

*

1996-05-31
2000-09-05
ファルマシア・アンド・アップジョン・カンパニー

Aryl-substituted cyclic amines as selective dopamine D3 ligands

US6242198B1
(en)

1996-07-25
2001-06-05
Cambridge Neuroscience, Inc.
Methods of treatment of eye trauma and disorders

US6756389B2
(en)

*

1996-08-09
2004-06-29
Cambridge Neuroscience, Inc.
Pharmaceutically active compounds and methods of use

WO1998048786A1
(en)

*

1997-04-30
1998-11-05
Eli Lilly And Company
AMINOTETRALINS AS 5-HT1Dα AGONISTS

US6355674B1
(en)

1997-04-30
2002-03-12
Eli Lilly And Company
Aminotetralins as 5-HT1D α Agonists

US20050032873A1
(en)

*

2003-07-30
2005-02-10
Wyeth
3-Amino chroman and 2-amino tetralin derivatives

US20100006191A1
(en)

*

2008-07-09
2010-01-14
Brush Wellman, Inc.
HIGH STRENGTH Be/Cu ALLOYS WITH IMPROVED ELECTRICAL CONDUCTIVITY

DE102010020553A1
(en)

2010-05-14
2011-11-17
Bayer Schering Pharma Aktiengesellschaft

Substituted 8-alkoxy-2-aminotetralin derivatives and their use

KR102137517B1
(en)

2012-07-20
2020-07-24
바이엘 파마 악티엔게젤샤프트
Novel 5-aminotetrahydroquinoline-2-carboxylic acids and use thereof

ES2603262T3
(en)

2012-07-20
2017-02-24
Bayer Pharma Aktiengesellschaft

Substituted aminoindane-carboxylic and aminotetralin-carboxylic acids and their use

JP6925080B2
(en)

2017-08-25
2021-08-25
▲広▼州市恒▲諾▼康医▲薬▼科技有限公司Ｇｕａｎｇｚｈｏｕ Ｈｅｎｏｖｃｏｍ Ｂｉｏｓｃｉｅｎｃｅ Ｃｏ．， Ｌｔｄ

Long-acting Lasagirin prodrug, its manufacturing method and applications

Citations (2)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

AU7619787A
(en)

*

1986-07-28
1988-02-04

Whitby Research, Inc.

Substituted 2-aminotetralins

AU8241787A
(en)

*

1986-12-10
1988-06-16

Bayer Aktiengesellschaft

Substituted basic 2-aminotetralins

Family Cites Families (6)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

DE2846691C2
(en)

*

1977-10-27
1983-11-10
Torii & Co., Ltd., Tokyo

Amino- or guanidino-1,2,3,4-tetrahydro-1-naphthoic acid esters, processes for their preparation and pharmaceuticals containing these compounds

DE2803582A1
(en)

*

1978-01-27
1979-08-02
Sandoz Ag
2-Amino-tetra:hydro-naphthol derivs. – used as adrenergic and dopamine receptor stimulants useful for treating heart failure, cardiac infarct, hypertension and Parkinsonism

SE8004002L
(en)

*

1980-05-29
1981-11-30
Arvidsson Folke Lars Erik

THERAPEUTICALLY APPLICABLE TETRALIN DERIVATIVES

DE3271003D1
(en)

*

1981-09-15
1986-06-12
Ici Plc
Amino-substituted tetralins and related homocyclic compounds

US4546107A
(en)

*

1982-09-07
1985-10-08
Yoshitomi Pharmaceutical Industries, Ltd.
1,4-Methano-2-benzazepine derivatives useful as cerebal dysfunction-improving drugs, anti-convulsant, anti-epileptic or anti-anxiety drugs

US4510157A
(en)

*

1982-12-27
1985-04-09
Ayerst, Mckenna & Harrison, Inc.
6,7,8,9-Tetrahydro-1H-benz(g)indol-8-amine derivatives

1987

1987-06-15
DE
DE19873719924
patent/DE3719924A1/en
not_active
Withdrawn

1987-12-01
NO
NO875005A
patent/NO167282C/en
unknown

1987-12-08
EP
EP87118112A
patent/EP0272534A3/en
not_active
Withdrawn

1987-12-15
US
US07/132,372
patent/US4873262A/en
not_active
Expired – Fee Related

1987-12-16
HU
HU875719A
patent/HUT46653A/en
unknown

1987-12-18
JP
JP62319089A
patent/JP2596956B2/en
not_active
Expired – Lifetime

1987-12-18
IL
IL84875A
patent/IL84875A0/en
unknown

1987-12-18
NZ
NZ222977A
patent/NZ222977A/en
unknown

1987-12-18
FI
FI875598A
patent/FI875598A/en
not_active
Application Discontinuation

1987-12-21
DK
DK675787A
patent/DK675787A/en
not_active
Application Discontinuation

1987-12-21
PT
PT86425A
patent/PT86425B/en
not_active
IP Right Cessation

1987-12-22
KR
KR1019870014682A
patent/KR880007432A/en
not_active
Application Discontinuation

1987-12-22
AU
AU83029/87A
patent/AU613884B2/en
not_active
Ceased

1987-12-22
CN
CN198787101285A
patent/CN87101285A/en
active
Pending

1989

1989-05-22
US
US07/354,950
patent/US4968679A/en
not_active
Expired – Fee Related

1990

1990-07-13
US
US07/553,294
patent/US5047422A/en
not_active
Expired – Fee Related

Patent Citations (2)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

AU7619787A
(en)

*

1986-07-28
1988-02-04
Whitby Research, Inc.
Substituted 2-aminotetralins

AU8241787A
(en)

*

1986-12-10
1988-06-16
Bayer Aktiengesellschaft
Substituted basic 2-aminotetralins

Cited By (1)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

AU634366B2
(en)

*

1990-03-21
1993-02-18
Merrell Dow Pharmaceuticals Inc.
Novel 8-sulfamylmethylene-2-amino tetralins

Also Published As

Publication number
Publication date

FI875598A
(en)

1988-06-23

JP2596956B2
(en)

1997-04-02

NO875005L
(en)

1988-06-23

DK675787A
(en)

1988-06-23

US4968679A
(en)

1990-11-06

US4873262A
(en)

1989-10-10

NZ222977A
(en)

1990-07-26

KR880007432A
(en)

1988-08-27

NO167282B
(en)

1991-07-15

DE3719924A1
(en)

1988-06-30

CN87101285A
(en)

1988-08-17

DK675787D0
(en)

1987-12-21

NO875005D0
(en)

1987-12-01

US5047422A
(en)

1991-09-10

PT86425A
(en)

1988-01-01

PT86425B
(en)

1990-11-20

IL84875A0
(en)

1988-06-30

EP0272534A2
(en)

1988-06-29

EP0272534A3
(en)

1989-07-26

AU8302987A
(en)

1988-06-30

HUT46653A
(en)

1988-11-28

FI875598A0
(en)

1987-12-18

JPS63190857A
(en)

1988-08-08

NO167282C
(en)

1991-10-23

Similar Documents

Publication
Publication Date
Title

AU613884B2
(en)

1991-08-15

8-substituted 2-aminotetralins

US5026857A
(en)

1991-06-25

Substituted basic 2-aminotetralin in pharmaceuticals

EP0729457B1
(en)

1998-12-23

Diaminocyclobutene-3,4-diones as smooth muscle relaxants

US20030153596A1
(en)

2003-08-14

Novel thiourea derivatives and the pharmaceutical compositions containing the same

JPS5989625A
(en)

1984-05-23

Aromatic substituted cyclic amidine obstipantia

US5506252A
(en)

1996-04-09

Substituted N-heteroaryl and N-aryl-1,2-diaminocyclobutene-3,4-diones

US4118417A
(en)

1978-10-03

Process for resolving cis-1-substituted phenyl-1,2-cyclopropanedicarboxylic acids

US5021438A
(en)

1991-06-04

1,3,4,5-tetrahydrobenz(c,d)indoles

JP3323420B2
(en)

2002-09-09

Benzimidazole derivatives

PL134491B1
(en)

1985-08-31

Process for preparing novel 2-guanidine-4-heteroarylothiazoles

CA1077488A
(en)

1980-05-13

Phenylethanolamines

JPH08268983A
(en)

1996-10-15

Aniline derivative useful/as intermediate

US4886898A
(en)

1989-12-12

Intermediates for circulation-active substituted aminomethyl-5,6,7,8-tetrahydronaphthyloxy-acetic acids

US5250540A
(en)

1993-10-05

Aminomethyl-substituted 2,3-dihydropyrano[2,3-b]pyridines and their use in medicaments

JP2661841B2
(en)

1997-10-08

Indoline derivatives

EP0585116B1
(en)

1996-02-28

1-Alkoxy-naphthalene-2-carboxamide derivatives with high affinity for the serotonin 5-HT1A receptor

EP0187509A2
(en)

1986-07-16

9-Aminoalkylfluorenes

JP2001502663A
(en)

2001-02-27

Method for producing substituted valinamide derivatives

HU202506B
(en)

1991-03-28

Process for producing benzoxazolone derivatives

EP0185368B1
(en)

1990-06-06

Aminobenzamide derivatives

US4904816A
(en)

1990-02-27

Process for the manufacture of anilinofumarate via chloromaleate or chlorofumarate or mixtures thereof

KR890000419B1
(en)

1989-03-17

Process for production of encanide

US4461728A
(en)

1984-07-24

Preparation of 4-phenyl-1,3-benzodiazepins

US4321398A
(en)

1982-03-23

Thienyl and benzothienyl-tertiary butylaminophenoxypropanols

SUGASAWA et al.

1939

Synthesis of Some 1, 2-Polymethylene-tetrahydro-isoquinolines

Download PDF in English