Method of treating disorders of the dopaminergic systems using 2,5-diaminotetralines

The invention relates to novel 2,5-diaminotetralines of the formula: ##STR1## wherein R1, R2, R3 and R4 are defined herein, processes for preparing them and their use in pharmaceutical compositions. The novel 2,5-diaminotetralines are useful in treating diseases caused by disorders of the dopaminergic systems.

1. DEFINITIONS 
The invention relates to new 2,5-diaminotetralines 
(2,5-diamino-1,2,3,4-tetrahydronaphthalines), the preparation thereof and 
their use as pharmaceutical compositions. The 2,5-diaminotetralines 
according to the invention correspond to general formula 1 
##STR2## 
wherein R.sup.1 represents hydrogen, C.sub.1-12 alkyl, C.sub.3-12 alkenyl, 
C.sub.3-12 alkynyl, --(CH.sub.2).sub.a -cycloalkyl, aralkyl and a 
represents one of the numbers 1,2,3,4,5,6,7,8,9,10,11,12; 
R.sup.2 represents C.sub.1-12 alkyl, C.sub.3-12 alkenyl, C.sub.3-12 
alkynyl, --(CH.sub.2).sub.b -cycloalkyl, 
##STR3## 
--(CH.sub.2).sub.h heteroaryl, acyl and 
b represents one of the numbers 1,2,3,4,5,6,7,8, 9,10,11,12, 
c represents one of the numbers 1,2,3,4,5,6,7,8 9,10,11,12, 
d represents one of the numbers 1,2,3,4,5,6, 
e represents one of the numbers 1,2,3, 
f represents one of the numbers 0,1,2,3,4, 
g represents one of the numbers 1,2,3,4,5,6, 
h represents one of the numbers 1,2,3,4,5,6,7,8 
9,10,11,12,13,14,15,16,17,18,19,20, and 
Y represents C.sub.1-12 alkyl, halogen, alkoxy or hydroxy; 
R.sup.3 represents hydrogen, C.sub.1-12 alkyl, C.sub.3-12 alkenyl, 
C.sub.3-12 alkynyl, --(CH.sub.2).sub.i -cycloalkyl, aralkyl, formyl, acyl, 
alkylcarbonyl, alkyloxycarbonyl, 
##STR4## 
R.sup.5 represents alkyl, R.sup.6 represents alkyl, 
R.sup.5 and R.sup.6 together with the nitrogen atom may also represent a 
heterocyclic group which may also contain another heteroatom (such as 
nitrogen, oxygen or sulphur), for example a morpholine, piperidine or 
piperazine ring and 
i represents one of the numbers 1,2,3,4,5,6,7,8 9,10,11,12; 
R.sup.4 represents hydrogen or C.sub.1-12 alkyl. 
Preferred compounds are the compounds of general formula 1 wherein 
R.sup.1 represents hydrogen, C.sub.1-6 alkyl, C.sub.3-6 alkenyl, C.sub.3-6 
alkynyl, --(CH.sub.2).sub.a -cycloalkyl, aralkyl carbon atoms in the 
aliphatic part and a represents one of the numbers 1,2,3,4,5,6; 
R.sup.2 represents C.sub.1-6 alkyl, C.sub.3-6 alkenyl, C.sub.3-6 alkynyl, 
--(CH.sub.2).sub.b -cycloalkyl, 
##STR5## 
acyl and b represents one of the numbers 1,2,3,4,5,6, 
c represents one of the numbers 1,2,3,4,5,6,7, 8,9,10, 
d represents one of the numbers 1,2,3, 
e represents one of the numbers 1,2, 
f represents one of the numbers 0,1,2, 
g represents one of the numbers 1,2,3,4, 
h represents one of the numbers 1,2,3,4,5,6,7, 8,9,10,12,13,14 and 
Y represents C.sub.1-6 alkyl, halogen, lower alkoxy or hydroxy, 
T represents oxygen, sulphur or nitrogen; 
R.sup.3 represents hydrogen, C.sub.1-6 alkyl, C.sub.3-6 alkenyl, C.sub.3-6 
alkynyl, --(CH.sub.2).sub.i -cycloalkyl, phenylalkyl, formyl, aryl, 
alkylcarbonyl, alkoxycarbonyl, 
##STR6## 
R.sup.5 represents lower alkyl, R.sup.6 represents lower alkyl, 
R.sup.5 and R.sup.6 together with the nitrogen atom may also form a 
heterocyclic group which may also contain a further heteroatom (such as 
nitrogen, oxygen or sulphur), for example a morpholine, piperidine or 
piperazine ring and 
i represents one of the numbers 1,2,3,4,5,6; 
R.sup.4 represents hydrogen or lower alkyl. 
Particularly preferred compounds are those of general formula I wherein 
R.sup.1 represents hydrogen, methyl, ethyl, propyl, allyl, propargyl, 
cyclopropylmethyl, benzyl; 
R.sup.2 represents methyl, ethyl, propyl, allyl, propargyl, 
cyclopropylmethyl, 
##STR7## 
acyl and c represents one of the numbers 1,2,3,4,5,6,7,8,9, 
g represents one of the numbers 2,3, 
h represents one of the numbers 1,2,3,4,5,6,7,8,9, 10,11,12, 
Y represents methyl, fluorine, chlorine, bromine, methoxy, hydroxy, 
T represents oxygen or sulphur; 
R.sup.3 represents hydrogen, methyl, ethyl, propyl, allyl, propargyl, 
cyclopropylmethyl, benzyl, phenylethyl, phenylpropyl, formyl, acyl, 
methylcarbonyl, ethylcarbonyl, trifluoromethylcarbonyl, methoxycarbonyl, 
aminocarbonyl; 
R.sup.4 represents hydrogen, methyl, ethyl, n-propyl and isopropyl. 
The 2,5-diaminotetralines according to the invention 
(2,5-diamino-1,2,3,4-tetrahydronaphthalines) contain at least one carbon 
atom with a centre of asymmetry and, depending on the pattern of 
substitution, may also have a plurality of centres of asymmetry and may 
therefore exist in various stereochemical forms. 
Examples include the following isomers of the substituted 
2,5-diaminotetralines of general formula 1a and 1b 
##STR8## 
The invention relates to the individual isomers, mixtures thereof and the 
corresponding physiologically acceptable acid addition salts with organic 
or inorganic acids. Preferred salts include, for example, salts obtained 
with hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic, 
ethanesulphonic, toluenesulphonic, benzenesulphonic, lactic, malonic, 
succinic, maleic, fumaric, malic, tartaric, citric or benzoic acid. 
Unless otherwise stated, the general definitions are used as follows: 
Alkyl generally represents a branched or unbranched hydrocarbon radical 
with 1 to 12 carbon atoms which may optionally be substituted with a 
halogen atom or several halogen atoms, preferably fluorine, which may be 
identical or different, the lower alkyl groups being preferred. Lower 
alkyl generally means a branched or unbranched hydrocarbon group with 1 to 
about 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, 
butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, 
isoheptyl, octyl and isooctyl. 
Alkenyl generally represents a straight-chained or branched hydrocarbon 
radical with 3 to 12 carbon atoms and with one or more, preferably one or 
two double bonds, which may optionally be substituted with a halogen atom 
or several halogen atoms, preferably fluorine, which may be identical or 
different. A lower alkenyl group with 3 to about 6 carbon atoms and one or 
two double bonds is preferred. An alkenyl group with 3 or 4 carbon atoms 
and one double bond is particularly preferred. Examples of this are allyl, 
propenyl, isopropenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, 
heptenyl, isoheptenyl, octenyl and isooctenyl. 
Alkynyl generally means a straight-chained or branched hydrocarbon group 
with 3 to 12 carbon atoms and with one or more, preferably one or two 
triple bonds. A lower alkynyl group with 3 to about 6 carbon atoms and one 
or two triple bonds is preferred, optionally substituted with a halogen 
atom or several halogen atoms which may be identical or different. An 
alkynyl group with 3 or 4 carbon atoms and one triple bond is particularly 
preferred. Examples include propargyl and but-2-ynyl. 
Cycloalkyl generally represents a saturated or unsaturated cyclic 
hydrocarbon group with 3 to 9 carbon atoms which may optionally be 
substituted by a halogen atom or several halogen atoms which may be 
identical or different. Cyclic hydrocarbons with 3 to 6 carbon atoms are 
preferred. Examples include cyclopropyl, cyclobutyl, cyclopentyl, 
cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, 
cycloheptadienyl and cyclooctyl, cyclooctenyl, cyclooctadienyl, 
cyclononynyl. 
Aralkyl generally represents an aryl group with 7 to 14 carbon atoms bound 
via an alkylene chain, wherein the aromatic group may be substituted by 
one or more lower alkyl groups, alkoxy groups, alkoxycarbonyl groups, 
hydroxy groups, cyano groups, nitro groups, amino groups and/or one or 
more halogen atoms (which may be identical or different). Aralkyl groups 
with 1 to 6 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in 
the aromatic part are preferred. The preferred aralkyl groups are: benzyl, 
naphthylmethyl, phenethyl and phenylpropyl. 
Alkoxy generally represents a straight-chained or branched hydrocarbon 
group with 1 to 12 carbon atoms bound via an oxygen atom. A lower alkoxy 
group with from 1 to about 6 carbon atoms is preferred. An alkoxy group 
with 1 to 4 carbon atoms is particularly preferred. Examples include 
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.-butoxy, 
pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or 
isooctoxy. 
Acyl generally represents benzoyl or alkylcarbonyl groups such as 
straight-chained or branched lower alkyl groups with 1 to about 6 carbon 
atoms which are bound via a carbonyl group, whilst the alkyl group may 
optionally be substituted by one or more halogen atoms which may be 
identical or different. Alkyl groups with up to 4 carbon atoms are 
preferred. Examples include: acetyl, trifluoroacetyl, ethylcarbonyl, 
propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl. 
Alkoxycarbonyl may be represented, for example, by the formula 
##STR9## 
Alkyl here represents a straight-chained or branched hydrocarbon group with 
1 to 12 carbon atoms. A lower alkoxycarbonyl group with 1 to 6 carbon 
atoms is preferred. An alkoxycarbonyl group with 1 to 4 carbon atoms in 
the alkyl group is particularly preferred. The following alkoxycarbonyl 
groups may be mentioned by way of example: methoxycarbonyl, 
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or 
isobutoxycarbonyl. 
Heteroaryl within the scope of the above definitions generally represents a 
5- to 6-membered ring which may contain oxygen, sulphur and/or nitrogen as 
heteroatoms and which may have a further aromatic ring fused thereon. 5- 
and 6-membered aromatic rings which contain an oxygen, a sulphur and/or up 
to two nitrogen atoms and which are optionally benzofused are preferred. 
Examples of particular heteroaryl groups include thienyl, furyl, pyridyl, 
pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, 
quinoxalyl, thiazolyl, benzothiazolyl, isothiazolyl, oxazolyl, 
benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl and 
indolyl. 
Unless otherwise stated, halogen represents fluorine, chlorine or bromine 
and, to a lesser extent, iodine. 
2. Pharmacological properties 
The new compounds of general formula 1 and the pharmacologically acceptable 
acid addition salts thereof embody centrally active dopamine agonists. 
Depending on their individual chemical structures they exhibit different 
selectivities for morphologically and/or functionally differentiated 
dopamine receptors and various activity profiles resulting from them. They 
can therefore be used therapeutically in the treatment of various diseases 
caused by disorders of the dopaminergic systems, e.g. for the treatment of 
schizophrenia, Parkinson's disease, prolactin hyperfunction and high blood 
pressure. 
It has proved particularly valuable to use compounds or hydrochlorides 
thereof of general formula 1 wherein R.sup.1 and R.sup.2 independently of 
each other represent hydrogen (with the exception of R.sup.2), methyl, 
ethyl, propyl, phenyl, benzyl, phenethyl, phenylpropyl or a heteroaryl 
group bound via an alkyl chain with 1 to 5 carbon atoms, with furan, 
thiophene, pyridine and indole being preferred heterocycles and R.sup.3 
representing hydrogen, methyl or acetyl and R.sup.4 representing hydrogen. 
The following compounds have proved particularly valuable as 
enantiomerically pure substances and also in the form of mixtures or 
racemates or the pharmacologically active salts thereof: 
A: (.+-.)-5-amino-2-(3-phenylpropyl-amino)-tetraline 
B: (.+-.)-5-amino-2-[N-(3-phenylpropyl)-N-n-propylamino]-tetraline 
C: (.+-.)-5-amino-2-(4-phenylbutyl-amino)-tetraline 
D: (.+-.)-5-amino-2-[N-(4-phenylbutyl)-N-n-propyl-amino]-tetraline 
2.1 Determining the inhibition of dopamine synthesis 
The procedure followed is that of J. R. Walters and R. H. Roth 
[Naunyn--Schmiedeberg's Arch. Pharmacol. 296, (1976) 5]: five animals are 
each given 10 mg/kg s.c. of the test substance. After 5 minutes they are 
given 750 mg/kg i.p. of .gamma.-butyrolactone in order to rule out the 
influence of post-synaptic feedback loops on the dopamine synthesis rate 
by blocking the pre-synaptic impulse connection. The administration of 
.gamma.-butyrolactone results in a substantial increase in the synthesis 
of DOPA or dopamine. In order to inhibit the decarboxylation of DOPA, 200 
mg/kg of 3-hydroxybenzylhydrazine hydrochloride are administered by 
intraperitoneal route after a further 5 minutes. 40 minutes after the 
substance has been administered the animals are killed and the Corpus 
striatum is dissected out. The DOPA-content is measured using HPLC with 
electrochemical detection (standard: dihydroxybenzylamine). 
The percentage inhibition, brought about by the test substance, in the 
DOPA-accumulation stimulated by .gamma.-butyrolactone is determined by 
comparison with the control animals treated with 0.9% saline solution. 
The results of this test are assembled in the following Table: 
______________________________________ 
Inhibition of dopa-accumu- 
lation in % compared with 
Dose the control animals 
Substance (mg/kg s.c.) 
treated with saline 
______________________________________ 
A 10 45.5 
B 10 63.5 
______________________________________ 
3. Method of preparation 
The compounds of general formula 1 can be prepared by various methods known 
per se. The methods listed in the reaction plan (page 13) are preferred. 
The key compounds are 5-amino-2-tetralones (2) which may be prepared for 
example analogously to the 5-acetylamino compound ((2), --Z=--COCH.sub.3) 
(J. W. Cornforth et al., J. Chem. Soc. 1955, 3348). 
##STR10## 
--Z is an acid group which may be retained if it has the meaning acyl 
given in the general formula 1 for --R.sup.3. However, it may also act as 
a precursor --CO--R.sup.7 which is converted into one of the substituents 
--R.sup.3 or --R.sup.4 defined in general formula 1. Finally, it may also 
have the function of a protective group [T. W. Greene, Protective Groups 
in Organic Synthesis, John Wiley and Sons, New York 1981], which are split 
off again in the course of the synthesis of compounds of general formula 1 
and are replaced by --H. 
The compounds of general formula 1 are chiral substances which may occur in 
racemic (.+-.)-forms or in enantiomerically pure form as (+)- and 
(-)-forms. The latter are obtained by stereoselective synthesis, racemate 
resolution of intermediate products or racemate resolution of racemic 
substances of general formula 1. 
The compounds of general formula 1 are isolated and purified by methods 
known per se and crystallised as bases or with therapeutically acceptable 
acids in the form of acid addition compounds. 
The individual methods or reaction steps specified in the reaction plan on 
page 13 are explained hereinafter and supported by the Examples in Section 
4. 
3.1 2-Amino-5-Z-amino-tetralines (13), (3) and (4) from corresponding 
5-Z-amino-2-tetralones (2) 
By reductive amination of 5-Z-amino-2-tetralones (2) with ammonia or the 
relevant primary or secondary amines, the desired compounds (13), (3) or 
(4) are obtained via intermediate ketimines, Schiff bases or enamines. The 
intermediate products can be isolated then hydrogenated or reduced to form 
the end products. It is simpler to carry out both steps in a one-pot 
process. 
The intermediate compounds are formed in suitable solvents, preferably in 
the presence of a catalyst and an agent which dries the reaction. Suitable 
solvents include all inert organic solvents which remain unchanged or at 
least substantially unchanged under the reaction conditions used and do 
not interfere with the progress of the reaction. These include amides such 
as dimethylformamide or hexamethyl phosphoric acid triamide or esters such 
as methyl acetate or ethyl acetate or ethers such as diethylether, 
tert.-butylmethylether, din-butylether, glycoldimethylether (glyme), 
diglycolide methylether (diglyme), tetrahydrofuran and dioxan, and 
preferably alcohols, especially methanol and ethanol. These and other 
solvents may be used in the form of mixtures. The starting compounds are 
preferably reacted in solution but may also be brought to reaction in 
suspension. Suitable catalysts are acids, especially protonic acids. These 
preferably include inorganic acids such as hydrochloric, phosphoric or 
sulphuric acid or organic acids with from 1 to 6 carbon atoms which may 
optionally be substituted by fluorine, chlorine and/or bromine. Examples 
of these acids are formic, acetic, trifluoroacetic, trichloroacetic or 
propionic acid. The preferred acids also include sulphonic acids with 
C.sub.1-4 alkyl groups or aryl groups which may optionally be substituted 
by halogens, such as methanesulphonic acid, trifluoromethanesulphonic 
acid, ethanesulphonic acid, benzenesulphonic acid or toluenesulphonic 
acid. Hydrochloric and hydrobromic acid are particularly preferred. These 
acids may be used in catalytic amounts, but it is preferable to use 
equivalent quantities or an excess. It is advantageous to eliminate the 
water which forms during the reaction from the equilibrium e.g. by 
distilling or by the addition of drying agents such as phosphorus 
pentoxide or preferably molecular sieves. The reaction may be carried out 
within a wide temperature range which in practice is limited at the lower 
end by an insufficient reaction speed and at the upper end by the 
predominance of subsidiary reactions. A favourable range is between 
0.degree. and 100.degree. C., preferably between 20.degree. and 50.degree. 
C. The reaction is usually carried out under normal pressure but it is 
also possible to work at higher or lower pressures. The reactants are used 
in equimolar quantities but, depending on the reactants used, it is 
favourable to have an excess of the amine component, preferably up to a 
5-fold excess. 
The further reaction of the intermediates is carried out for example by 
catalytic hydrogenation in suitable solvents, preferably in methanol or 
ethanol. However, it is also possible to use other solvents such as 
carboxylic acids, ethers and the like as well as mixtures of solvents. 
Examples of suitable catalysts are the known hydrogenation catalysts, e.g. 
those based on palladium, platinum or nickel. For reduction with hydrogen, 
the reaction is carried out under the reaction conditions known for 
catalytic hydrogenation, depending on the catalysts, solvents and 
reactants used in each particular case [K. Harada in Patai, "The Chemistry 
of the Carbon-Nitrogen Double Bond", Interscience Publishers, London 1970, 
page 276 and cited literature; P. N. Rylander, Catalytic Hydrogenation 
over Platinum Metals, Academic Press, New York 1967, page 123; F. Moller 
and R. Schroter in Houben-Weyl, Methoden der organischen Chemie, Volume 
XI/1, Georg Thieme Verlag, Stuttgart 1957, p. 602; W. S. Emerson, Org. 
Reactions 4 (1949) 174; E. M. Hancock and A. C. Cope, Org. Synth., Coll. 
Vol. III (1955) 501; J. C. Robinson and H. R. Snyder, Org. Synth., Coll, 
Vol. III (1955) 717; D. M. Malcolm and C. R. Noller, Org. Synth., Coll. 
Vol. IV (1963) 603]. It is particularly preferred to carry out 
hydrogenation with palladium on charcoal (containing 10% palladium) in 
methanol. As a rule, hydrogenation can be successfully carried out at 
normal pressure and ambient temperature. However, these parameters may be 
varied. Preferably, the pressures used are from 1 to 5 bar and the 
temperatures used are between 0.degree. and 100.degree. C. and more 
particularly 20.degree. to 50.degree. C. Alternatively, the intermediate 
products may also be reduced by other methods. It is preferable to use for 
this purpose complex hydrides, particularly those of aluminium or boron 
such as lithium aluminium hydride, sodium borohydride and especially 
sodium cyanoborohydride. The work is carried out in solvents which are 
suitable for the hydrides in question, e.g., in the case of lithium 
aluminium hydride, in ethers such as diethylether or tetrahydrofuran, or 
in the case of sodium borohydride and sodium cyanoborohydride, in water or 
alcohols, preferably methanol or ethanol. Reduction with complex hydrides 
may be catalysed in known manner, especially with protonic acids and 
preferably with the acids used to form the intermediate products, when the 
one-pot method is used. The reaction temperature may vary within wide 
limits, which are defined in practice by an insufficient reaction speed, 
at the lower end, and by the predominance of subsidiary reactions, at the 
other end. It is preferred to use temperatures within the range from 
-50.degree. to +150.degree. C., particularly from 0.degree. to 75.degree. 
C. As a rule, calculated quantities of the reducing agents are required; 
however, an excess preferably from 10 to 25% may prove advantageous. 
If the substituent --Z has the definition of --R.sup.3 =acyl, as defined in 
general formula 1, the end products (3) and (4) obtained correspond to the 
substances claimed. If --Z has one of the other meanings defined in 
general formula 1, there is subsequent conversion of --Z into --R.sup.3 or 
--R.sup.4 (see the reaction plan on page 13). 
3.2 2,5-Diamino-tetralines (5) and (6) by cleaving the corresponding 
Z-derivatives (4) and (5) 
Numerous methods of splitting off Z--where Z has the meanings given for 
R.sup.3 with the exception of acyl-- are known from the prior art [T. W. 
Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New 
York 198I and cited literature]. 
This cleavage is most easily carried out by acid or alkaline hydrolysis. 
For acid hydrolysis, it is preferred to use strong inorganic acids such as 
sulphuric acid, hydrohalic acid such as hydrobromic acid and preferably 
hydrochloric acid in an aqueous, alcoholic or aqueous-alcoholic solution. 
Boiling in constantly boiling hydrochloric acid (about 6 N HCl) or in 
aqueous-ethanolic hydrochloric acid is a particularly simple and well 
tried method. It is also possible to work at higher or lower temperatures, 
the range of which is limited in practice by an insufficient reaction 
speed, at the lower end, and by a predominance of secondary reactions, at 
the other end. 
For alkaline hydrolysis, it is expedient to use strong bases such as alkali 
or alkaline earth hydroxides, preferably potassium, sodium or barium 
hydroxide, in an aqueous, alcoholic or aqueous-alcoholic solution. In 
order to be able to perform the reaction at higher temperatures--which may 
be necessary under certain circumstances--it may be carried out in glycol 
or in diglycol. The reaction temperature may vary within wide limits, 
which are defined by an insufficient reaction speed, at the lower end, and 
by the predominance of secondary reactions, at the upper end. The 
temperature is expediently within the range from 0.degree. to 200.degree. 
C. and preferably between 50.degree. and 150.degree. C. 
3.3 2-Alkylamino- and 2-dialkylamino-5-Z-aminotetralines (3) and (4) by 
alkylation of 2-amino-5-Z-amino-tetralines (13) and (3) 
The methods of alkylation which may be used include reductive amination of 
aldehydes or ketones with the amines (13) or (3). 
The same basic method is used as in Section 3.1. For reductive amination of 
formaldehyde resulting in N-methyl derivatives of (3) or (4), there is 
also the Leukart-Wallach reaction in which formic acid acts as a reducing 
agent. The reaction conditions for reductive amination of this kind are 
known [Autorenkolektiv, Organikum, VEB Deutscher Verlag der 
Wissenschaften, Berlin 1986 (16th Edition) p. 491; C. Ferri, Reaktionen 
der organischen Synthese, Georg Thieme Verlag, Stuttgart 1978, p. 133 and 
cited literature; F. Moller and R. Schroter in Houben-Weyl, Methoden der 
organischen Chemie, Volume XI/1, Georg Thieme Verlag, Stuttgart 1957, p. 
648]. 
Alternatively, the primary or secondary 2-amino compounds (13) and (3) are 
reacted with alkylating agents R.sup.1 X or R.sup.2 X. X represents a 
leaving group which leaves as an anion X.sup.-, such as for example X=Cl, 
Br, I, O--SO.sub.2 --OR, O--SO.sub.2 --CH.sub.3, O--SO.sub.2 --C.sub.6 
H.sub.5 or O--SO--C.sub.6 H.sub.4 --CH.sub.3. The alkylating agent is used 
in calculated quantities or in an excess, preferably from 10 to 25%, and 
the reaction is expediently carried out in a suitable solvent or mixture 
of solvents. Examples of suitable solvents are alcohols, ethers or 
halogenated, preferably chlorinated, hydrocarbons. Methanol, ethanol, 
tetrahydrofuran and dimethylformamide are preferred. Mixtures of 
dimethylformamide and tetrahydrofuran have proved particularly suitable. 
In order to achieve complete reaction, it is generally necessary to add an 
acid binding agent such as potassium carbonate or potassium hydrogen 
carbonate, sodium carbonate, lithium carbonate, calcium carbonate, and 
preferably sodium hydrogen carbonate. The reaction temperature may be 
varied within wide limits which are defined in practice by an insufficient 
reaction speed, at the lower end, and a predominance of secondary 
reaction, at the upper end. The temperatures used in practice range 
between 0.degree. and 200.degree. C., preferably between 50.degree. and 
150.degree. C. 
If the substituent --Z has the definition of --R.sup.3 =acyl, as defined 
for general formula 1, the compounds (3) and (4) obtained correspond to 
the substances claimed in general formula 1. If --Z has one of the other 
meanings given under 3, there will be a subsequent conversion of --Z into 
--R.sup.3 or --R.sup.4 (see the reaction plan on p. 13). 
3.4 2-Alkylamino-5-Z-amino-tetralines (3) by dealkylation of 
2-dialkylamino-5-Z-amino-tetralines (4) 
Tertiary amides can be dealkylated to secondary amines by various methods. 
Demethylation and debenzylation are of particular preparative value. 
For demethylation, numerous reagents are known, of which bromocyanogen, 
phosgene, chloroformic acid esters and related substances are of 
particular importance in laboratory practice. The manner in which the 
reactions are carried out will depend on the nature of the demethylating 
agent. 
Dealkylation in the form of catalytic debenzylation is of considerable 
practical value [see also T. W. Greene, Protective Groups in Organic 
Synthesis, John Wiley and Sons, New York 1981 and literature cited 
therein]. The work is expediently done in solvents such as water, 
alcohols, acetic acid or mixtures thereof. However, other solvents are 
also suitable. Typical debenzylation catalysts are used, based on 
palladium, platinum or nickel, for example. As a rule, the reaction is 
carried out at ambient temperature under normal pressure. However, in 
certain circumstances, somewhat higher temperatures and pressures may have 
a favourable effect on the course of the reaction. The temperature may be 
up to 100.degree. C. and the pressure up to 10 bar, but generally 
pressures of 20.degree. to 50.degree. C. and pressures of 1 to 5 bar are 
preferred. 
If, in the dealkylation product (3), the substituent --Z has the meaning 
--R.sup.3 =acyl as defined for general formula 1, these products will 
correspond to the substances claimed in general formula 1. If on the other 
hand --Z has one of the other meanings given for R.sup.3 or R.sup.4, there 
will be subsequent conversion of --Z into --R.sup.3 or --R.sup.4 (see the 
reaction plan on page 13). 
3.5 5-Amino-(2-alkylamino- and 2-dialkylamino)tetralines (6) and (5) by 
reduction of 2-acylamino precursors (15) and (8) 
The starting compounds (15) and (8) may be prepared as follows, for example 
(see the reaction plan on page 13): 2-amino-5-Z-amino-tetralines (13) and 
(3), obtained by the method described in 3.1, are modified at the 
2-amino-nitrogen to form corresponding 2-acylamino derivatives (14) and 
(7), respectively. After selective cleavage of --Z, the latter yield the 
compounds (15) and (8). In these starting compounds (15) and (8), the acyl 
groups --COR.sup.8 at the 2-amino function are such that the 
N-substituents --R.sup.1 or --R.sup.2 obtained therefrom by reduction 
correspond to the definition given in general formula 1. 
The reaction of compounds (15) and (8) to obtain the corresponding 
compounds (6) and (5) is carried out by means of reducing agents. These 
reductions of acid amides are known from the prior art and may be carried 
out using the method of electrochemical reduction, by reduction with 
alkali metals or by catalytic reduction [R. Schroter in Houben-Weyl, 
Methoden der organischen Chemie, Volume XI/1, Georg Thieme Verlag, 
Stuttgart 1957, p. 574] or with diborane or hydrogen boride derivatives 
[J. Fuhrhop and G. Penzlin, Organic Synthesis--Concepts--Methods--Starting 
Materials, published by VCH of Weinheim 1986, p. 90]. Of the methods 
available for this purpose, reduction with complex hydrides is 
particularly suitable in practice. Complex hydrides of aluminium and boron 
are preferred, and lithium aluminium hydride is particularly preferred. 
The reactions are carried out in suitable inert solvents which will depend 
on the nature of the hydride. Reactions with lithium aluminium hydride are 
preferably carried out in ethers, e.g. diethylether, diisopropylether and, 
particularly, in tetrahydrofuran, optionally in the presence of a 
catalyst. [N. G. Gaylord, Reduction with Complex Metal Hydrides, Wiley 
N.Y. 1965; A. Hajos, Complex Hydrides, Elsevier N.Y. 1979; V. Bazant, M. 
Capka, M. Cerny, V. Chvalovsky, K. Kochloefl, M. Kraus and J. Malek, 
Tetrahedron Lett. 9 (1968) 3303]. As a rule, it is favourable to use an 
excess of the hydride over and above the calculated quantity and this 
excess is between 5 and 100%, preferably between 10 and 50% of the 
calculated quantity. The reactants are usually combined whilst being 
cooled with ice and are then heated. The temperatures are variable within 
wide limits and are limited in practice by an insufficient reaction speed, 
at the lower end of the range, and by the predominance of secondary 
reactions, at the upper end of the range. 
3.6 2-Alkylamino- and 2-dialkylamino-5-alkylaminotetralines (12) and (9) by 
reduction of 5-Z-amino precursors (3) and (4) 
Compounds (12) and (9) according to the invention are obtained by reduction 
from compounds (3) and (4) if the substituents --Z are such 
(--Z=--COR.sup.7) that when reacted they are converted into substituents 
--R.sup.3 or --R.sup.4 as claimed in general formula 1. Otherwise, the 
procedure is as specified in the preceding paragraph 3.5. 
3.7 5-Z-(N-alkylamino)-2-dialkylamino-tetralines (10) and (16) by 
amide-alkylation of 5-Z-amino-2-dialkylamino-tetralines (4) and (3) 
The starting compounds are the substances (4) and (3) wherein --NH--Z 
represents an amide group. For selective alkylation on the amide nitrogen, 
salts of the amide function are expediently used. Suitable salts include, 
in particular, the alkali metal salt, preferably sodium salts, which are 
formed, for example, when sodium hydride or sodium amide reacts with 
compounds (4) and (3). These salts can be isolated before the alkylation 
step. It is simpler to produce them and alkylate them in situ in suitable 
solvents. Examples of reaction media which may be used for this purpose 
include ethers such as glycolide methylether (glyme), diglycolide 
methylether (diglyme) and preferably tetrahydrofuran or sulphoxides such 
as dimethylsulphoxide or acid amides, of which dimethylformamide is 
particularly preferred [G. Spielberger in Houben-Weyl, Methoden der 
organischen Chemie, Georg Thieme Verlag, Stuttgart 1957, p. 96; W. F. 
Fone, J. Org. Chem. 14 (1949) 1099; R. A. W. Johnstone, D. W. Payling and 
C. Thomas, J. Chem. Soc. [C] 1969, 2223]. 
For alkylation, alkylating agents R.sup.3 --X are used and the procedure 
used is as described in Section 3.3. The reaction will take place at 
ambient temperature but may also be carried out at lower temperatures 
provided that acceptable reaction speeds are achieved, or at higher 
temperatures provided that no disruptive secondary reactions occur. A 
temperature range from -25.degree. to +150.degree. C. is preferred, whilst 
it is particularly preferable to work at a temperature in the range from 
0.degree. to 75.degree. C. 
If in the reaction products the substituent --Z in general formula I has 
the meaning acyl, of the definitions for R.sup.3, the reaction products 
correspond to the substances claimed in general formula 1. If on the other 
hand --Z has one of the other meanings defined in general formula 1, --Z 
will be converted into --R.sup.4. 
3.8 5-Acylamino-2-dialkylamino-tetralines (4) and (10) by acylation of 
5-amino-2-dialkylamino-tetralines (5) and (9) 
The compounds (5) and (9) according to the invention are reacted by 
acylation at the aniline nitrogen to form compounds (4) and (10) which 
also correspond to the substances claimed in general formula 1 if --Z has 
the definition --R.sup.3 =acyl. 
There are various methods available for such acylations [C. Ferri, 
Reaktionen der organischen Synthese, Georg Thieme Verlag, Stuttgart 1978, 
p. 222 ff]. It is advantageous in practice to carry out reactions with 
typical acylating agents such as carboxylic acid halides, preferably 
carboxylic acid chlorides, or carboxylic acid anhydrides. The work is done 
in suitable inert solvents in the presence of acid binding agents. The 
inert solvents used are generally organic solvents which do not change 
under the reaction conditions used, such as hydrocarbons, e.g. benzene, 
toluene, xylene or petroleum fractions, or halohydrocarbons such as 
methylene chloride, chloroform or carbon tetrachloride or preferably 
ethers, such as diethylether, glycoldimethylether (glyme), 
diglycoldimethylether (diglyme) and tetrahydrofuran. However, it is also 
possible to use the method of Schotten-Baumann in water in the presence of 
soda or sodium hydroxide solution [B. C. Challis and J. A. Challis in 
Zabicky (Ed.), The Chemistry of Amides, Interscience, New York, N.Y. 1970 
p. 731 ff]. It is advantageous to carry out acylation by the Einhorn 
variant in pyridine [Autorenkollektiv, Organikum, VEB Deutscher Verlag der 
Wissenschaften, Berlin, 1988, (17th Edition) p. 407; L. Gattermann and T. 
Wieland: Die Praxis des organischen Chemikers, Walter de Gruyter, Berlin, 
1982, (43rd Edition) p. 673], which on the one hand has good dissolving 
qualities and on the other hand acts as an acid binding agent. The 
reaction temperature may vary within wide limits, the lower limit being an 
insufficient reaction speed and the upper limit being the predominance of 
secondary reactions. In practice, the work is done at -50.degree. to 
+150.degree. C. and preferably in the range from 0.degree. to 100.degree. 
C. 
It is also possible to use special methods of acylation, e.g. with 
carboxylic acids which are reacted at higher temperatures, preferably 
150.degree. to 200.degree. C. with compounds (5) or (9) [A. L. J. Beckwith 
in: Zabicky (Ed.), The Chemistry of Amides, Interscience, New York, N.Y. 
1970, p. 105 ff]. A gentler method is to convert the carboxylic acids 
temporarily into reactive derivatives which can then be reacted under 
milder conditions, preferably at 0.degree. to 50.degree. C. 
Dicyclohexylcarbodiimide or carbonyldiimidazole, for example, are suitable 
for activating carboxylic acids in this way. The intermediate carboxylic 
acid derivatives can be isolated or they may preferably be formed and then 
further reacted in situ. 
3.9 5-Alkylamino-2-(mono- and dialkyl-)-aminotetralines (12) and (9) by 
reduction of diamide precursors (17) and (7) 
To prepare the diamides (17) and (7), intermediate products (15) and (3) 
are used as starting materials. The substituents --COR.sup.7, --COR.sup.8 
and --Z are such that they are converted by reduction into the 
substituents --R.sup.1 --R.sup.4 defined in general formula 1. The 
conversion of (15) and (3) into the diamides (17) and (7), respectively, 
is carried out by acylation analogously to the method described in 
paragraph 3.8. The diamides are reduced analogously to the methods 
described in 3.5 to obtain the desired compounds (12) and (9). 
3.10 Compounds (12) and (9) by cleaving --Z from (16) and (10) 
The cleavage of compounds (16) and (10) to obtain (12) and (9) is carried 
out by the methods described in paragraph 3.2. 
3.11 2,5-Bis-(dialkylamino)-tetralines (11) by reduction of amide 
precursors (10) 
In the compounds of type (10), --Z has the meaning of an acid ester 
--COR.sup.7 which can be converted, during the reduction step, analogously 
to the methods specified in Section 3.5, into a substituent --R.sup.3 or 
--R.sup.4 as defined for formula (1). 
3.12 5-Alkylamino-2-dialkylamino-tetralines (9) by dealkylation of 
5-dialkylamino analogs (11) 
Dealkylations of compounds (11) to obtain compounds (9) can be carried out 
using methods as described in Section 3.4. 
3.13 Enantiomerically pure compounds (1) 
Enantiomerically pure compounds (1) ((-)-1) and (+)-(1)) can be prepared 
from the racemic compounds, for example, using known methods of racemate 
resolution. It is also possible to obtain enantiomerically pure compounds 
of general formula 1 starting from enantiomerically pure intermediate 
products. Finally, it is possible to prepare enantiomerically pure 
compounds of general formula 1 by stereoselective methods of synthesis. 
3.14 Galenic preparations 
The 2,5-diamino-tetraline derivatives of general formula I and the 
pharmacologically harmless acid addition salts thereof may be converted in 
known manner into the usual formulations such as tablets, coated tablets, 
pills, granules, aerosols, syrups, emulsions, suspensions and solutions 
using inert pharmaceutically acceptable carriers or solvents. The 
proportion of the pharmaceutically active compounds may be in the range 
from 0.5 to 90% by weight of the total composition, i.e. in quantities 
which are sufficient in order to achieve the dosage range specified 
hereinafter. 
The formulations are prepared for example by extending the active 
substances with solvents and/or carriers, optionally using emulsifiers 
and/or dispersing agents, whilst if water is used as a diluent, for 
example, organic solvents may be used as solubilising agents or as 
auxiliary solvents. 
Examples of excipients include water, pharmaceutically acceptable organic 
solvents such as paraffins (e.g. petroleum fractions), vegetable oils 
(e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. 
ethanol or glycerol), carriers such as natural mineral powders (e.g. 
kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly 
dispersed silica and silicates), sugars (e.g. glucose, lactose and 
dextrose), emulsifiers (e.g. lignin, sulphite waste liquors, methyl 
cellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium 
stearate, talc, stearic acid and sodium laurylsulphate). 
The compositions are administered in the usual way, preferably by oral or 
parenteral route, more particularly through the tongue or intravenously. 
If they are taken orally, the tablets may of course contain in addition to 
the above-mentioned carriers, other additives such as sodium citrate, 
calcium carbonate and dicalcium phosphate together with various additives 
such as starch, preferably potato starch, gelatin and the like. It is also 
possible to add lubricants such as magnesium stearate, sodium 
laurylsulphate and talc in order to form tablets. In the case of aqueous 
suspensions, the active substances may be combined with various flavour 
enhancers or dyes in addition to the above-mentioned excipients. 
The tablets may also consist of several layers. In the same way, coated 
tablets may be produced by coating cores which have been made analogously 
to the tablets with substances normally used for tablet coatings, e.g. 
collidone or shellac, gum arabic, talc, titanium dioxide or sugar. In 
order to achieve delayed release or prevent intolerance, the core may also 
consist of several layers. Similarly, the tablet coating may be made up of 
several layers in order to achieve delayed release and for this purpose 
the excipients given for the tablets may be used. 
Elixirs of the active substances or combinations of active substances 
according to the invention may additionally contain a sweetener such as 
saccharin, cyclamate, glycerol or sugar as well as a flavour enhancer, 
e.g. a flavouring such as vanillin or orange extract. They may also 
contain suspension adjuvants or thickeners such as sodium carboxymethyl 
cellulose, wetting agents, such as condensation products of fatty alcohols 
with ethylene oxide or preservatives such as p-hydroxybenzoates. 
Injectable solutions are obtained in the usual way, e.g. by adding 
preservatives such as p-hydroxybenzoates or stabilisers such as 
complexones and bottling the solution in injection vials or ampoules. 
Capsules containing the active substances or combinations of active 
substances may be produced, for example, by mixing the active substances 
with inert carriers such as lactose or sorbitol and enclosing them in 
gelatine capsules. 
Suitable suppositories may be produced for example by mixing the active 
substances or combinations of active substances envisaged for this purpose 
with the usual carriers such as neutral fats or polyethyleneglycol or 
derivatives thereof. 
For parenteral administration, solutions of the active substances may be 
used, with suitable liquid carrier materials. 
The dosage for oral use is 1 to 300 mg, preferably between 5 and 150 mg. 
However, it may possibly be necessary to deviate from these amounts 
depending on the body weight and method of administration, the individual 
reaction to the drug, the nature of the formulation and the time or period 
of time over which the drug is administered. Thus, in certain cases it may 
be possible to use less than the minimum quantity specified whereas in 
other cases the upper limit will have to be exceeded. If larger quantities 
are administered it may be advisable to divide them into several smaller 
doses over the day. Moreover, the compounds of general formula 1 and the 
acid addition salts thereof may also be combined with active substances of 
other kinds.