The present invention provides dibenzo(de,g)quinoline derivatives of the general formula: ##STR1## wherein R is an unsaturated aliphatic hydrocarbon radical containing up to 6 carbon atoms or a cycloalkylalkyl radical containing 4 to 6 carbon atoms; and the pharmacologically acceptable salts thereof. The present invention also provides processes for the preparation of these compounds and pharmaceutical compositions containing them. Furthermore, the present invention is concerned with the use of these compounds for combating colds and allergies.

The present invention is concerned with new dibenzo(de,g)quinoline 
derivatives, with the preparation thereof and with pharmaceutical 
compositions containing them. 
The new dibenzo(de,g)quinoline derivatives according to the present 
invention are compounds of the general formula: 
##STR2## 
wherein R is an unsaturated aliphatic hydrocarbon radical containing up to 
6 carbon atoms or a cycloalkylalkyl radical containing 4 to 6 carbon 
atoms; and the pharmacologically-acceptable salts thereof. 
The wavy line in the 6a-position of the compounds of general formula (I) 
means that the compounds can be either in racemic form or can also occur 
as enantiomers, those compounds with a 6aS-configuration being preferred. 
Those compounds of general formula (I) are preferred in which R is an 
unsaturated aliphatic hydrocarbon radical containing 3 to 6 carbon atoms 
or a cycloalkylalkyl radical containing 4 to 6 carbon atoms. 
More, particularly, R is preferably, for example, an allyl, methallyl, 
dimethylallyl, but-2-enyl, 3-methbut-3-enyl, propargyl, cyclopropylmethyl, 
cyclobutylmethyl or cyclopentylmethyl radical. 
The compounds (I) according to the present invention can be prepared, for 
example, by one of the following methods: 
(a) a compound of the general formula: 
##STR3## 
in which R.sup.1 and R.sup.2, which may be the same or different, are 
hydrogen atoms or methyl radicals, is N-alkenylated, N-alkynylated or 
N-cycloalkylalkylated, whereafter, when R.sup.1 and/or R.sup.2 is a 
hydrogen atom, the product obtained is O-methylated; or 
(b) a compound of the general formula: 
##STR4## 
in which R.sup.2 is a hydrogen atom or a methyl radical, is N-alkenylated, 
N-alkynylated or N-cycloalkylalkylated, then cyclised and subsequently 
O-methylated. 
The N-alkenylation, N-alkynylation or N-cycloalkylalkylation of compounds 
(II) and (III) can take place by methods known for the N-alkenylation, 
N-alkynylation and N-cycloalkylalkylation of secondary amines, the most 
simple method being by means of reactive derivatives of the general 
formula: 
EQU X-R (IV), 
in which R has the same meaning as above and X is a halogen atom. 
Furthermore, it is also possible to introduce the substituent R as an acyl 
radical with the appropriate number of carbon atoms, the amide so obtained 
then being converted into the substituent R by reduction of the carbonyl 
group. The use of complex hydrides, for example of lithium aluminium 
hydride or of sodium dihydrido-bis-(2-methoxyethoxy)-aluminate, has proved 
to be useful for this reduction. Apart from the amide carbonyl group, any 
phenol ester groups possibly present, which have been formed in the case 
of the acylation of phenolic amines, are thereby also reduced, with the 
reformation of the free phenols. 
The cyclisation of the tetrahydroisoquinolines of general formula (III) and 
of the N-alkenyl, N-alkynyl, N-cycloalkylalkyl and N-acyl derivatives 
thereof takes place by means of the usual processes of oxidative phenol 
coupling. According to the present invention, the oxidative cyclisation of 
7-hydroxytetrahydroisoquinolines with vanadium oxytrichloride according to 
the method described in Federal Republic of Germany Patent Specification 
No. 27 57 281 is especially advantageous. 
The O-methylation of the N-alkenyl-, N-alkynyl-, N-cycloalkylalkyl- and 
N-acylnoraporphines can be carried out by processes conventionally used 
for the O-alkylation of phenols, for example by methylation with 
diazomethane or dimethyl sulphate. However, O-methylation with basic 
phenyltrimethylammonium compounds according to the method described in 
Federal Republic of Germany Patent Specification No. 27 57 335 has proved 
to be especially advantageous. 
The compounds of general formula (II) serving as starting materials for the 
preparation of compounds of general formula (I) according to the present 
invention are known compounds. They can be obtained, for example, by the 
oxidative cyclisation (see Federal Republic of Germany Patent 
Specification No. 27 57 281) and O-methylation of 1-hydroxy-N-noraporphine 
or of its N-trifluoroacetyl derivative (for example according to the 
method described in Federal Republic of Germany Patent Specification No. 
27 57 335; or according to J. Org. Chem., 41, 4049/1976). 
The tetrahydroisoquinolines of general formula (III) used as starting 
materials in process (b) are also known compounds, i.e. N-norreticuline 
(R=H) and N-norcodamine (R=CH.sub.3). The synthesis of racemic and 
optically-active N-norreticuline is described by K. C. Rice and A. Brossi 
(J. Org. Chem., 45, 592/1980) and the preparation of racemic norcodamine 
is disclosed in J. Org. Chem., 41, 4049/1976 (footnote 6). 
The working up of the reaction products, as well as the isolation and 
purification of the compounds (I), is carried out in known manner, for 
example, by crystallisation in the form of the bases or of acid-addition 
compounds, optionally after previous chromatographic purification. 
Another advantageous route for the preparation of the enantiomers is, in 
the case of processes (a) and (b), starting from optically-active 
compounds of general formula (II) or (III). An especially preferred 
starting material is the compound of general formula (III), wherein 
R.sup.2 is a methyl radical, since it can be separated into the optical 
antipodes with (+)-and (-)-anilinotartaric acids (see J. Org. Chem., 33, 
3993/1968) and especially with o-bromoanilinotartaric acid, or with 
N-acetyl-L-leucine. In comparison with N-norreticuline (III; R.sup.2 
.dbd.H), the optical separation of which with bromoanilinotartaric acid 
has been described in the literature (see J. Org. Chem., 45, 592/1980), 
this starting material has the advantage of being easily prepared from 
inexpensive materials. Furthermore, in the case of the oxidative 
cyclisation to aporphine with vanadium oxytrichloride according to process 
(b), less by-products are formed. 
The compounds of general formula (I) can be in racemic or optically-active 
form. The optically-active forms can be prepared in known manner, for 
example by fractional crystallisation of the diastereomeric salts. 
The conversion of the free bases of general formula (I) into their 
pharmacologically-acceptable salts takes place by neutralisation with 
appropriate organic or inorganic acids, for example hydrochloric acid, 
sulphuric acid, phosphoric acid, hydrobromic acid, acetic acid, fumaric 
acid, oxalic acid, lactic acid, citric acid, malic acid, salicylic acid, 
malonic acid, maleic acid, succinic acid, tartaric acid or ascorbic acid. 
For the preparation of pharmaceutical compositions, the active materials 
are worked up with conventional additives and liquid or solid carrier 
materials. The compounds (I) can be administered orally and parenterally 
in liquid or solid form within wide dosage ranges. 
Conventional additives for liquid forms include, for example, tartrate and 
citrate buffers, ethanol, complex formers (for example 
ethylenediamine-tetraacetic acid and the non-toxic salts thereof) and high 
molecular weight polymers (such as liquid polyethylene oxide) for 
viscosity regulation. Solid carrier materials include, for example, 
starch, lactose, mannitol, methyl cellulose, talc, highly dispersed 
silicic acids, high molecular weight fatty acids (for example stearic 
acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal 
and vegetable fats and solid high molecular weight polymers (for example 
polyethylene glycol). Compositions suitable for oral administration can, 
if desired, contain flavouring and/or sweetening materials. 
The compounds of general formula (I) possess valuable pharmacological 
properties. In particular, they exhibit antitussive, analgesic, 
anti-allergic and neuroleptic actions and inhibit the aggregation of blood 
platelets. The new compounds thereby considerably exceed the known 
antitussive action of 
5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-5-methyl-4H-dibenzo(de,g)quinoli 
ne (glaucine) with regard to the strength and length of activity. Thus, in 
the coughing experiment according to Domenjoz (Arch. f. Pathol. u. 
Pharmakol., 19, 215/1952) on cats, the compound of Example 1, in the case 
of the intravenous administration of 1 mg./kg. body weight, gives an 
inhibition of coughing lasting 20 minutes, whereas the standard compound 
glaucine, at a dosage of 2 mg./kg. i.v., only inhibits coughing for 10 
minutes. 
The following Table summarises some of the animal experimental results 
obtained: 
______________________________________ 
toxicity in 
dosage and antitussive effect in 
mice LD.sub.50 in 
Compound experiments on cats mg./kg. 
______________________________________ 
glaucine 2.0 mg./kg., i.v.: 10 min. cough 
58.3 i.v. 
inhibition 
10.0 mg./kg., sc.: no cough 
20.0 sc. 
inhibition 
4.0 mg./kg., id.: 40 min. cough 
530.6 ig. 
inhibition 
Example 1 
1.0 mg./kg., i.v.: 20 min. cough 
150.0 i.v. 
inhibition 
6.25 mg./kg., sc.: 40 min. cough 
150.0 sc. 
inhibition 
6.25 mg./kg., id.: 90 min. cough 
about 
inhibition 1200.0 ig. 
______________________________________ 
Depending upon the indications, the peroral individual dose of the 
compounds (I) is in the range of from 30 to 200 mg., which can be 
administered up to three times daily. 
The following Examples are given for the purpose of illustrating the 
present invention: