Bibyclic heteroacrylpiperazine derivatives having psychotropic activity, and pharmaceutical compositions containing these derivatives

The invention relates to new compositions with pyschotropic activity which comprise a compound of formula 1 of the formula sheet as the active substance. The compounds of formula 1 are for the greater part new compounds. The invention therefore also relates to these new compounds and to the preparation thereof in a manner known for the synthesis of analogous compounds.

The invention relates to new pharmaceutical compositions having a 
psychotropic activity, to new piperazine derivatives which may be used in 
such compositions as the active substance, and to the preparation of the 
said compositions and active compounds. 
It was found that compounds of the general formula 1 
##STR1## 
wherein --R.sub.1 is alkyl, cycloalkyl, optionally esterified 
hydroxyalkyl, alkoxyalkyl, optionally substituted phenyl or heteroaryl, 
alkoxy, aryloxy, alkylthio, arylthio, alkyl-, alkoxy-, amino-, mono-or 
dialkylaminocarbonyl, nitro, amino, mono- or dialkylamino, arylamino, 
cyano, halogen, trifluoromethyl, trifluoromethoxy, optionally esterified 
hydroxyl, alkyl- or aminosulphonyl or -sulphinyl, mono- or 
dialkylaminosulphonyl or -sulphinyl, and p has the value 0-3; 
--R.sub.2 is an alkyl group and n and q can have the value 0 or 1; 
--R.sub.3 may have the same meaning as R.sub.1, or is alkylidene, an oxo or 
thioxogroup, and m has the value 0-2; 
--A forms, with the two carbon atoms of the phenyl group, an optionally 
entirely or partly unsaturated cyclic group having 5-7 atoms in the ring, 
which comprises 1-3 hetero atoms from the group O, S and N, with the 
proviso that the sum of the number of oxygen and sulphur atoms is at most 
2, and the acid addition salts of these compounds have interesting 
psychotropic properties. 
As a halogen atom, R.sub.1 is preferably fluoro, chloro or bromo, and as an 
alkyl group, for example, a straight or branched, saturated or unsaturated 
group having 1-5 carbon atoms. 
When R.sub.2 is an alkyl group, this is preferably the methyl group or 
ethyl group. 
As a hydroxyalkyl group, the group R.sub.3 preferably comprises 1-3 carbon 
atoms. 
When R.sub.1 or R.sub.3 is an esterified hydroxyl group or hydroxylalkyl 
group, the ester group preferably has the formula 
EQU O--CO--R.sub.4 or --O--CS--R.sub.4 
in which R.sub.4 is alkyl, aralkyl, aryl, heteroaryl, hetero aralkyl, and 
alkyl may be branched or unbranched, and the (hetero) aryl part may 
optionally be substituted, or R.sub.4 may be an alkoxy, heteroalkoxy or 
dialkylamino group, in which the two alkyl groups can form a heterocyclic 
ring with the nitrogen atom. 
When R.sub.1 or R.sub.3 is an etherified hydroxyl group or hydroxyalkyl 
group, the ether group preferably has the formula --O--R.sub.5, wherein 
R.sub.5 is a straigth, branched or cyclic alkyl group having 1-5 C-atoms, 
or an alkoxyalkyl group having 1 or 2 C-atoms in both the alkoxy part and 
in the alkyl part thereof. 
Compounds which are preferred on the basis of their activity pattern are: 
a) 1-[5-(1,4-benzodioxanyl)]piperazine, 
b) 1-[8-(1,3-benzodioxanyl)]piperazine, 
c) 1-[7-(benzofuranyl)]piperazine, 
d) 1-[4-(1,3-benzodioxolyl)]piperazine, 
e) 1-[5-(2-methoxymethyl-1,4-benzodioxanyl)]piperazine, 
f) 1-[7-(5-fluorobenzofuranyl)]piperazine, 
g) 1-[8-(1,2,3,4-tetrahydroquinolyl)]piperazine, 
h) 1-[8-(2-oxo-1-benzopyranyl)]piperazine, 
i) 1-[8-(2H-1-benzopyranyl)]piperazine, 
j) 1-[5-(2-methyl-1,4-benzodioxanyl)]piperazine, 
k) 1-[7-(4-fluorobenzofuranyl)]piperazine, 
l) 1-[8-(isoquinolyl)]piperazine, 
m) 1-[7-(4-bromobenzofuranyl)]piperazine, 
n) (+)-1-[5-(2-methoxymethyl-1,4-benzodioxanyl)]piperazine, 
o) 1-[7-(4-methylbenzofuranyl)]piperazine, 
p) 1-[7-(4-chlorobenzofuranyl)]piperazine, 
q) 1-[7-(5-chlorobenzofuranyl)]piperazine. 
The so-called prodrugs of the compounds of formula 1, i.e. derivatives of 
compounds of the formula 1 which are inactive as such and which after 
administration are converted in the body into active compounds of formula 
1 also belong to the invention. 
When a chiral carbon atom is present, both the racemate and the individual 
isomers belong to the invention. 
Suitable acids with which the compounds of formula 1 can form 
pharmaceutically acceptable acid additon salts are, for example, 
hydrochloric acid, sulphuric acid, phosphoric aced, nitric acid, and 
organic acids such as citric acid, fumaric acid, maleic acid, tartaric 
acid, acetic acid, benzoic acid, p-toluenesulphonic acid, methanesulphonic 
acid, and naphtalenesulphonic acid. 
The above-described compounds of formula 1 have a psychotropic activity and 
are hence excellently suitable for the treatment of affections or diseases 
which are the result of disturbances in the central nervous system, for 
example, psychoses, aggression, fear, depression, etc. Some of the 
compounds moreover have also a good central analgetic activity. 
Dependent on the meanings of the symbols A, R.sub.1 -R.sub.3, m, n, p and q 
some compounds of the formula 1 have a strong thrombolytic activity. This 
property makes these compounds particularly suitable for use in the 
treatment of hematological disorders. 
An important advantage of the present compounds of formula 1 is that their 
activity is very specific. It was found, for example, that in mice the 
antiaggressive activity is not associated with undesired sedative effects. 
As a rule the antipsychotic activity is produced without the side effects, 
which are generally considered to be undesired, as a result of 
dopaminolytic and sedative activity. 
Dependent on the meanings of the groups A and R.sub.1 -R.sub.3, both the 
antiaggressive activity and the antipsychotic activity may be most 
prominent. 
The antiaggressive activity of the compounds was measured in a test 
suitable for that purpose on isolated mice (Advances in Pharmacol. 5, 
(1967), 79). In this test, male albino mice were kept isolated for a 
period of 4 weeks and were then selected for the test on the basis of 
fighting behaviour present. The selection criterion is the occurrence of 3 
or more fighting periods within 3 minutes after a mouse which had not been 
kept isolated is placed in the cage of the mouse which had been kept 
isolated. 
The compounds to be investigated were administered orally to the selected 
mice. Five mice per dose were used. Sixty minutes after administration of 
the compound to be investigated, the animals were again evaluated for 
fighting behaviour. The compound to be investigated is inactive in the 
administered dose when in this case also 3 or more fighting periods were 
observed within 3 minutes after a mouse which had not been kept isolated 
was placed in the cage of the mouse which had been kept isolated. The 
ED.sub.50 -value in mg of active substance per kg of body weight was 
calculated form the results obtained. 
The compounds according to the invention have an ED.sub.50 -value which is 
smaller than 20 mg/kg and for most of the compounds the ED.sub.50 -value 
is 0.1-5 mg/kg. 
Due to the strong antiaggressive activity and the absence of undesired side 
effects, for example, sympatholytic, dopaminolytic, muscle relaxing and 
sedative properties, the compounds are excellently suitable for use in the 
treatment of intra- and extrapunitive behaviour and overt aggressive 
behaviour in man and animal. 
For use in humane medicine are to be considered first of all the control of 
aggressive symptoms in psychiatric diseases and serious forms of 
psychopathological aggression. 
As application possibilities in the veterinary field are to be considered 
especially those forms of aggression which occur in the transport of 
agricultural domestic animals and the mixing of groups of these animals. 
The antipsychotic activity of the compounds of formula 1 was determined in 
a test procedure in which the suppression of conditioned behaviour in test 
animals was measured according to procedures known per se. The compounds 
are considered to be active if they show at least a suppression of 50% of 
the conditioned behaviour after oral administration in dosages of 50 mg/kg 
or less. The dopaminolytic activity of these compounds can be determined 
according to known behavioural or biochemical tests, for example, 
induction of catalepsy, increasing of the dopamine synthesis or conversion 
rate in the central nervous system, and by the affinity to dopamine 
receptors which is determined by displacement of a radioactive labelled 
ligand in a tissue homogenate. 
The sedative activity of these compounds was studied in a test in which the 
influencing of the spontaneous locomotoric activity of test animals is 
measured according to known methods. 
For the active compounds of formula 1 it was found that generally 
dopaminolytic and sedative effects do not occur in dosages which are at 
least a factor three higher than the dosages which give 50% suppression of 
the conditioned behaviour. 
The quantity, frequency and way of administration may differ for each 
individual case, also dependent on the nature and the severity of the 
disturbances. A dosage of 5-500 mg and preferably of 25-150 mg daily are 
generally suitable for humane application. 
For veterinary purposes the dosage preferably is 0.1-10 mg/kg of body 
weight. 
The analgetic activity of the compounds was determined in an analgetic test 
in mice (Brit. J. Pharm. 9, (1954), 280). In this test the pain stimulus 
was generated by placing bulldog clips on the tailhead of a mouse. The 
animals try to remove the pain stimulus by biting. The non-occurence of 
the pain response after administration of test substances is a measure of 
the analgetic activity. The compounds to be tested were administered 
orally. Five mice were used per dose. Sixty minutes after the 
administration of the compounds to be tested, the occurrence of the pain 
response was established. From the results obtained the ED.sub.50 -values 
in mg/kg of active substance per kg of body weight were calculated. 
The thrombolytic activity is determined using the method described by 
Kumada et al (Thrombosis Research, 18, (1980), 189-203). 
The active compounds according to the invention and their salts can be 
processed, according to known standard methods, to compositions such as 
pills, tablets, coated tablets, capsules, powders, injection liquids, and 
the like while using the conventional auxiliary substances, for example, 
solid and liquid carrier materials. 
The compounds of formula 1 are new compounds with the exception of the 
compounds wherein n and q are 0, and A together with the two carbon atoms 
of the phenyl group forms a heterocyclic group having 5 or 6 ringatoms, 
which as the only hetero atom contains one nitrogen atom at the meta 
position in relation to the piperazine group (some of these compounds are 
known from French patent specification 81.23744), and compounds in which n 
and q are 0, and the group of formula 2 
##STR2## 
is a 4-(or 7-)benzimidazolyl group which may be substituted in position 2 
with alkyl or phenyl, or a 7-indolyl group, or a 4-(or 7-)benzotriazolyl 
group (which compounds are known from Netherlands Patent Application 
82.01708), or a 5-(or 8-)carbo (or 3,4-dihydrocarbo-)styryl group (which 
compounds are known from Netherlands patent application 81.04923), or an 
8-quinolinyl group (which compound is known from Ber. 74B, (1941), pp. 
1661-1663). 
The new compounds according to the invention can be prepared in a manner 
known for the synthesis of analogous compounds (see, for example, U.S. 
Pat. No. 2,976,290 and J. Med. Chem. 8, (1965), pp. 104-107). 
The compounds can be obtained, for example, by reaction of a compound of 
formula 3 
##STR3## 
with a compound of formula 4, 
##STR4## 
in which formula L is a so-called leaving group, preferably chlorine, 
bromine, alkyl-SO.sub.3 or aryl-SO.sub.3. 
This reaction may be carried out both in an inert apolar organic solvent, 
and in a protic polar solvent. Examples of suitable solvents are 
chlorobenzene, toluene, pyridine, acetonitrile, lower aliphatic alcohols, 
for example, ethanol, propanol and butanol. In order to bind the releasing 
acid, an acid binder, for example NaHCO.sub.3 or K.sub.2 CO.sub.3 or an 
organic base, for example, triethylamine, may be used. The reaction 
temperature usually is between room temperature and the boiling-point of 
the solvent used. 
It is sometimes necessary or desired in this mode of preparation first to 
replace the hydrogen atom at the nitrogen atom in the starting material of 
formula 4 by a protective group, for example, the benzyl group, an 
aryloxycarbonyl group or alkoxycarbonyl group the alkoxy group of which 
comprises 1-4 C-atoms. Said protective group can then be removed from the 
resulting final product by means of the methods conventionally used for 
this purpose, for example, by catalytic hydrogenation or by acid 
hydrolysis. Conventional solvents are lower aliphatic alcohols and 
aliphatic esters thereof or aqueous mineral acid. The reactions are 
carried out at temperatures between room temperature and reflux 
temperature of the solvent used. 
The compounds of formula 1 can furthermore be obtained by reduction of a 
compound of formula 5 
##STR5## 
or formula 6, 
##STR6## 
in which the symbols have the above-mentioned meanings. This reduction 
reaction may be carried out, for example, with suitable reduction agents, 
for example LiAlH.sub.4 or a BH.sub.3.S(CH.sub.3).sub.2 -complex in a 
suitable solvent, for example, ether or tetrahydrofuran. The reaction is 
carried out at temperatures between room temperature and the reflux 
temperature of the solvent used. This method can be used readily only when 
besides the keto group or keto groups to be reduced, no other groups 
sensitive to reduction are present in the starting substances of formula 5 
or 6. 
Another suitable method of preparing the compounds of formula 1 is the 
reaction of a compound of formula 7 
##STR7## 
with a piperazine of formula 8, 
##STR8## 
in which A, R.sub.1 -R.sub.3, p, n, q and m have the above-mentioned 
meanings and L is a leaving group, for example, a halogen atom or nitro 
group. This reaction is carried out in a suitable organic solvent, for 
example, toluene, xylene, or a mono- or polyalcohol of higher 
boiling-point, at the reflux temperature of the solvent used. 
The compounds of formula 1 can further be prepared by reaction of a 
compound of formula 9 
##STR9## 
with NaNO.sub.2 in the manner described, inter alia, in J. Chem. Soc. 
1971, 3994-3999 in a sulphuric acid or hydrochloric acid medium, in which 
the resulting diazonium salt is decomposed with, for example, 50% 
hypophosphoric acid. The reaction is carried out at temperatures between 
0.degree. C. and room temperature. 
Some compounds of formula 1 can furthermore be obtained by conversion of 
another compound of formula 1. For example, compounds of formula 1, in 
which R.sub.1 and/or R.sub.3 is/are an esterified hydroxyl function, can 
be converted by hydrolysis via a method known per se into compounds in 
which R.sub.1 and/or R.sub.3 is/are hydroxyl. The reverse is also 
possible. Another possibility is to saturate or introduce a double bond in 
compounds of formula 1, by hydrogenation or dehydrogenation, dependent on 
the structure. 
Moreover, compounds of the formula 1, wherein n and/or q has the value 1 
can be obtained by introducing one or two groups R.sub.2 starting with the 
corresponding compounds of the formula 1 wherein n and/or q has the value 
0. According to this process (Chem. Rev. 78, (1978), 275 and 84, (1984), 
471) a compound of the formula 1 is converted into a compound of the 
formula 10 
##STR10## 
wherein R.sub.1 -R.sub.3, m, n, p and q have the above meanings, and 
R.sub.6 is an activating group, for example a nitroso group. Then the 
compound of formula 10 is alkylated with a compound R.sub.2 -L, wherein 
R.sub.2 and L have the above meanings. After the alkylation the activating 
group R.sub.6 is removed in a way known per se, whereby the desired 
compound of formula 1 is obtained. 
The reaction is carried out in a suitable organic solvent such as for 
example a lower alkane, diethyl ether or tetrahydrofuran, in the presence 
of a strong base, for example aryl- or alkyllithium or a lithium 
dialkylamine, at temperatures preferably between -100.degree. C. and 
0.degree. C. 
Finally, compounds of formula 1 can be obtained, dependent on the meaning 
of A, by converting compounds of formula 11 
##STR11## 
into compounds of formula 1 by a cyclisation reaction. This cyclisation 
generally takes place, dependent on the meanings of Z and Z' and the 
desired meaning of A, via methods known per se for this type of substances 
or analogous thereto. 
The starting materials to be used in the above-described methods can be 
obtained, in so far as these are new compounds, in a manner known for the 
synthesis of analogous compounds.