Hexahydro-pyrido(4,3-b)indole derivatives as antipsychotic drugs

This invention relates to hexahydro-pyrido[4,3-b]indole derivatives having 
therapeutic potential in psychotic disorders, and processes for their 
preparation; it further relates to compositions comprising these 
derivatives, as well as their use as a medicine. 
A number of hexahydro-pyrido[4,3-b]indole compounds substituted on the 
2-position with an alkyl group bearing a substituted phenyl and an 
hydroxy, which have antipsychotic properties as evidenced by their ability 
to block the action of dopamine receptors of the central nervous system, 
are disclosed in J. Med. Chem. 22:677-683 (1979) and J. Med. Chem. 
29:2093-2099 (1986). J. Med. Chem. 23:949-952 (1980) describes 
4a,9b-trans-8-fluoro-5-(4-fluorophenyl)-2-[4-(4-fluorophenyl)-4-hydroxy-bu 
tyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole hydrochloride as a 
neuroleptic agent capable of blocking dopamine receptors. 
The problem which this invention sets out to solve is to provide compounds 
having besides central dopamine antagonistic activity also central 
serotonin antagonistic activity at the same dosage, a combination which is 
considered advantageous in potential antipsychotic drugs. 
The compounds of the present invention differ from the cited art compounds 
structurally, by the fact that the tricyclic hexahydro-pyrido[4,3-b]indole 
moiety, also known as a hexahydro .gamma.-carboline moiety, is invariably 
substituted on the 2-position with an alkyl group bearing a pyrimidinyl 
derivative, and by their favourable pharmacological properties, in 
particular by the fact that in addition to their excellent central 
dopamine antagonistic activity the compounds of the present invention also 
have potent central serotonin antagonistic activity. 
The present invention concerns the compounds of formula 
##STR2## 
the N-oxide forms, the pharmaceutically acceptable addition salts and the 
stereochemically isomeric forms thereof, wherein 
Alk is C.sub.1-6 alkanediyl; 
R.sup.1 is hydrogen, C.sub.1-6 alkyl, aryl or arylC.sub.1-6 alkyl; 
R.sup.2, R.sup.3 and R.sup.4 are each independently selected from hydrogen, 
halo, hydroxy, nitro, cyano, trifluoromethyl, C.sub.1-6 alkyl, C.sub.1-6 
alkyloxy, C.sub.1-6 alkylthio, mercapto, amino, mono- and di(C.sub.1-6 
alkyl)amino, carboxyl, C.sub.1-6 alkyloxycarbonyl and C.sub.1-6 
alkylcarbonyl; 
R.sup.5 is hydrogen, C.sub.1-6 alkyl, phenyl or phenylC.sub.1-6 alkyl; 
R.sup.6 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, C.sub.1-6 
alkylthio, or a radical of formula --NR.sup.8 R.sup.9, wherein R.sup.8 and 
R.sup.9 are each independently selected from hydrogen, C.sub.1-6 alkyl, 
phenyl or phenylC.sub.1-6 alkyl; 
R.sup.7 is hydrogen or C.sub.1-6 alkyl; or 
R.sup.6 and R.sup.7 taken together may form a bivalent radical of formula 
--R.sup.6 --R.sup.7 --, 
wherein --R.sup.6 --R.sup.7 --represents 
______________________________________ 
--CH.sub.2 --CH.sub.2 --CH.sub.2 -- 
(a-1), 
--CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 -- (a-2), 
--CH.dbd.CH--CH.sub.2 -- (a-3), 
--CH.sub.2 --CH.dbd.CH-- (a-4) or 
--CH.dbd.CH--CH.dbd.CH-- (a-5); 
______________________________________ 
wherein one or two hydrogen atoms of said radicals (a-1) to (a-5) each 
independently may be replaced by halo, C.sub.1-6 alkyl, arylC.sub.1-6 
alkyl, trifluoromethyl, amino, hydroxy, C.sub.1-6 alkyloxy or C.sub.1-10 
alkylcarbonyloxy; or where possible, two geminal hydrogen atoms may be 
replaced by C.sub.1-6 alkylidene or arylC.sub.1-6 alkylidene; or 
--R.sup.6 --R.sup.7 -- may also be 
______________________________________ 
--S--CH.sub.2 --CH.sub.2 -- 
(a-6), 
--S--CH.sub.2 --CH.sub.2 --CH.sub.2 -- (a-7), 
--S--CH.dbd.CH-- (a-8), 
--NH--CH.sub.2 --CH.sub.2 -- (a-9), 
--NH--CH.sub.2 --CH.sub.2 --CH.sub.2 -- (a-10), 
--NH--CH.dbd.CH-- (a-11), 
--NH--CH.dbd.N-- (a-12), 
--S--CH.dbd.N-- (a-13) or 
--CH.dbd.CH--O-- (a-14); 
______________________________________ 
wherein one or where possible two or three hydrogen atoms in said radicals 
(a-6) to (a-14) each independently may be replaced by C.sub.1-6 alkyl or 
aryl; and 
aryl is phenyl or phenyl substituted with one, two or three substituents 
selected from halo, hydroxy, nitro, cyano, trifluoromethyl, C.sub.1-6 
alkyl, C.sub.1-6 alkyloxy, C.sub.1-6 alkylthio, mercapto, amino, mono- and 
di(C.sub.1-6 alkyl)amino, carboxyl, C.sub.1-6 alkyloxycarbonyl and 
C.sub.1-6 alkylcarbonyl. 
As used in the foregoing definitions and hereinafter, halo is generic to 
fluoro, chloro, bromo and iodo; C.sub.1-6 alkyl defines straight and 
branched chain saturated hydrocarbon radicals having from 1 to 6 carbon 
atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 
2-methylpropyl, 2,2-dimethylethyl, pentyl, hexyl, 3-methylbutyl, 
2-methylpentyl and the like; C.sub.1-10 alkyl is meant to comprise 
C.sub.1-6 alkyl and the higher homologues thereof having from 7 to 10 
carbon atoms such as, for example, heptyl, octyl, nonyl, decyl and the 
like; C.sub.1-2 alkanediyl defines bivalent straight chain saturated 
hydrocarbon radicals having 1 or 2 carbon atoms such as, for example, 
methylene and 1,2-ethanediyl; C.sub.1-6 alkanediyl is meant to comprise 
C.sub.1-2 alkanediyl and the higher straight and branched chain saturated 
hydrocarbon homologues thereof having from 3 to 6 carbon atoms such as, 
for example, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 
1,6-hexanediyl and the like; the term C.sub.1-6 alkylidene defines 
bivalent straight or branch chained alkylidene radicals having from 1 to 6 
carbon atoms such as, for example, methylene, ethylidene, 1-propylidene, 
1-butylidene, 1-pentylidene, 1-hexylidene and the like. 
The pharmaceutically acceptable addition salts as mentioned hereinabove are 
meant to comprise the therapeutically active non-toxic acid and non-toxic 
base addition salt forms which the compounds of formula (I) are able to 
form. The compounds of formula (I) which appear in their free form as a 
base can be converted in their acid addition salt by treating said free 
base form with an appropriate acid. Appropriate acids comprise, for 
example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or 
hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or 
organic acids such as, for example, acetic, propanoic, hydroxyacetic, 
lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), 
maleic, fumaric, malic, tartaric, citric, methane-sulfonic, 
ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, 
p-aminosalicylic, pamoic and the like acids. 
The compounds of formula (I) which appear in their free form as an acid, 
i.e. having at least one acidic proton, may be converted in their 
pharmaceutically acceptable base addition salts by treating said free acid 
form with a suitable organic or inorganic base. Appropriate base salt 
forms comprise, for example, the ammonium salts, the alkali and earth 
alkaline metal salts, e.g. the lithium. sodium, potassium, magnesium, 
calcium salts and the like, salts with organic bases, e.g. the benzathine, 
N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such 
as, for example, arginine, lysine and the like. 
Conversely said salt forms can be converted by treatment with an 
appropriate base or acid into the free acid or base form. 
The term addition salt as used hereinabove also comprises the solvates 
which the compounds of formula (I) as well as the salts thereof, are able 
to form. Such solvates are for example hydrates, alcoholates and the like. 
The term stereochemically isomeric forms as used hereinbefore defines the 
possible different isomeric as well as conformational forms which the 
compounds of formula (I) may possess. Unless otherwise mentioned or 
indicated, the chemical designation of compounds denotes the mixture, and 
in particular the racemic mixture, of all possible stereochemically and 
conformationally isomeric forms, said mixtures containing all 
diastereomers, enantiomers and/or conformers of the basic molecular 
structure. All stereochemically isomeric forms of the compounds of formula 
(I) both in pure form or in admixture with each other are intended to be 
embraced within the scope of the present invention. 
The numbering of the tricyclic ring-system present in the compounds of 
formula (I), as defined by Chemical Abstracts nomenclature is shown in 
formula (I') 
##STR3## 
The compounds of formula (I) occur as "cis" or "trans" isomers. Said terms 
refer to the configuration of the hydrogen atoms on carbon atoms 4a and 9b 
of the hexahydropyrido[4,3-b]indole moiety and are in accordance with 
Chemical Abstracts nomenclature. When both hydrogen atoms are on the same 
side of the mean plane determined by the hexahydro-pyrido[4,3-b]indole 
moiety then the configuration is designated "cis", if not, the 
configuration is designated "trans". 
The N-oxide forms of the compounds of formula (I) are meant to comprise 
those compounds of formula (I) wherein one or several nitrogen atoms are 
oxidized to the so-called N-oxide. 
A special group of compounds are those compounds of formula (I) wherein one 
or two hydrogen atoms of the radicals (a-1) to (a-5) each independently 
are replaced by C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, hydroxy or C.sub.1-10 
alkylcarbonyloxy; and one or where possible two hydrogen atoms in the 
radicals (a-6) to (a-14) each independently are replaced by C.sub.1-6 
alkyl. 
A group of interesting compounds are those compounds of formula (I) wherein 
R.sup.6 and R.sup.7 are taken together to form a bivalent radical of 
formula --R.sup.6 --R.sup.7 --, in particular a bivalent radical of 
formula (a-1), (a-5), (a-6) or (a-8) wherein one of the hydrogen atoms may 
be replaced by C.sub.1-6 alkyl, in particular methyl; and R.sup.5 is 
phenyl or C.sub.1-6 alkyl and preferably is methyl. 
A particular group of compounds are those compounds of formula (I) wherein 
Alk is C.sub.1-2 alkanediyl. 
Another particular group of compounds are those compounds of formula (I) 
wherein R.sup.1 is hydrogen, C.sub.1-6 alkyl or phenyl substituted with 
halo. 
Still another particular group of compounds are those compounds of formula 
(I) wherein R.sup.2 is halo or C.sub.1-6 alkyloxy, in particular methoxy; 
and R.sup.3 and R.sup.4 are hydrogen. 
Preferred compounds are those compounds of formula (I) wherein the 
configuration between the hydrogen atom on carbon atom 4a and the hydrogen 
atom on carbon atom 9b of the hexahydro-pyrido[4,3-b]indole moiety is 
defined as trans. 
More preferred compounds of formula (I) are those wherein R.sup.1 is 
hydrogen, R.sup.2 is halo and is located on the 8-position of the 
hexahydro-pyrido[4,3-b]indole moiety, R.sup.3 and R.sup.4 are both 
hydrogen; Alk is C.sub.1-2 alkanediyl, R.sup.5 is phenyl or methyl; and 
R.sup.6 and R.sup.7 are taken together to form a bivalent radical of 
formula --R.sup.6 --R.sup.7 --, in particular a bivalent radical of 
formula (a-1), (a-5), (a-6) or (a-8) wherein one of the hydrogen atoms may 
be replaced by methyl. 
Most preferred compounds of formula (I) are 
3-[2-(8-fluoro-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)ethyl]-2- 
methyl-4H-pyrido[1,2-a]pyrimidin-4-one; 
6-[2-(8-fluoro-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)ethyl]-7- 
methyl-5H-thiazolo[3,2-a]pyrimidin-5-one; and 
6-[2-(8-chloro-1,3,4,4a,5,9b-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)ethyl]-7 
-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one; the stereoisomeric forms and the 
pharmaceutically acceptable addition salts thereof, and also the N-oxide 
forms thereof. 
The compounds of the present invention can generally be prepared by 
N-alkylating an intermediate of formula (II) with an intermediate of 
formula (III), wherein W is an appropriate leaving group such as, for 
example, chloro, bromo, methanesulfonyloxy or benzenesulfonyloxy. The 
reaction can be performed in a reaction-inert solvent such as, for 
example, toluene, dichloromethane, methyl isobutylketone or 
N,N-dimethyl-formamide, in the presence of a suitable base such as, for 
example, sodium carbonate, sodium hydrogen carbonate or triethylamine, and 
optionally in the presence of potassium iodide. Stirring may enhance the 
rate of the reaction. The reaction may conveniently be carried out at a 
temperature ranging between room temperature and reflux temperature. 
##STR4## 
Compounds of formula (I) wherein the carbon atom of Alk by which it is 
attached to the nitrogen atom on the 2 position of the 
hexahydro-pyrido[4,3-b]indole moiety has at least one hydrogen atom, said 
compounds being represented by formula (I-a) and said Alk being 
represented by Alk'H, can be prepared by reductively N-alkylating an 
intermediate of formula (II) with an aldehyde or ketone of formula (IV), 
wherein the --Alk'.dbd.O moiety is derived from an --Alk'H.sub.2 moiety by 
replacing two geminal hydrogen atoms by an oxo group, following art-known 
reductive N-alkylation procedures. 
##STR5## 
Said reductive N-alkylation may be performed in a reaction-inert solvent 
such as, for example, dichloromethane, ethanol, toluene or a mixture 
thereof, and in the presence of a reducing agent such as, for example, a 
borohydride, e.g. sodium borohydride, sodium cyanoborohydride or 
triacetoxy borohydride. It may also be convenient to use hydrogen as a 
reducing agent in combination with a suitable catalyst such as, for 
example, palladium-on-charcoal or platinum-on-charcoal. In case hydrogen 
is used as reducing agent, it may be advantageous to add a dehydrating 
agent to the reaction mixture such as, for example, aluminium 
tert-butoxide. In order to prevent the undesired further hydrogenation of 
certain functional groups in the reactants and the reaction products, it 
may also be advantageous to add an appropriate catalyst-poison to the 
reaction mixture, e.g. thiophene or quinoline-sulphur. To enhance the rate 
of the reaction, the temperature may be elevated in a range between room 
temperature and the reflux temperature of the reaction mixture and 
optionally the pressure of the hydrogen gas may be raised. 
The compounds of formula (I) may further be prepared by converting 
compounds of formula (I) into each other according to art-known group 
transformation reactions. 
The compounds of formula (I) may also be converted to the corresponding 
N-oxide forms following art-known procedures for converting a trivalent 
nitrogen into its N-oxide form. Said N-oxidation reaction may generally be 
carried out by reacting the starting material of formula (I) with an 
appropriate organic or inorganic peroxide. Appropriate inorganic peroxides 
comprise, for example, hydrogen peroxide, alkali metal or earth alkaline 
metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate 
organic peroxides may comprise peroxy acids such as, for example, 
benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, 
e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. 
peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. 
Suitable solvents are, for example, water, lower alkanols, e.g. ethanol 
and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, 
halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such 
solvents. 
The intermediates of formula (II) can generally be prepared as outlined in 
the following paragraphs. Some intermediates of formula (II) are art-known 
from J. Med. Chem. 22:677-683 (1979) and J. Med. Chem. 29:2093-2099 
(1986). 
For instance, intermediates of formula (II) can be prepared by 
hydrogenation of intermediates of formula (VI), wherein R.sup.1 is 
hydrogen and P is a suitable protective group such as, e.g. benzyl, and 
subsequent removal of the protecting group P. For instance, when P is 
benzyl, P can be removed by catalytic hydrogenation with 
palladium-on-carbon in a reaction-inert solvent and in the presence of 
hydrogen. 
##STR6## 
Said hydrogenation reaction can give intermediates of formula (V-1) wherein 
the configuration between the hydrogen atom on carbon atom 4a and the 
hydrogen atom on carbon atom 9b of the hexahydro-pyrido[4,3-b]indole 
moiety is defined as cis, when intermediates of formula (VI) are submitted 
to art-known catalytic hydrogenation procedures such as, e.g. stirring in 
a reaction-inert solvent, e.g. methanol or methanolic ammonia, in the 
presence of a suitable catalyst, e.g. Raney nickel or palladium-on-carbon 
and in the presence of hydrogen. To enhance the rate of the reaction, the 
temperature may be elevated in a range between room temperature and the 
reflux temperature of the reaction mixture and optionally the pressure of 
the hydrogen gas may be raised. Intermediates of formula (V-2) wherein the 
configuration between the hydrogen atom on carbon atom 4a and the hydrogen 
atom on carbon atom 9b of the hexahydro-pyrido[4,3-b]indole moiety is 
defined as trans, can be prepared by treating intermediates of formula 
(VI) with an appropriate reagent such as, e.g. BH.sub.3 -tetrahydro-furan 
complex in a reaction-inert solvent, e.g. tetrahydrofuran, as described in 
J. Med. Chem. 23:949-952 (1980); or NaBH.sub.4 in a reaction-inert 
solvent, e.g. 2-methoxyethyl ether. 
Intermediates of formula (V-a), defined as intermediates of formula (V) 
wherein R.sup.1 is hydrogen, can be converted into intermediates of 
formula (V-b) wherein R.sup.1' is the same as R.sup.1 but other than 
hydrogen, by submitting intermediates of formula (V-a) to art-known 
N-alkylation methods, as described herein above. 
##STR7## 
A number of intermediates and starting materials are known compounds which 
may be prepared according to art-known methodologies. For example, 
intermediates of formula (VI) and their preparations are described in J. 
Med. Chem. 9:436-438 (1966), J.C.S. (C) 1235 (1968), J. Org. Chem. 
44:1063-1068 (1979) and J. Med. Chem. 23:635-643 (1980). Also, 
intermediates of formula (III) and their preparations are described in 
EP-A-0,037,265, EP-A-0,070,053, EP-A-0,110,435, EP-A-0,196,132 and 
EP-A-0,378,255. 
Compounds of formula (I) and some of the intermediates in the present 
invention contain at least one asymmetric carbon atom. Pure 
stereochemically isomeric forms of said compounds and said intermediates 
can be obtained by the application of art-known procedures. For example, 
diastereoisomers can be separated by physical methods such as selective 
crystallization or chromatographic techniques, e.g. counter current 
distribution, liquid chromatography and the like methods. Enantiomers can 
be obtained from racemic mixtures by first converting said racemic 
mixtures with suitable resolving agents such as, for example, chiral 
acids, to mixtures of diastereomeric salts or compounds; then physically 
separating said mixtures of diastereomeric salts or compounds by, for 
example, selective crystallization or chromatographic techniques, e.g. 
liquid chromatography and the like methods; and finally converting said 
separated diastereomeric salts or compounds into the corresponding 
enantiomers. An alternative manner of separating the enantiomeric forms of 
the compounds of formula (I) and intermediates involves liquid 
chromatography, in particular liquid chromatography using a chiral 
stationary phase. 
Pure stereochemically isomeric forms of the compounds of formula (I) may 
also be obtained from the pure stereochemically isomeric forms of the 
appropriate intermediates and starting materials, provided that the 
intervening reactions occur stereospecifically. The pure and mixed, in 
particular racemic, stereochemically isomeric forms of the compounds of 
formula (I) are intended to be embraced within the scope of the present 
invention. 
The compounds of formula (I) display central dopamine antagonistic activity 
in combination with central serotonin antagonistic activity as can be seen 
in the "apomorphine, tryptamine, norepinephrine (ATN) test in rats", 
described in pharmacological example C.1. Centrally acting dopamine 
antagonists are potential antipsychotic drugs, in particular when 
simultaneously displaying serotonin antagonism. Moreover, most of the 
compounds lack relevant .alpha.-adrenergic antagonist activity in the 
norepinephrine test, suggesting absence of hypotensive activity. 
The compounds of the present invention also show interesting 
pharmacological activity in the "mCPP Test on Rats", which test is 
described in WO 96/14320. 
The compounds of formula (I), their pharmaceutically acceptable addition 
salts, stereochemically isomeric forms, or N-oxide forms thereof, are 
antagonists of the neurotransmitters dopamine and serotonin. Antagonizing 
said neurotransmitters will suppress or relieve a variety of symptoms 
associated with phenomena induced by the release, in particular the 
excessive release, of these neurotransmitters. Therapeutic indications for 
using the present compounds are mainly in the CNS area, especially 
psychotic disorders such as, e.g. schizophrenia, depression, neuroses, 
psychoses, bipolar disorders, aggressive behaviour, anxiety, migraine and 
the like. Further, serotonin is a potent broncho- and vasoconstrictor and 
thus the present antagonists may be used against hypertension and vascular 
disorders. In addition, serotonin antagonists have been associated with a 
number of other properties such as, the suppression of appetite and 
promotion of weight loss, which may prove effective in combatting obesity; 
and also the alleviation of withdrawal symptoms in addicts trying to 
discontinue drinking and smoking habits. The present compounds also appear 
to be useful therapeutic agents for combatting autism. 
The present invention thus also relates to compounds of formula (I) as 
defined hereinabove for use as a medicine. 
In view of the usefulness of the subject compounds in the treatment or 
prevention of disorders associated with the release, in particular the 
excessive release, of dopamine and/or serotonin, the present invention 
provides a method of treating warm-blooded animals suffering from such 
disorders, in particular psychotic disorders, said method comprising the 
systemic administration of a therapeutic effective amount of a compound of 
formula (I), a N-oxide or a pharmaceutically acceptable addition salt 
thereof, effective in treating disorders associated with the release or 
excessive release of dopamine and/or serotonin in particular psychotic 
disorders such as, e.g. schizophrenia, depression, neuroses, psychoses, 
bipolar disorders, aggressive behaviour, anxiety, migraine and the like. 
For administration purposes, the subject compounds may be formulated into 
various pharmaceutical forms. To prepare the pharmaceutical compositions 
of this invention, a therapeutically effective amount of the particular 
compound, in addition salt or in free acid or base form, as the active 
ingredient is combined in intimate admixture with a pharmaceutically 
acceptable carrier, which may take a wide variety of forms depending on 
the form of preparation desired for administration. These pharmaceutical 
compositions are desirably in unitary dosage form suitable, preferably, 
for administration orally, percutaneously, or by parenteral injection. For 
example, in preparing the compositions in oral dosage form, any of the 
usual pharmaceutical media may be employed, such as, for example, water, 
glycols, oils, alcohols and the like in the case of oral liquid 
preparations such as suspensions, syrups, elixirs and solutions; or solid 
carriers such as starches, sugars, kaolin, lubricants, binders, 
disintegrating agents and the like in the case of powders, pills, capsules 
and tablets. Because of their ease in administration, tablets and capsules 
represent the most advantageous oral dosage unit form, in which case solid 
pharmaceutical carriers are obviously employed. For parenteral 
compositions, the carrier will usually comprise sterile water, at least in 
large part, though other ingredients, for example, to aid solubility, may 
be included. Injectable solutions, for example, may be prepared in which 
the carrier comprises saline solution, glucose solution or a mixture of 
saline and glucose solution. Injectable solutions containing compounds of 
formula (I) may be formulated in an oil for prolonged action. Appropriate 
oils for this purpose are, for example, peanut oil, sesame oil, cottonseed 
oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty 
acids and mixtures of these and other oils. Injectable suspensions may 
also be prepared in which case appropriate liquid carriers, suspending 
agents and the like may be employed. In the compositions suitable for 
percutaneous administration, the carrier optionally comprises a 
penetration enhancing agent and/or a suitable wettable agent, optionally 
combined with suitable additives of any nature in minor proportions, which 
additives do not cause any significant deleterious effects on the skin. 
Said additives may facilitate the administration to the skin and/or may be 
helpful for preparing the desired compositions. These compositions may be 
administered in various ways, e.g., as a transdermal patch, as a spot-on 
or as an ointment. Addition salts of compounds of formula (I) due to their 
increased water solubility over the corresponding free base or free acid 
form, are obviously more suitable in the preparation of aqueous 
compositions. 
It is especially advantageous to formulate the aforementioned 
pharmaceutical compositions in dosage unit form for ease of administration 
and uniformity of dosage. Dosage unit form as used in the specification 
and claims herein refers to physically discrete units suitable as unitary 
dosages, each unit containing a predetermined quantity of active 
ingredient calculated to produce the desired therapeutic effect, in 
association with the required pharmaceutical carrier. Examples of such 
dosage unit forms are tablets (including scored or coated tablets), 
capsules, pills, powder packets, wafers, injectable solutions or 
suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated 
multiples thereof. 
Those of skill in the treatment of such disorders could determine the 
effective therapeutic daily amount from the test results presented 
hereinafter. An effective therapeutic daily amount would be from about 
0.001 mg/kg to about 1 mg/kg body weight, more preferably from about 0.01 
mg/kg to about 0.2 mg/kg body weight.

The following examples are intended to illustrate and not to limit the 
scope of the present invention. 
Experimental Part 
Hereinafter "THF" means tetrahydrofuran, "DIPE" means diisopropylether, 
"DCM" means dichloromethane, "DMF" means N,N-dimethylformamide and "ACN" 
means acetonitrile. 
A. Preparation of the Intermediates. 
EXAMPLE A.1 
A mixture of ethyl 1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate 
(49.2 g), prepared as described in J. Med. Chem. 23:635-643 (1980), in 
NH.sub.3 /CH.sub.3 OH (400 ml) was hydrogenated with Raney nickel (5 g) as 
a catalyst. The mixture was cooled and the catalyst was filtered off. The 
filtrate was evaporated. The residue was dissolved in anhydrous diethyl 
ether (600 ml) and HCl(g) was allowed to bubble through the solution for 
30 minutes. The resulting precipitate was filtered off, dissolved in water 
(200 ml) and extracted with diethyl ether (100 ml). The organic layer was 
separated, dried, filtered and the solvent was evaporated. The residue was 
solidified in DIPE (150 ml), cooled to 0.degree. C., filtered off and 
dried, yielding 34.3 g (70%) of (.+-.)-ethyl 
cis-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate 
(intermediate 1). 
EXAMPLE A.2 
A mixture of intermediate 1 (22.46 g), benzoic acid (11.8 g) and thiophene 
(4%, 2 ml) in methanol (440 ml) was hydrogenated with palladium-on-carbon 
(10%, 3 g) as a catalyst. After uptake of hydrogen (1 equivalent), the 
catalyst was filtered off. The filtrate was evaporated, yielding 30 g 
(99%) of (.+-.)-ethyl 
cis-1,3,4,4a,5,9b-hexahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indole-2-carb 
oxylate (intermediate 2). 
In a similar way, (.+-.)-ethyl 
cis-1,3,4,4a,5,9b-hexahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indole-2-carb 
oxylate (intermediate 3) and (.+-.)-ethyl 
cis-1,3,4,4a,5,9b-hexahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indole-2-carb 
oxylate (intermediate 4) were prepared. 
EXAMPLE A.3 
A mixture of intermediate 4 (30.2 g) and potassium hydroxide (50 g) in 
2-propanol (300 ml) was stirred and refluxed for 4 hours. The solvent was 
evaporated. Water (250 ml) was added to the residue and the organic 
solvent was removed by azeotropic distillation. The aqueous residue was 
cooled and extracted with DCM (2.times.200 ml). The organic layer was 
separated, dried, filtered and the solvent was evaporated. The residue was 
washed with petroleum ether (100 ml), filtered off and dried, yielding 
15.5 g (65%) of (.+-.)-cis-2,3,4,4a,5,9b-hexahydro-5-(phenylmethyl)-1H 
pyrido[4,3-b]indole (intermediate 5). In a similar way, 
(.+-.)-cis-2,3,4,4a,5,9b-hexahydro-5-(2-phenylethyl)-1H-pyrido[4,3-b]-indo 
le (intermediate6) and 
(.+-.)-cis-2,3,4,4a,5,9b-hexahydro-5-methyl-1H-pyrido[4,3-b]-indole 
(intermediate 7) were prepared. 
EXAMPLE A.4 
A mixture of 
2,3,4,5-tetrahydro-8-methoxy-2-(phenylmethyl)-1H-pyrido[4,3-b]indole 
monohydrochloride (39.5 g), prepared as described in J. Org. Chem. 
44:1063-1068 (1979), in 2-methoxyethyl ether (250 ml) was stirred and 
cooled in an ice bath, under a N.sub.2 flow. Sodium borohydride (11.7 g, 
solid) was added in 8 portions. The mixture was stirred overnight at room 
temperature, then cooled to 5.degree. C. Ice water (500 ml) was added 
dropwise. Precipitation resulted. The mixture was stirred for 2 hours. The 
precipitate was filtered off. 1,4-Dioxane (350 ml) was added and the 
mixture was stirred. HCl (200 ml, 12N) was slowly added and the mixture 
was heated to reflux temperature. The mixture was stirred and refluxed for 
1 hour, then cooled and the solvent was evaporated. The residue was 
stirred in water (300 ml) and this mixture was alkalized with an aqueous 
NaOH solution. The mixture was stirred for 1 hour. The mixture was 
extracted with DCM (2.times.200 ml). The combined extracts were dried, 
filtered and the solvent was evaporated. The residue was dissolved in DIPE 
(300 ml), then filtered and the filtrate was evaporated, yielding 11.3 g 
(32%) of 
(.+-.)-trans-2,3,4,4a,5,9b-hexahydro-8-methoxy-2-(phenylmethyl)-1H-pyrido[ 
4,3-b]indole (intermediate 8). 
In a similar way, 
(.+-.)-trans-8-chloro-2,3,4,4a,5,9b-hexahydro-2-(phenylmethyl)-1H-pyrido[4 
,3-b]indole (intermediate 9) was prepared. 
EXAMPLE A.5 
A mixture of intermediate 8 (11.3 g) in methanol (250 ml) was hydrogenated 
with palladium-on-carbon (10%, 2 g) as a catalyst. After uptake of 
hydrogen (1 equivalent), the catalyst was filtered off and the filtrate 
was evaporated. The residue was solidified in DIPE (30 ml). The 
precipitate was filtered off and dried, yielding 6.1 g (78%) of 
(.+-.)-trans-2,3,4,4a,5,9b-hexahydro-8-methoxy-1H-pyrido[4,3-b]indole 
(intermediate 10). 
EXAMPLE A.6 
Sodium carbonate (20.1 g) was added to a solution of intermediate 9 (45 g) 
in DCM (500 ml). Ethyl chloroformate (20.6 g) was added dropwise at 
5.degree. C. The reaction mixture was stirred for 1 hour at 5.degree. C., 
then for 24 hours at room temperature. More sodium carbonate (20.1 g) was 
added. More ethyl chloroformate (20.6 g) was added dropwise and the 
reaction mixture was stirred overnight at room temperature. The 
precipitate was filtered off and the filtrate was evaporated. The residue 
was suspended in petroleum ether (200 ml), decanted off and the residue 
was dissolved in ACN (100 ml). The compound crystallized out. The mixture 
was cooled to 0.degree. C. The precipitate was filtered off and dried, 
yielding 26.5 g (50%) of (.+-.)-diethyl 
trans-8-chloro-3,4,4a,9b-tetrahydro-2H-pyrido[4,3-b]indole-2,5(1H)-dicarbo 
xylate (intermediate 11). 
EXAMPLE A.7 
Using the same reaction procedure as described in example A.3, intermediate 
11 was hydrolysed to 
(.+-.)-trans-8-chloro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole 
(intermediate 12). 
EXAMPLE A.8 
Borane-THF complex (1:1) (400 ml) was transferred into a 4 necked flask 
with a syringe (under N.sub.2 flow). This solution was cooled to 0.degree. 
C. A solution of 
2,3,4,5-tetra-hydro-2-(phenylmethyl)-1H-pyrido[4,3-b]indole (52.5 g), 
prepared as described in J. Med. Chem. 9:436-438 (1966), in THF (400 ml) 
was added over a 1 hour period at 0-5.degree. C. The reaction mixture was 
stirred for 1 hour at room temperature. The reaction mixture was stirred 
and refluxed for 4 hours, then cooled to room temperature. 6N HCl (300 ml) 
was added. The organic solvent was removed by evaporation. Dioxane (400 
ml) was added to the residue and the mixture was stirred and refluxed for 
1 hour. The solvent was evaporated. Water (300 ml) was added to the 
residue and this mixture was alkalized with a diluted NaOH solution. This 
mixture was extracted with DCM. The organic layer was separated, dried, 
filtered and the solvent was evaporated. The residue was purified by 
column chromatography over silica gel (eluent: CHCl.sub.3 /CH.sub.3 OH 
95/5). The pure fractions were collected and the solvent was evaporated. 
The residue (20 g) was crystallized from DIPE (100 ml). The crystals were 
filtered off and dried, yielding 7.5 g (14%) of 
(.+-.)-trans-1,3,4,4a,5,9b-hexahydro-2-(phenylmethyl)-2H-pyrido[4,3-b]indo 
le (intermediate 13). 
EXAMPLE A.9 
Using the same reaction procedure as described in example A.5, intermediate 
13 was converted to 
(.+-.)-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (intermediate 
14). 
B. Preparation of the Final Compounds. 
EXAMPLE B.1 
A mixture of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 
(2.45 g), disclosed in EP-0,196,132, intermediate 5 (2.7 g), sodium 
carbonate (3.3 g) and potassium iodide (0.1 g) in methyl isobutyl ketone 
(250 ml) was stirred and refluxed for 18 hours. The reaction mixture was 
cooled, filtered and the filtrate was evaporated. The residue was purified 
by column chromatography over silica gel (eluent: CHCl.sub.3 /CH.sub.3 OH 
90/10). The pure fractions were collected and the solvent was evaporated. 
The residue was crystallized from ACN (25 ml). The crystals were filtered 
off and dried, yielding 2.3 g (50%) of 
(.+-.)-cis-3-[2-[1,3,4,4a,5,9b-hexahydro-5-(phenylmethyl)-2H-pyrido[4,3-b] 
indol-2-yl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (compound 9, mp. 
145.1.degree. C.). 
EXAMPLE B.2 
A mixture of 6-(2-chloroethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 
(3.4 g), prepared as described in EP-A-0,070,053, intermediate 14 (2.6 g), 
sodium carbonate (4.8 g) and potassium iodide (0.1 g) in methyl isobutyl 
ketone (70 ml) was stirred for 18 hours at 90.degree. C. The solvent was 
evaporated. Water (100 ml) was added and this mixture was extracted with 
DCM. The separated organic layer was dried, filtered and the solvent was 
evaporated. The residue was purified by column chromatography over silica 
gel (eluent: CHCl.sub.3 /CH.sub.3 OH 95/5). The pure fractions were 
collected and the solvent was evaporated. The residue was treated with ACN 
(15 ml). The solid was filtered off and dried, yielding 1.5 g (28%) of 
(.+-.)-trans-6-[2-(1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)ethy 
l]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (compound 11, mp. 
152.5.degree. C.). 
EXAMPLE B.3 
Using the same reaction procedure as described in example B.1, 
6-(2-chloroethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (3.4 g), 
prepared as described in EP-A-0,070,053, was reacted with 
(.+-.)-trans-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole, 
prepared as described in J. Med. Chem. 22:677--(1979), to form 
(.+-.)-trans-6-[2-(8-fluoro-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol- 
2-yl)ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (compound 15, mp. 
140.9.degree. C.). 
EXAMPLE B.4 
A mixture of 
6-(2-bromoethyl)-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one 
monohydrobromide (3.6 g), prepared as described in EP-0,110,435, 
(.+-.)-trans-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido 
[4,3-b]indole (2.9 g), described in J. Med. Chem. 29:2093--(1986), and 
sodium carbonate (3.2 g) in DMF (70 ml) was stirred for 18 hours at 
90.degree. C. The cooled reaction mixture was poured out into water (400 
ml) and the resulting precipitate was filtered off and dissolved in DCM 
(200 ml). This organic solution was washed with water (50 ml), dried, 
filtered and the solvent was evaporated. The residue was solidified in 
DIPE (50 ml), filtered off and dissolved in methanol (300 ml). The 
solution was treated for 30 minutes with activated charcoal. This mixture 
was filtered over dicalite. The filtrate was evaporated. The residue was 
washed in methanol (20 ml). The precipitate was filtered off, dried and 
purified by column chromatography over silica gel (eluent: CH.sub.2 
Cl.sub.2 /CH.sub.3 OH 98/2). The pure fractions were collected and the 
solvent was evaporated. The residue was washed with methanol (5 ml) and 
dried, yielding: 1.5 g (31%) of 
(.+-.)-trans-6-[2-[8-fluoro-5-(4-fluoro-phenyl)-1,3,4,4a,5,9b-hexahydro-2H 
-pyrido[4,3-b]indol-2-yl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyri 
midin-5-one (compound 22, mp. 110.degree. C.). 
Tables 1 and 2 list the compounds that were prepared according to one of 
the above Examples. 
TABLE 1 
__________________________________________________________________________ 
#STR8## 
Co. No. Ex. No. R.sup.2 R.sup.1 
--R.sup.6 --R.sup.7 -- Physical 
data (mp. in .degree. C.) 
__________________________________________________________________________ 
1 B.2 
H H cis --S--CH.dbd.CH-- 
mp. 165.4.degree. C. 
2 B.4 H H cis --S--CH.dbd.C(CH.sub.3)-- mp. 149.6.degre 
e. C. 
3 B.2 H H cis --CH.dbd.CH--CH.dbd.CH-- mp. 109.6.degree 
. C. 
4 B.2 H --CH.sub.3 cis --S--CH.dbd.CH-- .HCl.2(H.sub.2 O)/ 
mp. 
167.4.degree. C. 
5 B.1 H --CH.sub.3 cis --CH.dbd.CH--CH.dbd.CH-- .3HCl.3/2H.sub 
.2 O 
mp. 194.degree. C. 
6 B.4 H --CH.sub.3 cis --(CH.sub.2).sub.4 -- .2HCl.1/2(H.s 
ub.2 O) 
mp. 210.4 .degree.C. 
7 B.1 H --CH.sub.2 C.sub.6 H.sub.5 cis --S--CH.dbd.CH-- 
mp. 132.8.degree. C. 
8 B.1 H --CH.sub.2 C.sub.6 H.sub.5 cis --S--CH.sub.2 --CH.sub.2 
-- .1/2(H.sub.2 O) 
mp. 126.1.degree. C. 
9 B.1 H --CH.sub.2 C.sub.6 
H.sub.5 cis --CH.dbd.CH--CH.dbd 
.CH-- mp. 145.1.degree. C. 
10 B.1 H --(CH.sub.2).sub.2 
C.sub.6 H.sub.5 cis --CH.dbd.CH-- 
CH.dbd.CH-- mp. 108.degree. 
C. 
11 B.2 H H trans --S--CH.dbd.CH-- mp. 152.5.degree. 
C. 
12 B.4 H H trans --S--CH.dbd.C(CH.sub.3)-- mp. 215.7.degre 
e. C. 
13 B.4 H H trans --S--CH.sub.2 --CH.sub.2 -- mp. 
99.1.degree. C. 
14 B.2 H H trans --CH.dbd.CH--CH.dbd.CH-- mp. 172.8.degre 
e. C. 
15 B.3 F H trans --S--CH.dbd.CH-- mp. 140.9.degree. 
C. 
16 B.1 F H trans --S--CH.dbd.C(CH.sub.3)-- mp. 83.2.degre 
e. C. 
17 B.2 F H trans --CH.dbd.CH--CH.dbd.CH-- mp. 193.7.degr 
ee. C. 
18 B.1 F H trans --(CH.sub.2).sub.4 -- mp. 203.5.deg 
ree. C. 
19 B.2 H --CH.sub.3 trans --S--CH.dbd.CH-- .(E)-butenedioat 
e mp. 
205.0.degree. C. 
20 B.2 H --CH.sub.3 trans --CH.dbd.CH--CH.dbd.CH-- .2HCl.H.su 
b.2 O 
mp. 240.degree. 
C. 
21 B.2 H --CH.sub.3 trans --(CH.sub.2).sub.4 -- .2HCl mp. 
&gt;260.degree. C. 
- 22 B.2 F 
trans --S--CH.dbd.CH 
-- mp. 197.2.degree. C. 
- 23 B.3 F 
trans --S--CH.sub.2 
--CH.sub.2 -- mp. 110.degree. 
C. 
- 24 B.4 F 
trans --S--CH.dbd.C(CH 
.sub.3)-- mp. 184.7.degree. C. 
- 25 B.2 F 
trans --(CH.sub.2). 
sub.4 -- mp. 145.5.degree. 
C. 
- 26 B.1 Cl H trans --S--CH.dbd.CH-- mp. 224.9.degree. 
C. 
27 B.1 Cl H trans --S--CH.dbd.C(CH.sub.3)-- mp. 201.3.degree 
. C. 
28 B.1 Cl H trans --CH.dbd.CH--CH.dbd.CH-- mp. 192.6.degree. 
C. 
29 B.1 --OCH.sub.3 H trans --S--CH.dbd.CH-- mp. 201.4.degr 
ee. C. 
30 B.1 --OCH.sub.3 H trans --CH.dbd.CH--CH.dbd.CH-- mp. 
166.8.degree. C. 
__________________________________________________________________________ 
TABLE 2 
__________________________________________________________________________ 
#STR14## 
Co. 
Ex. Phys. data 
No. No. R.sup.2 R.sup.1 R.sup.5 R.sup.6 R.sup.7 
(mp. in .degree. C.) 
__________________________________________________________________________ 
31 B.1 
F H --CH.sub.3 
--NHCH.sub.2 C.sub.6 H.sub.5 
--CH.sub.3 
mp. 96.8.degree. C. 
- 32 B.2 F 
--CH.sub.3 --NHCH.sub.2 C.sub.6 
H.sub.5 --CH.sub.3 mp. 217.2.degree. 
C. 
- 
33 B.2 
H --CH.sub.3 --C.sub.6 H.sub.5 
--CH.dbd.CH--CH.dbd.CH--* 
.2HCl.H.sub.2 O mp. 
198.2.degree. 
C. 
__________________________________________________________________________ 
*: R.sup.6 and R.sup.7 taken together to form a bivalent radical of 
formula --R.sup.6 --R.sup.7 --- 
C. Pharmacological Example 
EXAMPLE C.1 
"Apomorphine, Tryptamine, Norepinephrine (ATN) Test in Rats" 
The central dopamine antagonistic and serotonin antagonistic activity of 
the subject compounds is evidenced by the experimental data obtained in 
the combined apomorphine (APO), tryptamine (TRY) and norepinephrine (NOR) 
test in rats. Said combined apomorphine, tryptamine and norepinephrine 
test is described in Arch. Int. Pharmacodyn., 227, 238-253 (1977) and 
provides an empirical evaluation of the relative specificity with which 
drugs may effect particular neurotransmitter systems centrally (CNS) as 
well as peripherally. In this test, rats were observed for effects or 
responses indicating peripheral and central activity. Central dopamine 
antagonism is evaluated by challenging rats, subcutaneously pretreated 
with different doses of the test compound, with apomorphine which is a 
dopamine agonist. Next, serotonin antagonism is evaluated by challenging 
the same rats, subcutaneously pretreated with different doses of the test 
compound, with tryptamine which is an agonist at serotonin 5HT.sub.2 
-receptors. Both central and peripheral serotonin antagonism can be 
assessed in this test. Centrally acting serotonin antagonists are 
potential antipsychotic drugs, in particular when simultaneously 
displaying dopamine antagonism in the first part of this test. Finally, 
.alpha.-adrenergic antagonistic activity of the test compounds is 
evaluated by challenging the same rats, subcutaneously pretreated with 
different doses of the test compound, with norepinephrine which is an 
.alpha.-adrenergic agonist. 
The experimental data are summarized in Table 3 and expressed as ED.sub.50 
values in mg/kg body weight, which are defined as the dose at which each 
of the tested compounds protects 50% of the tested animals from a relevant 
response evoked by the above-mentioned challenging substances. Column APO 
lists the results of the apomorphine challenge, indicating central 
dopamine antagonistic activity. Column TRY convulsions and TRY hyperaemia 
list the results of the tryptamine challenge, indicating central and 
peripheral serotonin antagonistic activity respectively. Column NOR lists 
the results of the norepinephrine challenge, indicating .alpha.-adrenergic 
antagonist activity. The favourable pharmacological properties of the 
compounds of formula (I) lie in their potent central dopamine (column APO) 
and serotonin (column TRY convulsions) antagonistic activity. 
TABLE 3 
______________________________________ 
Combined test in rats, ED.sub.50 in mg/kg 
Compound TRY TRY 
Number APO convulsions hyperaemia NOR 
______________________________________ 
11 0.31 0.31 .ltoreq.0.04 
&gt;10 
12 1.25 1.25 0.02 &gt;10 
13 2.5 5 .ltoreq.0.04 &gt;10 
14 0.31 1.25 .ltoreq.0.16 &gt;10 
15 0.31 0.31 .ltoreq.0.0025 &gt;10 
16 0.25 0.45 0.015 &gt;10 
17 0.08 0.5 .ltoreq.0.04 .gtoreq.10 
18 0.31 2 0.02 &gt;10 
19 8 1.25 0.31 5 
20 1.25 1.25 .ltoreq.0.63 5 
22 1.25 1.25 0.08 0.5 
23 0.12 0.08 .ltoreq.0.01 0.03 
24 5 1.25 .ltoreq.0.04 0.31 
25 0.31 0.12 0.02 0.08 
26 0.03 0.02 0.005 &gt;10 
27 0.31 0.31 0.005 &gt;10 
28 0.08 0.12 0.005 &gt;10 
29 5 5 0.02 .gtoreq.10 
30 .gtoreq.10 2 .ltoreq.0.16 &gt;10 
31 1.25 .gtoreq.10 .ltoreq.0.16 &gt;10 
______________________________________ 
D. Composition Examples 
"Active ingredient" (A.I.) as used throughout these examples relates to a 
compound of formula (I), a pharmaceutically acceptable addition salt or a 
stereochemically isomeric form thereof. 
EXAMPLE D.1 
Capsules 
20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose, 0.8 
g colloidal silicon dioxide, and 1.2 g magnesium stearate are vigorously 
stirred together. The resulting mixture is subsequently filled into 1000 
suitable hardened gelatin capsules, each comprising 20 mg of the A.I. 
EXAMPLE D.2 
Film-Coated Tablets 
Preparation of Tablet Core 
A mixture of 100 g of the A.I., 570 g lactose and 200 g starch is mixed 
well and thereafter humidified with a solution of 5 g sodium dodecyl 
sulfate and 10 g polyvinyl-pyrrolidone in about 200 ml of water. The wet 
powder mixture is sieved, dried and sieved again. Then there are added 100 
g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The 
whole is mixed well and compressed into tablets, giving 10.000 tablets, 
each comprising 10 mg of the active ingredient. 
Coating 
To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanol 
there is added a solution of 5 g of ethyl cellulose in 150 ml of 
dichloromethane. Then there are added 75 ml of dichloromethane and 2.5 ml 
1,2,3-propanetriol. 10 g of polyethylene glycol is molten and dissolved in 
75 ml of dichloromethane. The latter solution is added to the former and 
then there are added 2.5 g of magnesium octadecanoate, 5 g of 
polyvinyl-pyrrolidone and 30 ml of concentrated colour suspension and the 
whole is homogenated. The tablet cores are coated with the thus obtained 
mixture in a coating apparatus. 
EXAMPLE D.3 
Oral Solution 
9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl 4-hydroxybenzoate 
were dissolved in 4 l of boiling purified water. In 3 l of this solution 
were dissolved first 10 grams of 2,3-dihydroxybutanedioic acid and 
thereafter 20 grams of the A.I. The latter solution was combined with the 
remaining part of the former solution and 12 l 1,2,3-propanetriol and 3 l 
of sorbitol 70% solution were added thereto. 40 Grams of sodium saccharin 
were dissolved in 0.5 l of water and 2 ml of raspberry and 2 ml of 
gooseberry essence were added. The latter solution was combined with the 
former, water was added q.s. to a volume of 20 l providing an oral 
solution comprising 5 mg of the active ingredient per teaspoonful (5 ml). 
The resulting solution was filled in suitable containers. 
EXAMPLE D.4 
Injectable Solution 
1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl 4-hydroxybenzoate 
were dissolved in about 0.5 l of boiling water for injection. After 
cooling to about 50.degree. C. there were added while stirring 4 grams 
lactic acid, 0.05 grams propylene glycol and 4 grams of the A.I. The 
solution was cooled to room temperature and supplemented with water for 
injection q.s. ad 1 l, giving a solution comprising 4 mg/ml of A.I. The 
solution was sterilized by filtration and filled in sterile containers.