Compounds of diphenylcyclopentylamine type and methods for their preparation

Compounds of the formula ##STR1## and pharmaceutically acceptable salts thereof, wherein X and Y are the same or different and each represents a hydrogen atom, a chloro or a methoxy group, n is an integer 0 or 1 and R.sup.1 and R.sup.2 are the same or different and each representing a hydrogen atom or a methyl group; processes for their preparation; pharmaceutical preparations containing at least one of these compounds and the use thereof in the treatment of depressive states.

This invention relates to new compounds of the diphenylcyclopentylamine 
type and methods for their preparation. The invention also relates to the 
preparation of pharmaceutical preparations containing such compounds and 
to methods for the pharmacological use of the compounds. 
The main object of the invention is to provide compounds having 
psychopharmacological, especially anti-depressive properties. 
Depressions are considered to depend on changes in the biochemical 
processes of the brain which control the mood. The nature of this 
biochemical deficiency is largely unknown but in depressive states there 
is evidence for a decreased activity of monoaminergic brain neurons. The 
monoamines, noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine 
(5-HT), are of great interest in this respect. 
It has been demonstrated that NA, DA and 5-HT are localized in three 
different types of neurones and may function as transmittors in the 
central nervous system. The monoamines are stored in special structure, 
granules, situated in enlargements of the nerve endings, varicosities. The 
varicosity is separated from the effector neuron by a space, the synaptic 
cleft or spatium. As a result of a nerve stimulation, the transmittor is 
released from the granule into the synaptic cleft and reaches the receptor 
of the effector neuron and generates a nerve impulse. After impulse 
generation, the amines are inactivated by mainly two mechanisms: a 
re-uptake mechanism at the cell membrane and enzymatic conversion by 
cathechol-O-methyltransferase to form methylated metabolites. There is 
also an inactivating enzyme within the varicosities, monoamine oxidase 
(MAO), that is stored in the mitochondria and inactivates the amines 
intracellularly. 
When MAO-inhibitors are administered, an increased amount of transmittor 
substance becomes available for release at the nerve ending. 
Another way of increasing the amine levels at the receptor is exerted by 
the tricyclic antidepressants. It has been shown that this type of 
compound inhibits the re-uptake mechanism of NA and 5-HT, and the 
antidepressive action is assumed to be related to the uptake inhibition of 
NA and 5-HT. 
The overall clinical effect of the tricyclic anti-depressants consists 
according to Keilholz (Deutsch Med. Wschr. 93, 1968) of three main 
components in various proportions: 
1. Psychomotor activating or increase in drive 
2. Elevation of mood 
3. Relief of anxiety. 
It has been proposed that the correlation between the clinical effects and 
the biochemical changes in the adrenergic neurones might be that the NA 
neurones are involved in psychomotor activity and the 5-HT-neurones are 
involved in the elevation of mood. The third component, relief of anxiety, 
may be caused by blockade of the NA and DA receptors, but probably not the 
5-HT receptors. However, it should be pointed out that these theories are 
much simplified. 
A compound frequently used for controlling depressions is imipramine 
(Tofranil.RTM.) 
##STR2## 
This compound is both mood elevating and psychomotor activating, but it 
possesses several disadvantages. It is anticholinergic and causes 
anticholinergic symptoms such as dryness of the mouth, tremor, tachycardia 
and sweating. In higher doses it can provide serious heart arrythmias and 
in normal doses it can cause toxic interactions in persons with heart 
failures. Furthermore, another drawback of treatment with imipramine is 
the late onset of the antidepressive effect which effect is observable 
first after 3 weeks of treatment. 
According to the present invention, it has now been found that the 
above-mentioned disadvantages can be overcome by using compounds selected 
from the group consisting of compounds of the general formula 
##STR3## 
wherein X and Y are the same or different and each representing a hydrogen 
atom, a chloro or a methoxy group, n is an integer 0 or 1, and R.sup.1 and 
R.sup.2 are the same or different and each representing a hydrogen atom or 
a methyl group, and pharmaceutically acceptable acid addition salts 
thereof. 
The preferred compounds of the invention are those in which at least one of 
the groups X and Y is other than a hydrogen atom. Especially preferred is 
the compound 1-amino-3-(4-chlorophenyl)-3-phenylcyclopentane. 
Compounds described above which contain an asymmetric carbon atom exist in 
the form of optically active forms, and can be resolved into their optical 
antipodes by well-known methods such as by using optically active acids 
such as tartaric acid, camphor-10-sulphonic acid, dibenzoyl tartaric acid 
and the like. 
Some of the compounds described above can exist as stereoisomers, which 
forms constitute a further aspect of this invention. Mixtures of such 
isomers can be separated by methods known to the state of the art. 
For example, the preferred compound, 
1-amino-3-(4-chlorophenyl)-3-phenylcyclopentane, exhibits both optical and 
geometric isomerism. The optical isomerism results from the asymetric 
carbon atom attached to the amino group while the geometric isomerism 
results from the position of the chlorine substituted phenyl group with 
respect to the amino group. 
The compounds described above can be used as mixtures of the 
above-mentioned isomeric forms or in the form of pure isomers. 
The compounds of this invention with the general formula I can be prepared 
according to different methods. 
A. The compounds of the invention with the general formula 
##STR4## 
wherein X and Y have the meaning given above, can be obtained according to 
the reaction scheme 
##STR5## 
wherein X and Y have the meaning given above. 
B. The compounds of the invention with the general formula 
##STR6## 
wherein X, Y, R.sup.1 and R.sup.2 have the meaning given above can be 
prepared according to the reaction scheme 
##STR7## 
wherein X, Y, R.sup.1 and R.sup.2 have the meaning given above. 
C. The compounds of the invention with the general formula 
##STR8## 
wherein X, Y, R.sup.1 and R.sup.2 have the meaning given above can be 
obtained according to the reaction scheme 
##STR9## 
wherein X, Y, R.sup.1 and R.sup.2 have the meaning given above. 
D. The compounds of the invention with the general formula 
##STR10## 
wherein X and Y have the meaning given above, can be obtained according to 
the reaction scheme 
##STR11## 
wherein X and Y have the meaning given above. 
E. The compounds of the invention with the general formula 
##STR12## 
can be obtained by reacting a compound of the general formula 
##STR13## 
in which formulas X, Y, n, R.sup.1 and R.sup.2 have the previously given 
definition and Z is a hydroxy group, a halogen group, e.g. chlorine or 
another acid residue, e.g., an acid anhydride, with hydrozoic acid 
(HN.sub.3) or an inorganic salt thereof according to the conditions of the 
Schmidt reaction, which gives a primary amine, and if a secondary or 
tertiary amine is desired converting the obtained primary amine in ways 
known per se to the corresponding secondary or tertiary amine. 
In the cases where an intermediate acylic derivative or the like is 
obtained in any of the methods A - E hydrolysis is necessary to obtain the 
compounds of the formula I. 
Both organic and inorganic acids can be employed to form non-toxic 
pharmaceutically acceptable acid addition salts of the compounds of this 
invention. Illustrative acids being sulfuric, nitric, phosphoric, 
hydrochloric, citric, acetic, lactic, tartaric, pamoic, ethanedisulfonic, 
sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic and benzoic. These 
salts are readily prepared by methods known to the art. 
In clinical practice the compounds of the present invention will normally 
be administered orally, or by injection, in the form of pharmaceutical 
preparations comprising the active ingredient either as a free base or as 
a pharmaceutically acceptable non-toxic, acid addition salt, e.g., the 
hydrochloride, lactate, acetate, sulfamate, and the like, in association 
with a pharmaceutically acceptable carrier. Accordingly, terms relating to 
the novel compounds of this invention, whether generically or 
specifically, are intended to include both the free amine base and the 
acid addition salts of the free base, unless the context in which such 
terms are used, e.g., in the specific examples, would be inconsistent with 
the broad concept. The carrier may be a solid, semisolid or liquid diluent 
or capsule. These pharmaceutical preparations constitute a further aspect 
of this invention. Usually the active substance will constitute between 
0.1 and 95% by weight of the preparation, more specifically between 0.5 
and 20% by weight for preparation intended for injection and between 2 and 
50% by weight for preparations suitable for oral administration. 
To produce pharmaceutical preparations containing a compound of the 
invention in the form of dosage units for oral application, the selected 
compound may be mixed with a solid fine grain carrier, e.g., lactose, 
saccharose, sorbitol, mannitol, starches such as potato starch, corn 
starch or amylopectin, cellulose derivatives, or gelatin and a lubricant 
such as magnesium stearate, calcium stearate, polyethylene glycol waxes, 
and the like, and then compressed to form tablets. If coated tablets are 
required, the cores, prepared as described above, may be coated with a 
concentrated sugar solution which may contain, e.g., gum arabic, gelatin, 
talcum, titanium dioxide, and the like. Alternatively, the tablet can be 
coated with a lacquer dissolved in a readily volatile organic solvent or 
mixture of organic solvents. Dyestuffs may be added to these coatings in 
order to readily distinguish between tablets containing different active 
substances or different amounts of the active compound. 
For the preparation of soft gelatin capsules (pearl-shaped closed capsules) 
consisting of gelatin and, for example, glycerol or similar closed 
capsules, the active substance may be admixed with a vegetable oil. Hard 
gelatin capsules may contain granulates of the active substance in 
combination with solid, fine grain carriers such as lactose, saccharose, 
sorbitol, mannitol, starches (e.g. potato starch, corn starch or 
amylopectin), cellulose derivatives or gelatin. 
Liquid preparations for oral application may be in the form of syrups or 
suspensions, for example, solutions containing from about 0.2% to about 
20% by weight of the active substance herein described, the balance being 
sugar and a mixture of ethanol, water, glycerol and propyleneglycol. 
Optionally, such liquid preparations may contain coloring agents, 
flavoring agents, saccharine and carboxymethylcellulose as a thickening 
agent. 
Solutions for parenteral applications by injection can be prepared in an 
aqueous solution of a water-soluble pharmaceutically acceptable salt of 
the active substance preferably in a concentration of from about 0.5% to 
about 10% by weight. These solutions may also contain stabilizing agents 
and/or buffering agents and may conveniently be provided in various dosage 
unit ampoules. 
In therapeutical treatment the suitable diurnal doses of the compounds of 
the invention are 5-500 mg for oral application, preferentially 50-250 mg 
and 1-100 mg for parenteral application, preferentially 10-50 mg. 
The following examples will further illustrate the invention.

EXAMPLE 1 
1-Amino-3,3-diphenylcyclopentane [PUB 105] 
(a) 3,3-diphenylcyclopentanone (0.100 mole), hydroxylamine hydrochloride 
(0.250 mole), ethanol (100 ml) and pyridine (100 ml) were refluxed for two 
hours. The solvents were removed, water and chloroform added and the 
organic layer was separated. Chloroform was removed and the residue 
recrystallized from 90% ethanol. Yield 3,3-diphenylcyclopentanone oxime 
(85%). M.p. 113.degree.-115.degree. C. 
(b) The oxime (0.100 mole) was dissolved in ether (500 ml) and cooled to 
5.degree. C. Lithium aluminum hydride (0.250 mole) was added portionwise 
and the mixture was refluxed for 2 hours. After cooling, saturated sodium 
sulfate solution (75 ml) was added dropwise and the white precipitate was 
filtered off. The ether solution was extracted with 1 N HCl, the acid 
solution made alkaline and extracted with ether. After removing the ether, 
the residual 1-amino-3,3-diphenylcyclopentane crystallized. M.p. 
58.degree.-60.degree. C. Yield: 90% Hydrochloride: m.p. 
181.degree.-182.degree. C. 
According to the method described in Example 1, the following compounds 
were prepared: 
1-amino-3-(4-chlorophenyl)-3-phenylcyclopentane/PUN 122 /Hydrochloride m.p. 
251.degree.-254.degree. C. 
1-amino-3,3-di(4-chlorophenyl)cyclopentane/PUT 108 /Hydrochloride m.p. 
207.degree.-209.degree. C. 
1-amino-3-(4-methoxyphenyl)-3-phenylcyclopentane/PUT 104 /Hydrochloride 
m.p. 230.degree.-232.degree. C. 
EXAMPLE 2 
1-dimethylamino-3,3-diphenylcyclopentane/PUB 112/ 
To dimethylamine (1.00 mole) at -20.degree. C. was slowly added formic acid 
(0.25 mole). 3,3-diphenylcyclopentanone (0.100 mole) dissolved in 
N,N-dimethylformamide (100 ml) was added and the temperature allowed to 
rise. After boiling at 140.degree. C. for 5 hours, the solution was 
cooled. Benzene and water were added and the organic phase was extracted 
with 1 N HCl. The acid solution was made alkaline and extracted with 
benzene and ether. Removal of the solvents and distillation yielded the 
amine (80%). B.p. 150.degree. C./0.05 mm. M.P. 62.degree.-64.degree. C. 
Hydrochloride: M.p. 159.degree.-160.degree. C. 
According to the method described in Example 2, the following compounds 
were prepared: 
1-methylamino-3,3-diphenylcyclopentane/PUB 107 Hydrochloride m.p. 
197.degree.-199.degree. C. 
1-methylamino-3-(4-chlorophenyl)-3-phenylcyclopentane/PUN 125 
/Hydrochloride m.p. 209.degree.-211.degree. C. 
1-dimethylamino-3-(4-chlorophenyl)-3-phenylcyclopentane/PUN 123 
/Hydrochloride m.p. 168.degree.-170.degree. C. 
EXAMPLE 3 
1-aminomethyl-3,3-diphenylcyclopentane/PUE 119/ 
3,3-diphenylcyclopentanecarboxylic acid (0.100 mole) and thionyl chloride 
(100 ml) were refluxed for 2 hours. Thionyl chloride was removed and the 
residue was dissolved in ether. Ammonia was bled in for 2 hours, ammonium 
chloride filtered off and washed with benzene. The solvents were removed 
and the residual 3,3-diphenylcyclopentanecarboxylic acid amide 
crystallized from benzene/ether M.p. 118.degree.-119.degree. C. Yield: 
55%. 
The above amide (0.100 mole), dissolved in tetrahydrofuran (200 ml) was 
added dropwise to lithium aluminum hydride (0.250 mole) in tetrahydrofuran 
(200 ml). The mixture was refluxed for 3 hours, cooled, water and 15% NaOH 
was added and the mixture filtered. The filtrate was dried, the solvent 
removed and the residue distilled. B.p. 143.degree.-145.degree. C./0.2 mm 
Hg. n.sub.D.sup.25 = 1.5910. Yield 75%. Hydrochloride: m.p. 
186.degree.-187.degree. C. 
According to the method described in Example 3, the following compounds 
were prepared: 
1-methylaminomethyl-3,3-diphenylcyclopentane/PUE 122 /Hydrochloride m.p. 
221.degree.-223.degree. C. 
1-dimethylaminomethyl-3,3-diphenylcyclopentane/PUE 117 Hydrochloride m.p. 
220.degree.-222.degree. C. 
EXAMPLE 4 
1-amino-3,3-diphenylcyclopentane 
Method D 
To sodium (0.200 mole) dissolved in methanol (50 ml) was added 
3,3-diphenylcyclopentanecarboxylic acid amide (0.100 mole) in methanol (30 
ml). Bromine (0.100 mole) was added dropwise at 0.degree. C. The mixture 
was refluxed for 15 minutes and the methanol removed. Water (100 ml) was 
added, the solution made alkaline with ammonia and extracted with ether 
and benzene. The solvents were removed and the residue was refluxed in 
ethanol (500 ml) and 10 N NaOH (100 ml) for 4 hours. Ethanol was removed 
and the aqueous phase extracted with ether. 
The crude base was obtained after evaporation of the solvent. Yield: 50%. 
EXAMPLE 5 
1-amino-3,3-diphenylcyclopentane 
Method E 
To 3,3-diphenylcyclopentanecarboxylic acid (0.100 mole), in water (20 ml) 
and acetone (75 ml) at 10.degree. C. was added triethylamine (0.110 mole) 
in acetone (75 ml). Ethylchloroformate (0.120 mole) in acetone (50 ml.) 
was added at 5.degree. C. After one hour, sodium azide (1.50 mole) in 
water (30 ml) was added at 0.degree. C. 
After stirring at 0.degree. C. for one hour, the mixture was poured into 
water (500 ml) and the aqueous phase was extracted with ether. The ether 
was removed and the residue was heated with 70% aqueous acetic acid at 
100.degree. C. for two hours. Concentrated hydrochloric acid was added and 
the mixture was heated at 100.degree. C. for 15 hours. The solution was 
cooled and poured into ice water (500 ml) and made alkaline. The aqueous 
phase was extracted with ether and, after evaporation of the solvent, the 
residue was distilled. Yield: 65% B.p. 145.degree./0.1 mm Hg. M.p. 
72.degree.-73.degree. C. Hydrochloride: m.p. 181.degree.-183.degree. C. 
EXAMPLE 6 
Preparation of tablets 
(a) Each tablet contains: 
______________________________________ 
1-amino-3,3-diphenylcyclopentane-HCl 
10 mg 
Lactose 60 mg 
Starch 29 mg 
Magnesium stearate 1 mg 
______________________________________ 
The powders are mixed and directly compressed to tablets with a diameter of 
6 mm. 
The active substance shown above may be replaced by other pharmaceutically 
acceptable acid addition salts according to the invention. 
______________________________________ 
(b) 1-aminomethyl-3,3-diphenylcyclopentane 
50 mg 
Aerosil.sup..RTM. (silicium dioxide) 
20 mg. 
Lactose 100 mg 
Starch 30 mg 
Magnesium stearate 2 mg 
______________________________________ 
The active principle is mixed with the Aerosil.RTM.. This mixture is added 
to the other powders. Tablets are compressed with a diameter of 10 mm. 
The active substance shown above may be replaced by other pharmaceutically 
acceptable acid addition salts according to the invention. 
EXAMPLE 7 
Preparation of capsules 
______________________________________ 
(a) 1-amino-3,3-diphenylcyclopentane 
20 mg 
Peanut oil 60 mg 
______________________________________ 
The solution is filled into soft gelatine capsules. Each capsule containing 
20 mg of the active principle. 
The active substance shown above may be replaced by other pharmaceutically 
acceptable acid addition salts according to the invention. 
______________________________________ 
(b) 1-amino-3,3-diphenylcyclopentane 
10 mg 
Polyoxyethylene sorbitane monooleate 
100 mg 
______________________________________ 
The capsules are made as described above. 
The active substance shown above may be replaced by other pharmaceutically 
acceptable acid addition salts according to the invention. 
PHARMACOLOGICAL METHODS 
A. Biochemical Tests 
1. Inhibition of the uptake of tritiated 5-HT in vitro and in vivo 
The method is described by Ross and Renyi in European Journal of 
Pharmacology 7 (1969), 270-277. Tricyclic anti-depressant drugs of type 
imipramine given in vivo to mice decrease the uptake of .sup.3 H-5-HT in 
vitro. The drugs were administered intraperitoneally half an hour before 
the animals were killed and the midbrain was taken out and sliced and 
incubated in a mixture consisting of, per 100 mg of brain slices, 0.2 
.mu.mole of .sup.3 H-5-HT and 1 .mu.mole of glucose in 2 ml of 
Krebs-Henseleit buffer, pH 7.4. The incubation time was 5 minutes with 5 
minutes of preincubation before .sup.3 H-5-HT was added. The radioactive 
.sup.3 H-5-HT taken up in the slices was extracted with ethanol and the 
amount was determined by liquid scintillation. The dose producing 50% 
decrease of the active uptake (ED.sub.50) was determined graphically from 
dose response curves. Active uptake is defined as that part of the 
radioactive uptake which is inhibited by a high concentration of cocaine. 
All doses were given at least to four animals. 
2. Inhibition of the uptake of tritiated noradrenaline in vitro and in vivo 
The method is found in European Journal of Pharmacology 2 (1967), 181- 186. 
The animals were killed half or one hour after the administration of the 
drugs in vivo (i.p.). The slices, made from cortex, were preincubated for 
five minutes and incubated with 0.1 .mu.mole per ml of .sup.3 
H-noradrenaline for further five minutes. The incubation mixture consisted 
of 0.2 .mu.mole of .sup.3 H-NA and the brain slices in 2 ml of 
Krebs-Henseleits buffer, pH 7.4. The radioactive .sup.3 H-NA taken up in 
the slices was extracted with ethanol and the amount was determined by 
liquid scintillation. The dose producing 50 percent decrease of the active 
uptake (ED.sub.50) was determined graphically from dose response curves. 
At least four animals were used at each dose level. 
B. Pharmacological tests 
1. 5-HTP response potentiation test 
Inhibition of the uptake of 5-HT potentiates the effects of administered 
5-hydroxytryptophane (5-HTP) probably by increasing the amount of 5-HT at 
the receptor. Three mice are given the test drugs one hour (or 4, 24 
hours) before dl-5-HTP 90 mg/kg i.v. 5-HTP alone gives only a weak 
behavioral syndrome but in pretreated mice there is seen a characteristic 
behavioral syndrome, which comes within five minutes: tremor, lordosis, 
abduction of the hindlegs, head-twitches. 
These small movements are quantitatively measured in an activity box, type 
Animex, which can distinguish between small and gross movements. The 
activity is measured during 20 minutes and only in the case the animals 
have a fullblown syndrome. Each group consists of 3 animals and at least 4 
groups were tested at 25 mg/kg i.p. Control groups receiving imipramine 
(Tofranil.RTM.) are used as reference, since imipramine constantly 
potentiated dl-5-HTP. 
2. Dopa response potentiation test 
Inhibition of monoamine oxidase together with blockage of the uptake of NA 
potentiate the effects of administrated 1-Dopa. This test is developed by 
G. M. Everett (Antidepressant Drugs, ed. S. Carattini, 1966). 
Mice in groups of 3 are pretreated with Pargyline.RTM. 40 mg/kg p.o. about 
10-16 hours before the test. The test drugs are given i.p. one or four 
hours before 1-Dopa 100 mg/kg i.p. The mice are observed for one hour 
after 1-Dopa administration. 1-Dopa gives a characteristic syndrome which 
is scored as follows: 
1. piloerection, slight salivation, slight increased motor activity 
2. piloerection, salivation, marked increased motor activity and 
irritability 
3. piloerection, profuse salivation, marked irritability and reactivity, 
jumping, squeaking, fighting. 
The control groups are Amitriptyline (20 mg/kg i.p. 4 hours before 1-Dopa) 
and saline (1 hour before 1-Dopa). Amitriptyline always scores three at 
this dose whereas saline gives a one score. The test drugs were all tested 
at 10 mg/kg i.p. 
Motor activity in mice 
The exploratory activity of mice was recorded in a locomotion cage in which 
the movements were counted each time the animals cross-circuit an 
electrical current in the bottom plate. The activity was recorded for ten 
minutes one hour after the administration of the drug. The animals were 
tested individually. Groups of six mice were used and the mice were only 
used once. The activity was expressed in percent of the activity of 
control groups ran simultaneously. 
Acute toxicity, behavior and anticholinergic effect (mydriasis) in mice 
The compounds were given by intravenous route to 3 mice. LD.sub.50 is the 
dose which kills 50% of the animals within 24 hours. Seizures, gait, 
sedation and grip strength were recorded. Pupil width (mydriasis) which 
reveals peripheral anti-cholinergic action was measured in green light. 
These data are expressed in percent of control values 10 minutes after 
injection. PD.sub.200 is the dose which increases the pupil by 200%. 
Drug Induced Arrhythmia in Rats: ECG changes and LD.sub.50 
Rats were infused intravenously with test drugs and relevant reference 
compounds. The doses are increased stepwise. The first dose causing ECG 
changes of any type was noted, and thereafter the doses were increased up 
to the lethal dose. 
__________________________________________________________________________ 
5-HTP.sup.3) 
L-DOPA.sup.4) 
Motor 
poten- 
poten- 
acti- 
Inhibition (50 %) of uptake 
tiation 
tiation 
vity 
Mydriasis ECG 
in vitro in vivo 25 mg/kg 
10 mg/kg 
ID.sub.50 
PD.sub.200 
Acute toxicity 
LD.sub.50 
changes 
5-HT.sup.1) 
NA.sup.2) 
5-HT.sup.1) 
Na.sup.2) 
i.p. i.p. mg/kg 
mg/kg LD.sub.50 
i.v. 
i.v. 
Substance 
.mu.g/ml 
mg/kg 
i.p. 
1h 4h 1h 4h i.p. 
i.v. mg/kg i.v. 
rat 
rat 
__________________________________________________________________________ 
PUB 105 
0.18 
0.15 
10-20.sup.5) 
20.sup.5) 
12.5 
25 3 3 &gt;50 19 22 58 14 
PUB 107 
1 0.7 
&gt;40 20 0 2 2 &gt;50 15 30 
PUB 112 
0.7 0.4 
&gt;40 25 25 2.5 
2 &gt;50 &lt;1 18 
PUE 119 
0.34 
0.025 
&gt;40 0 0 0 1.5 
1.5 &gt;50 2.5 22 
PUE 122 
4.2 0.05 
&gt;40 5.5 0 3 3 &gt;50 &gt;12.5 15 
PUE 117 
3.6 2.3 
&gt;40 17 0 3 1.5 
&gt;50 &lt;1 30 
PUN 122 
0.7 0.3 
20 30 25 3 3 &gt;50 &gt;12.5 15 
PUN 123 
1 1 40 30 25 0 0 3 
3 &gt;50 &lt;10 30 
PUN 125 
2 1 &gt;40 &gt;40 0 1 1 
PUT 108 
1 2.5 
&gt;40 &gt;40 &gt;25 &gt;10 &gt;50 &gt;23 23 
PUT 104 
0.5 1 &gt;40 &gt;40 &gt;25 &gt;10 &gt;40 &gt;40 
Imipramine 
0.10 
0.06 
24 6 25 0 2 1 45 13 28 9.3 
4.7 
__________________________________________________________________________ 
.sup.1) 5-HT = 5-hydroxytryptamine 10.sup.-7 M 
.sup.2) Na = dl-noradrenaline 10.sup.-7 M 
.sup.3) 5-HTP = 1-5-hydroxytryptophane 
.sup.4) 1-DOPA = 1-3,4-dihydroxyphenyl-alanine 
.sup.5) long duration 
0 = without effect 
Evaluation of the results obtained in the pharmacological tests 
The results are summarized in the table. 
In vitro, compounds PUN 122, PUN 123, PUB 112, PUB 107, PUB 105 and PUT 104 
are potent inhibitors of the uptake of both 5-hydroxytryptamine and 
noradrenaline. Two compounds PUE 119 and PUE 122 are strongly effective in 
inhibiting the uptake of noradrenaline, while having a considerably weaker 
effect on the uptake of 5-hydroxytryptamine. In vivo, strong inhibition of 
the uptake of both 5-hydroxytryptamine and noradrenaline is seen for 
compounds PUN 122, PUN 123 and PUB 105. Both PUN 122 and PUB 105 inhibit 
the uptake mechanism for a much longer time than does the reference 
substance imipramine. For PUB 105 and PUN 122 the uptake inhibition 
increases with time and it is maximal after four hours and it is still 
pronounced after 16 hours. Strong inhibition of the uptake of 
noradrenaline only is seen with compounds PUE 119 and PUE 122 and to a 
somewhat lower degree in PUE 117, PUB 107 and PUB 112. The uptake 
inhibition of the compounds of the invention having the amino nitrogen 
atom bound directly to the ring structure, e.g., PUN 122, PUN 123 and PUB 
105 differs from the known compound imipramine in having a substantially 
nonselective ability towards noradrenaline. Such nonselective activity may 
be desirable in the treatment of certain depressive disorders, especially 
in those disorders which are connected with synaptical lack of both said 
transmittors or in cases when it is known which transmittor is lacking. 
The interaction with 5-hydroxytryptophane and 1-dopa correlates well with 
the uptake inhibition of 5-hydroxytryptamine and noradrenaline. The 
intravenous toxicity of the compounds is about comparable to that of 
imipramine. PUB 105 has much weaker peripheral anticholinergic effects 
than imipramine, and causes ECG changes in a dose 3 times higher than that 
of imipramine. These results indicate that in this series of compounds it 
is possible to differentiate the uptake inhibition from the unwanted side 
effects and to find potent inhibitors of the uptake of 5-hydroxytryptamine 
and/or noradrenaline in the brain.