DE2227842A1 - Diphenylcyclopentyl derivatives and processes for their preparation - Google Patents

Description

Dr. Hans-Heinrich Wilirath _D _ ₆₂ Wiesbaden June 6, 1972

Dr. Dieter Weber. 222 7842 r-äaijot n / ep

rx. ι TM r / 1 r · .rr Gustav-Freytag-Strasse 25

Dipl.-Phys. Klaus praises «(o *!«!) »» »

'Telegram address: WILLPATENT

PATENT LAWYERS

LA 292-1 Vty

Astra Läkemedel Aktiebolag Kvarnbergagatan 16, S-151 85 Södertälje

Sweden

Diphenylcyclopentyl derivatives and processes for their preparation

Priority: from June 1st, 1971 in Sweden Note No .: 7631/71

The invention relates to new compounds from diphenylcyclopenty land, η ty ρ and process for their preparation. Also concerns the invention the production of pharmaceutical preparations containing such compounds, as well as methods for the pharmacological use of the compounds.

The main aim of the invention is to find compounds with psychopharmacological, particularly antidepressant properties, to obtain.

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2098 5 2/1109

ORIGINAL

«· O M.

Depression depends on changes in the brain's biochemical processes that regulate mood. the The nature of this biochemical deficiency symptom is world-wide unknown, but it appears in depressive states Decreased activity of monoamlnergic brain neurons on. The monoamines, norepinephrine (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT), are of great interest in this relationship.

It has been demonstrated that NA, DA and 5-HT are localized in three different types of neurons and act as transmitters in the Central nervous system can act. The monoamines are stored in special structures called granules that are in Enlargements of the nerve endings, varicosities, are located. The varicosity is from the nerve end organ through one Intermediate space, the synaptic gap or synaptic space, separated. As a result of nerve stimulation, will the transmitter delivered by the granule into the synaptic cleft and reaches the receptor of the nerve end organ and develops a nerve impulse. After the impulse development, the amines are inactivated mainly by two mechanisms: a reuptake mechanism on the cell membrane and an enzymatic conversion by catechol-O-methyltransferase with the formation of methylated metabolites. It there is also an inactivating enzyme in the varicose veins,

209852/1 109

namely monoaraine oxidase (MAO), which is found in the mitochondria is stored and the amines are inactivated intracellularly.

When MAO inhibitors are administered, there is an increased Amount of the transmitter substance for delivery to the nerve end available.

Another way of increasing the amine concentration at the receptor is through the tricyclic antidepressants. It has been shown that this type of compound is responsible for the recovery mechanism of KA and -5-KT, and it is believed that the antidepressant effect is related to the inhibition of uptake from NA and 5-HT stands.

The overall clinical effect of tricyclic antidepressants is according to Kielholz (German medical weekly publication 93, 1968) from three main components in different proportions:

1. Psychomotor activation or increase in drive,

2. mood enhancement,

3. Reduction of anxiety.

It has been suggested that the relationship between the clinical Effects and the biochemical changes in the adrenergic neurons could be that of the NA neurons have something to do with psychomotor activity and the 5-HT neurons have something to do with mood enhancement. The third component, the curvature reduction, can be achieved by,

'/ U;) a!,? / 1 1 0 9

a blockade of the NA and DA receptors / but probably not caused by the 5-HT receptors. It should be noted, however, that these theories are greatly simplified are.

A compound commonly used for depression control is imipramine (Tbfranil K ^)

This connection is both accelerating and psychomotor activating, but it has different ones Disadvantage. It is anticholinergic and causes anticholinergic symptoms such as dryness of the mouth, tremor, Tachycardia and sweats. In higher doses it can cause serious cardiac arrhythmias, and in no At doses it can cause toxic disorders in people with heart defects. Also, another disadvantage is one Treatment with imipramine the late onset of antidepressant effects, which can only be observed after three weeks of treatment is.

In accordance with the present invention it has now been found that these disadvantages can be overcome by making a connection from the group of the general formula

- 5th

2098S? / 11P9

_ ₅ _ 22278A2

used, wherein X and Y are the same or different and each is a hydrogen atom. Chlorine atom or mean a methoxy group, η is 0 or i and R and

R are identical or different and each represent hydrogen atoms or methyl groups, or if one is pharmaceutical compatible acid addition salts of these compounds used.

The above-described compounds containing an asymmetric carbon atom lie as optically active forms before and can be split into their optical antipodes by methods known per se, such as, for example by using optically active acids such as tartaric acid, camphor-10-sulfonic acid, dibenzoyltartaric acid and the like.

Some of the compounds described above may exist as stereoisomers, which is a further aspect of the present Invention represents. Mixtures of such isomers can be separated by methods known in the art.

The compounds described above can be used as mixtures of the mentioned isomeric forms or in the form of pure isomers.

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~ 6 -

be used. The compound of the invention that is particularly preferred is 1-amino-3,3-diphenylcyclopentane.

The compounds according to the invention with the general formula I can be prepared by different methods will.

A. The compounds according to the invention having the general formula

where X and Y have the above meaning, one can get according to the following reaction scheme:

.Y X

Reduction. medium _v

NOH

2 0 9 8 5 2/1109

where X and Y have the above meanings.

B. The compounds of the invention having the general formula χ

1 2 where X, Y, R and R have the above meaning be prepared according to the following reaction scheme:

HN

-R ¹

Reducing agent

1 2 wherein X, Y, R and R have the above meaning.

C. The compounds according to the invention having the general formula. '"

, γ

209R52 / 1109

in which X, Y, R ¹ and R ^{2 have} the above meanings, can be obtained according to the following reaction scheme:

» Fe-Ä - SOCl,

^w

COOH

COCl

Reduction

. middle

1 7
wherein X, Y, R ^x and R have the above meanings.

^D » The compounds according to the invention with the general formula

X Y

2 0Ρ857 / 11Π9

where X and Y have the above meaning, can be obtained according to the following reaction scheme:

where X and Y have the above meanings.

E. The compounds according to the invention having the general formula

can be achieved by reacting a compound of the general formula

2 ^y n

7/1109

22278A2

- Io -

1 2
wherein X, Y, η, R and R are as defined above and Z is a hydroxyl group, a halogen atom such as a chlorine atom, or another acid residue such as an acid anhydride, with hydrazoic acid (HN ₃ ) or an inorganic salt thereof among those Obtain Schmidt reaction conditions which yield a primary amine. If a secondary or tertiary amine is desired, the primary amine obtained is converted into the corresponding secondary or tertiary amine in a manner known per se.

In the cases where an acyclic derivative or the like is obtained as an intermediate in any of Methods A to E. hydrolysis is required to make the compounds of formula I.

Both organic and inorganic acids can form non-toxic, pharmaceutically acceptable acid addition salts of the compounds according to the invention can be used. Examples of such acids are sulfuric acid, Nitric acid, phosphoric acid, hydrochloric acid, citric acid, Acetic acid, lactic acid, vreic acid, pamoic acid, ethanedisulphonic acid, sulphamic acid, succinic acid, cyclohexylsulphamic acid, Fumaric acid, maleic acid and benzoic acid.

These salts are easily prepared by methods known per se.

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709852/1109

In clinical practice, the compounds of the present invention will normally be administered orally or by injection administered in the form of pharmaceutical preparations containing the active ingredient either as a free base or as a pharmaceutical Compatible, non-toxic acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate or the like, in Comprising compound with a pharmaceutically acceptable carrier. Thus, if here from the new connections according to the invention, both the free amine base is used in each case with the general term as well as in individual cases as well as the acid addition salts of the free base are meant, unless the overall context in which these Terms used as in the specific examples are inconsistent with this broader meaning. The carrier can be a solid, semi-solid, or liquid diluent or a capsule. This pharmaceutical Preparations form another aspect of this invention. Usually the active substance makes up 0.1 to 95% by weight of the Preparation, more specifically 0.5 to 20% by weight for preparations for injections and 2 to 50% by weight for preparations for oral use Administration.

For the production of pharmaceutical preparations which contain a compound according to the invention in the form of dosage units for oral administration, the selected compound can be coated with a solid, fine-grained carrier, like lactose, sucrose, sorbitol, mannitol, starches like potato starch, Corn starch or amylopectin, cellulose derivatives

_

? 0 9 "Π 7/1 1 0 9

th or gelatin, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol waxes and the like. mixed and then compressed into tablets. If coated tablets are required, the cores, which have been prepared as described above, can be coated with a concentrated sugar solution, for example gum arabic, gelatin, talc, titanium dioxide and the like. contains. Instead, the tablet can also be coated with a lacquer that is dissolved in a volatile organic solvent or a mixture of organic solvents. Colorants can be added to these coatings to easily distinguish between tablets of different active substances or different amounts of the active compound.

For the production of soft gelatin capsules (pearl-shaped closed capsules) made from gelatin and for example Glycerin, or similar closed capsules, the active substance can be mixed with a vegetable oil. Hard gelatin capsules can contain granules of the active substance in combination with solid, fine-grained carriers, such as lactose, sucrose, sorbitol, mannitol, starches (such as potato starch, corn starch or amylopectin), Contain cellulose derivatives or gelatin.

Liquid preparations for oral administration may be in the form of syrups or suspensions, such as than solutions containing about 0.2 to about 20% by weight of the here

2 (19857/1109 "" "

contain active substance described, the remainder of sugar with a mixture of ethanol, water, glycerin and propylene glycol. If necessary, such liquid preparations can also contain coloring agents that improve taste Contains agents, saccharin and carboxymethyl cellulose as thickeners.

Solutions for parenteral administration by injection can be prepared in such a way that an aqueous solution of a water-soluble pharmaceutically acceptable Salt of the active substance, preferably with a concentration from about 0.5 to about 10 weight percent. This solution may also contain stabilizing agents and / or buffering agents, and conveniently on ampoules of various Dosage units' are withdrawn. In the therapeutic For treatment, the suitable daily dosages of the compounds according to the invention are from 5 to 500 mg, preferably at 50 to 250 mg, for oral administration and at 1 to 100, preferably 10 to 50 mg, for parenteral administration.

The following examples serve to further illustrate the invention.

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example 1

l-amino-3, S-diphenylcyclopentane / PUB 105 /

aj ^ 3,3-Diphenylcyclopentanone (0.100 moles), hydroxylamine hydrochloride (0.25OMol), ethanol (100ml) and pyridine (100 ml) was refluxed for 2 hours. The solvents were removed, water and chloroform were added, and the organic layer was separated. The chloroform was removed and the residue from 90% Recrystallized ethanol. Yield 3,3-diphenylcyclopentanone oxime (85%), m.p. 113-115 ° C.

b) _ The oxime (0.100 mol) was dissolved in ether (500 ml) and cooled to 5 ° C. Lithium aluminum hydride (0.250 mol) was added portionwise and the mixture allowed to stand for 2 hrs. heated to reflux. After cooling, a saturated sodium sulfate solution (75 ml) was added dropwise and the white precipitate was filtered off. The ether solution was extracted with 1 η HCl, the acidic solution became alkaline made and extracted with ether. After removal of the ether, the remaining l-amino-3,3-diphenylcyclopentane crystallized, M.p. 58 to 60 ° C, yield 90%. Hydrochloride: 181-182 ° C.

Using the same method, the following connections were also made:

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1-Amino-3- (4-chlorophenyl) -3-phenylcyclopentane / PUN 1227

Hydrochloride m.p. 251-254 ° C

l-Amino-3,3-di- (4-chlorophenyl) -cyclopentane / PUT 1087 Hydrochloride F. 207 to 209 ° C

l-Amino-3- (4-methoxyphenyl) -3-phenylcyclopehtane / PUT 104 ^ 7

Hydrochloride F.230 bis. 232 ° C.

Example 2

l-dimethylamino-3,3-diphenylcyclopentane / PUB 1127

To dimethylamine (1.00 MoI) of -20 ⁰ C was slowly added formic acid (0.25 mol) was added. 3,3-Diphenylcyclopentanone (0.100 mol) dissolved in N, N-dimethylformamide (100 ml) was added and the temperature allowed to rise. After boiling at 150 ° C. for 5 hours, the solution was cooled. Benzene and water were added and the organic phase was extracted with 1 η HCl. The acidic solution was made alkaline and extracted with benzene and ether. Removal of the solvents and distillation gave the amine (80 %), b.p. _{f (Q5} = 150 ° C, mp = 62 to 64 ° C. Hydrochloride: mp 159 to 160 ° C.

The following compounds were also made by the same method manufactured:

1-methylamino-3,3-diphenylcyclopentane / PUB 1077 Hydrochloride M. 197 to 129 ° C

, - 16 -

? (J 9857/110 9

1-methylamino-3- (4-chlorophenyl) -3-phenylcyclopentane / PUN 125_7

Hydrochloride F. 209-211 ° C

1-Dimethylamino-3r (4-chlorophenyl) -3-phenylcyclopentane / PUE 1197

Hydrochloride m.p. 168-170 ° C

Example 3

1-aminomethyl-3,3-diphenylcyclopentane / PUN 123_7

S ^ -diphenylcyclopentanecarboxylic acid (0.100 mol) and thionyl chloride (100 ml) were refluxed for 2 hours. The thionyl chloride was removed and the residue dissolved in ether. Ammonia was introduced for 2 hours, the ammonium chloride was filtered off and washed with benzene. The solvents were removed and the remaining S ^ -diphenylcyclopentanecarboxamide was removed from benzene / Ether recrystallized. 118-119 ° C, 55% yield.

The above amide (0.100 moles) dissolved in tetrahydrofuran (200 ml) was added dropwise to lithium aluminum hydride (0.250 mol) in tetrahydrofuran (200 ml) was added. The mixture was refluxed for 3 hours, cooled, water and 15% sodium hydroxide solution were added and the mixture was filtered. The filtrate was dried, the Removed solvent and distilled the residue.

^Kp * 0.2 mm Hg ^{= i43 to 145} ° ^{c 'n} ^ ^{= 1} ^ ^910' yield 75%. Hydrochloride: m.p. 186-187 ° C.

- 17 209857 / 110P

- χ / -

Using the same method, the following connections were also made:

1-methylaminomethyl-3,3-diphenylcyclopentane / PUE 122: 7

Hydrochloride M. 221-223 ° C
1-Dimethylaminomethyl-S ^ -diphenylcyclopentane / PUE. 117 /

Hydrochloride F. 220 to 222 ° C.

Example 4

1-amino-3,3-f-diphenylcyclopentane

Methgde_D

To sodium (0.200 mol) dissolved in methanol (50 ml) was added S ^ -diphenylcyclopentanecarboxamide (0.100 mol) in methanol (30 ml). Bromine (0.100 mol) was added dropwise
at ⁰ ° C. added. The mixture was refluxed for 15 minutes and the methanol removed. Water (100 ml) was added, the solution was 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 η NaOH (100 ml) for 4 hours. The ethanol was removed and the aqueous phase extracted with ether.

The crude base was obtained after evaporation of the solvent, yield 50%.

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2098 5 7 / Π09

Example 5

1-amino-3,3-d.iphenylcyclopentane Method E.

Triethylamine (0.110 mol) in acetone (75 ml) was added to S ^ -diphenylcyclopentanecarboxylic acid (0.100 mol) in water (20 ml) and acetone (75 ml) at 10.degree. Ethyl chloroformate (0.120 mol) in acetone (50 ml) was added at 5 ° C. After 1 hour, sodium azide (1.50 mol) in water (30 ml) was added ^{at 0 ° C.}

After stirring at ⁰ ° C. for 1 hour, the mixture was poured into water (500 ml) and the aqueous phase was extracted with ether. The ether was removed and the residue is heated with 70% aqueous acetic acid for 2 hours at 100 ⁰ C. Concentrated hydrochloric acid was added and the mixture was heated at 100 ° 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%, bp _{Q χ} ^ _{n H} = 145 ° C, m.p. = 72 to 73 ° C.

Hydrochloride: mp 181-183 ° C.

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2098R9 / 1109

Example 6

Manufacture of tablets

a) Each tablet contains:

1-Amino-S / S-diphenylcyclopentane HCl 10 mg

Lactose 60 mg

Strength . 29 mg

Magnesium stearate 1 mg

The powders are mixed with one another and pressed directly into tablets with a diameter of 6 mm. the The active substance specified above can also be replaced by other pharmaceutically acceptable acid addition salts according to the Invention to be replaced.

1-aminomethyl-3,3-diphenylcyclopentane 50 mg

Aerosil ^ (silicon dioxide) 20 mg

Lactose 100 mg

Strength 30 mg

Magnesium stearate 2 mg

The active ingredient is mixed with the Aerosil ^. This mixture is added to the remaining powders. Tablets with a diameter of 10 mm are pressed.

The active substance shown above can be pharmaceutically by others compatible acid addition salts according to the invention

can be replaced.

- 2ο -

Example 7

Manufacture of capsules

1-Amino-S ^ -diphenylcyclopentane 20 mg

Peanut oil 60 mg

The solution is filled into soft gelatin capsules. Each capsule contains 20 mg of the active substance.

The active substance shown above can also be obtained by others pharmaceutically acceptable acid addition salts are replaced according to the invention.

1-amino-3,3-diphenylcyclopentane 10 mg

Polyoxyethylene sorbitan monooleate 100 mg

The capsules are made as described above.

The active substance shown above can also be replaced by other pharmaceutically acceptable acid addition salts according to the Invention to be replaced.

? 0 9 8 5? / 1 1 Π

Pharmacological methods A. Biochemical experiments

1. Inhibition of 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), pages 270-277. Imipramine-type tricyclic antidepressants, when administered in vivo to mice, decrease the in vitro uptake of H-5-HT. The agents were administered intraperitoneally 1/2 hour before the animals were sacrificed, and the midbrain was removed, cut into slices and incubated in a mixture containing 0.2 μmol per 100 mg of the brain slices

H-5-HT and 1.0 µmole of glucose in 2 ml of Krebs-Henseleit buffer at pH 7.4. The incubation time was 5 minutes with 5 minutes preincubation before H-5-HT was added. The uptake of radioactive H-5-IIT in the brain slices was extracted with ethanol and the amount determined by liquid scintillation. The dose that results in a 50% reduction in active substance intake (ED _ςο),

2 0 9 8 5 2/1109

was determined graphically from the dose-result curves. The uptake of active substance is defined as that part of the radioactive uptake that is inhibited by a high concentration of cocaine. All dosages were at least

Administered to 4 animals.

2. Inhibition of the uptake of tritiated norepinephrine in vitro and in vivo

The method can be found in European Journal of Pharmacology 2 (1967), pages 181 to 186. The animals were sacrificed 1/2 or 1 hour after administration of the agents in vivo (ip). The discs that were made from the cortex were 5 microns

per ml -> slots preincubated and further with 0.1 µmol / il-norepinephrine

Incubated for 5 minutes. The incubation mixture consisted of 0.2 »H-NA and the brain slices in 2 ml of Cancer" Henseleits-Puf he f

of pH 7.4. The uptake of radioactive H-NA in brain slices was extracted with ethanol, and the amount was determined by liquid scintillation. The dose which resulted in a reduction in the absorption of active constituents (ED _1st ) was determined graphically from the dose-result curves. At least 4 animals were used for each dose.

B. Pharmacological tests
1. 5-HTP potentiation test

Inhibiting the uptake of 5-HT potentiates the effects of administered 5-hydroxytryptophan (5-HTP), probably by increasing the amount of 5-'IT on the receptor. 3 mice received the Ter.tr :; π dance 1 hour (or 4 or 24

2098R? / 1109

Hours) before dl-5-HTP 90 mg / kg i.v. 5-HTP alone gives only a weak behavioral syndrome, but a characteristic behavioral syndrome can be seen in previously treated mice, that occurs within 5 minutes: tremor, lordosis, muscle movement of the hind legs, head twitching.

These small movements are measured quantitatively in an activity box, type Animex, which can differentiate between small and large movements. The activity is measured for 20 minutes and only in the event that the animals have a fully developed syndrome. Each group consists of 3 animals and at least 4 groups were tested at 25 mg / kg ip. Control groups that received imipramine (Tofranil * ~ *) were used as a reference value, since imipramine constantly potentiates dl-5-HTP.

2. Dopa potentiation test

The inhibition of Monoartd.noxid.ase along with the blocking the ingestion of NA potentiates the effects of administered 1-dopa. This test was carried out by G.M. Everett (antidepressant Drugs, edited by S. Carattini, 1966). ·

Mice in groups of 3 animals were given Pargyline ^, 40 mg / kg po about 10 to 16 hours prior to testing. The test substances are administered i.p. 1 or 4 hours before 1-dopa, 100 mg / kg i.p. administered. The mice are 1 hour after the administration of 1-dopa was observed. 1-dopa results in a

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? η 3 κ R -? / 11 ο 9

characteristic syndrome with the following score:

1. Piloerection, slight salivation, slightly increased motor activity.

2. Piloerection, salivation, markedly increased motor activity and irritability.

3. Piloerection, profuse salivation, noticeable irritability and reactivity, jumping around, squeaking, aggressiveness.

The control groups received amitriptyline (20 mg / kg i.p. 4 hours before 1-dopa) and saline (1 hour before 1-dopa). Amitriptyline always gives three points at this dosage, while saline only gives one point. -The test substances were all given at 10 mg / kg i.p. tested.

Motor activity in mice

The study activity of mice was in an exercise cage recorded in which the movements were counted in which the animals made an electrical circuit closed in the base plate. The activity was for 10 minutes, 1 hour after administration of the substance, recorded. The animals were tested individually. Groups of 6 mice were used and the mice were only used once. The activity was as a percentage of the activity expressed by control groups examined at the same time.

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Acute toxicity, behavior and anticholinergic effects (mydriasis) in mice

The compounds were administered to 3 mice by the intravenous route. LDc ₀ is the dose that kills 50% of the animals within 24 hours. Seizures, posture, sedation, and grip were recorded. Pupillary width (mydriasis), which reveals peripheral anticholinergic effects, was measured in green light. These values are expressed as a percentage of control values 10 minutes after injection. PD «- is the dose that dilates the pupil by 200%.

Test substance induced arrhythmia in rats'; ECG changes and LD ₅₀

Rats received test substances and reference compounds intravenously by infusion. The doses were gradually increased. The first dose that caused changes in the EKG of any kind was recorded, and thereafter were taken the doses increased up to the lethal dose.

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2098R7 / 1109

Tabel

substance Escapement (50 , µg / ml 1 %) the recording NA ² > 6.5 5-HTP ³⁾ pots l ^h i
I.
decoration in 'vitro 18 0.15 - in vivo i.p. 5.5 12.5 5-HT ¹ ) NA ² ) - 2/5 5-HT ¹ * 5) _2O 5) 17th 25 mg / kg O i.p. 105 - 5 1 mg / kg - - 25th 4 ^h : P-UB 107 O, 34 0.025 10 0.06 10-20 - 30th O 25th PUB 112 - 2 0.05 > 40 - O PUB 119 * __ 6 2.3 > 40 > 40 O PUE 122 O, 3 > 40 > 40 25th PUE 117 4, > 40 6th 25th PUE 122 3, > 40 O PUK 123 O, 20th > 25 pu :; 125 1 40 > 25 O PUN 108 - - 25th PUT 104 1 > 40 PUT Imiprarain O, > 40 O, 24 O

(Continued)

Table (Fortr-otxg.)

1) 5-HT = 5-hydroxytryptamine 10 ~ ^ M

2) NA = dl-norepinephrine 10 M

3) 5-HTP = 1-5-hydroxytryptophan

4) 1-dopa = 1- ^ 3,4-dihydroxyphenylalanine

5) long duration

0 = no effect

1-Dopa 'potentiation l ^h ig / kg ip XiIO tor is marriage Mydriasis acute LD ^ _n . "EKG 3 4- ^h activity ^PD 200 Toxicity τ, ^, ΙΙ ' changes
τΤι * K3ti.cn j,
LDcλ iV
^{D. u} .... - rats 2 3 mg / kg i.p. mg / kg i.v. mg / kg i.v. - - 10 ir 2.5 2 . 1.5 2 > 50 19th 22 58 14 3 1 β > 50 15th 30th 3 3 > 50 <1 18th 3 1.5 > 50 2.5 22nd 3 3 > 50 > 12.5 15th 1 3 > 50 <ι 30th > 10 1 > 50 > 12.5 15th > 10 > 50 <10 30th 2 1 > 50 > 23 23 > 40 > 40 45 13th 28 9.3 4.7

Evaluation of the pharmacological Try results obtained

The results are compiled in the table.

The compounds according to the invention block the uptake of noradrenaline and 5-hydroxytryptamine in brain slices in vitro and in vivo. The compounds PUE 119 and PUE 122 are about as effective as imipramine in blocking the Uptake of norepinephrine in vivo. PUB 105 is about twice as effective as imipramine in inhibiting 5-HT uptake, while PUN 122 is somewhat more effective, and both agents inhibit the diaphragm pump for much longer. In the connections PUB 105 and PUN 122 the inhibition of admission increases with time and is maximum after 4 hours and after 16 hours, strong. The interaction with 5-hydroxytryptophan and 1-dopa is in good agreement with the inhibition of the uptake of 5-hydroxytryptamine and norepinephrine. Intravenous toxicity the compounds is roughly comparable to that of imipramine. PUB 105 possesses much weaker peripheral anticholinergic Effects than imipramine, causing EKG changes at a dose three times higher than imipramine and is much less toxic to rats. These results show that in this series of connections it is possible to distinguish the inhibition of uptake from the undesirable side effects and potent and selective inhibitors for the Finding amine uptake in the brain.

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2 0 9 R B? / 1 1 0 9

Claims (11)

Claims where X and Y are identical or different and each represent hydrogen atoms, chlorine atoms or methoxy groups, 1 2
η denotes 0 or 1 and R1 and R2 are identical or different and each denotes hydrogen atoms or methyl groups, and their pharmaceutically acceptable acid addition salts. 2.) Compounds according to claim 1 in the form of a pure isomer. 3.) Compounds according to claim 1 and 2 in the form of an optical pure isomer. 4.) l-Amino-3,3-diphenylcyclopentane and its pharmaceutical compatible acid addition salts. 5.) (+) - l-Amino-3,3-diphenylcyclopentane and its pharmaceutical compatible acid addition salts. - 3o - 2098 5 7/1109 - 3ο - 6.) (-) - l-Amino-3,3-dlphenylcyclopentane and its pharmaceutically acceptable acid addition salts. 7.) Process for the preparation of compounds of the general formula .R ¹ "R ¹ and their pharmaceutically acceptable salts, wherein 1 2 X, Y, n, R and R have the above meanings, characterized in that one is a compound of the general formula : —Y - 31 - 209RR2 / 110Q 7227842 where X _r Y and n. have the above meaning and Z is a hydroxyl group, a halogen atom or another acid radical, with hydrazoic acid (HN-) or an inorganic salt thereof under the conditions of the Schmidt reaction to form a primary amine and, if a secondary or tertiary amine is desired, the primary amine obtained is converted into the corresponding secondary or tertiary amine in a manner known per se and the compound of the formula I thus obtained is optionally split into its isomers and / or its pharmaceutically acceptable · borrowed Salts transferred. 8.) Process for the preparation of compounds of the general formula where X and Y have the above meanings, and of their pharmaceutically acceptable salts, characterized in that one - 32 - a) a compound of the general formula 2277842 wherein X and Y have the above meaning, reduced or b) a compound of the general formula wherein X and Y have the above meaning, for example with hypobromite and then optionally converting the compound thus obtained into a stereoisomer of the same and / or in a pharmaceutically acceptable acid addition salt thereof transferred. 9.) Process for the preparation of compounds of the general formula - 33 - 2 0 9 8 Π? / 1 1 0 9 1 2
wherein X, Y, R and R have the above meanings, and of their pharmaceutically acceptable salts, characterized in that that one is a compound of the general formula wherein X and Y have the above meaning with a compound of the general formula pin code 12 '
wherein R and R have the above meaning, converts and optionally then convert the compound thus obtained into a stereoisomer thereof and / or a pharmaceutically acceptable acid addition salt same transferred. 10.) Process for the preparation of compounds of the general formula - 34 - 20985? / 1109 CH ₉ - N'T ₀ 1 2 wherein X, Y, R and R have the above meanings , and of pharmaceutically acceptable salts thereof, characterized in that a compound of the general formula 1 2 wherein X, Y, R and R have the above meanings, and optionally converts the compound thus obtained into a stereoisomer thereof and / or a pharmaceutically acceptable acid addition salt thereof. 11.) Agent for the treatment of depression, characterized in that it contains at least one of the compounds according to claims 1 to 6 , possibly in conjunction with a known and customary pharmaceutically acceptable carrier material. 209R52 / 1 109