Agents with an antidepressive effect

The present invention relates to an antidepressant containing 2-amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole, the (+) or (-) enantiomer thereof, their pharmacologically compatible acid addition salts in combination with sertraline. The invention also relates to the use of this agent.

Pramipexole, (-) - 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole, is a dopamine-D3 / D2 agonist, the synthesis of which is described in European Patent No. 186,087 and United States Patent No. 4 886 812. Pramipexole is known primarily for its use in the treatment of schizophrenia and in particular in the treatment of Parkinson's disease. DE 38 43 227 discloses that pramipexole reduces serum prolactin levels. In addition, it is known from DE 39 33 738 that pramipexole is used to reduce a high level of TSH. US Patent No. 5,112,842 discloses and in Patent Application No. WO PCT / EP93 / 03389 the use of pramipexole as an antidepressant.

Details on the preparation of the title compound can be taken from EP-A-85 116 016 and the reader of the text is referred specifically to the literature cited therein.

It has surprisingly been found that pramipexole, its (+) or (-) enantiomer, or its pharmacologically compatible acid addition salts, when used in combination with another antidepressant, sertraline, exhibit an antidepressant effect clearly greater than that which could both be exerted by the two components used. separately. The immediate initiation of the action of this combination of active substances is particularly important.

The present invention relates to an agent for treating depression, containing 2-amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole, one of its enantiomers or one of its acid addition salts, in combination with sertraline or one of its pharmaceutically compatible salts. .

Preferably, the agent comprises the (+) - 2-amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole enantiomer or one of its acid addition salts.

Preferably, the agent comprises the enantiomer of (-) - 2-amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole or one of its acid addition salts.

Particularly preferably, the composition comprises 2-amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole dihydrochloride, in particular 2-amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole dihydrochloride monohydrate.

Preferably the agent of the invention comprises 2-amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole, one of its enantiomers or one of its acid addition salts in an amount from 0.05 to 10 mg.

Preferably the composition comprises pramipexole or pramipexole dihydrochloride monohydrate in an amount from 0.05 to 10 mg.

More preferably, the agent comprises 2-amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole, one of its enantiomers or one of its acid addition salts in an amount from 0.088 to 1.5 mg.

It is particularly preferred that the composition comprises pramipexole or pramipexole dihydrochloride monohydrate in an amount from 0.088 to 1.5 mg.

It is particularly preferred that the composition comprises pramipexole in an amount of 0.088 mg to 1.1 mg or pramipexole dihydrochloride monohydrate in an amount of 0.125 to 1.5 mg.

Preferably the agent comprises sertraline in an amount from 25 to 200 mg.

Particularly preferably, the agent comprises sertraline in an amount of 50 mg.

Preferably, the agent is characterized in that, in combination, the active substances are separate compounds to be administered one after the other.

The invention also relates to the use of an agent as defined above for the manufacture of a medicament for the treatment of depression or depressive states.

Preferably, the agent described above in the preferred variants is used in the preparation of the medicament.

The invention also relates to the use of an agent as defined above for the preparation of a pharmaceutical composition for the treatment of depression.

Preferably, an agent as outlined above in the preferred variants is used for the preparation of the pharmaceutical composition.

PL 195 043 B1

The enhanced effect of pramipexole achieved by the concomitant administration of a second antidepressant was found in a so-called forced swimming test in rats administered pramipexole and sertraline. Details of this test method are found in, for example, Willner, Psychopharmacology, 83, 1-16 (1984) or Borsini and Meli, Psychopharmacology, 94, 147-160 (1988).

For the combination of pramipexole and sertraline [(1S-cis) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine] or their acid addition salts, a test was performed in as follows. The animals were divided into various groups and each group received either saline solution, or a therapeutically effective amount of pramipexole, or a therapeutically effective amount of sertraline, or a combination of both antidepressants, each in the same therapeutically effective amount as received by animals administered alone. one of these active substances.

Particularly preferred is the combination of 2-amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole, its (+) or (-) enantiomer, their compatible acid addition salts, and (1S-cis) -4- (3,4 -dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthaline amine (sertraline) as well as its acid addition salts, and a specially preferred combination of pramipexole and sertraline in the form of their hydrochlorides.

Another antidepressant may also be used in combination with pramipexole. This also applies to antidepressants which belong to the group of medicines such as:

<td>alprazolam</td><td>mirtazapine</td><td>trimipramine</td>

<td>chlordiazepoxide</td><td>moclobemide</td><td>tryptophan</td>

<td>clomipramin</td><td>nefazodone</td><td>venlafaxim or</td>

<td>quinpyrrole</td><td>nortriptyline</td><td>viloxazine</td>

<td>dibenzepin</td><td>opipramol</td><td></td>

<td>doxepin</td><td>paroxetine</td><td></td>

<td>fluvoxamine</td><td>lofepraminas</td><td>ulpyrid</td>

<td>maprotilin</td><td>tranylcypromin</td><td></td>

<td>mianserin</td><td>trazonone</td><td></td>

The term "combination" as used in the present description is understood to mean a combination of active substances composed of both essential active substances, as well as a combination in the sense of individual preparations of essential active substances which are only temporarily bound together in the medicament used.

Oral pharmaceutical preparations of pramipexole are known in the art and are available, for example, on the German or American market.

Separate active substances can be packaged together as a kit, in the sense of a package containing the individual drugs.

The combination of pramipexole and sertraline can be formulated analogously to the usual galenic preparations, usually together with a pharmaceutical carrier.

This means that an effective dose of the individual ingredients and, optionally, a pharmaceutical carrier is formulated in the form of a tablet, dragee, capsule, wafer, powder, solution, suspension, emulsion, syrup, suppository, etc.

In the case of pramipexole, the pharmaceutically effective dose for a patient is in the range of 0.01 to 10 mg, preferably in the range of 0.08 to 5 mg.

The therapeutically effective preferred doses of sertraline present in this combination are in the range of 25-200 mg. Particularly preferably, the agent contains 50 mg of sertraline.

In the combination according to the invention, the recommended dosage may also, in individual cases, be lower than the recommended dosage of the individual active substances used hitherto.

Description of the experiments

Pramipexole was used at doses ranging from 0.1 to 0.3 / kg. Additionally, experiments were conducted with 0.05 mg of pramipexole.

Sertraline was administered as shown in the tables below, with doses ranging from 5 to 10 mg / kg. The experiments were carried out with Wistar rats (male, 250-270 g) at room temperature, following the natural day-night rhythm.

Pramipexole hydrochloride was dissolved in physiological saline solution, and sertraline also in the form of hydrochloride in distilled water. Both substances were injected in an amount of 2 ml / kg.

PL 195 043 B1

Forced swimming test in rats

Total immobilization time was determined according to Porsolt et al. (1978) at five-minute observation periods. Pramipexole (0.05, 0.1 and 0.3 mg / kg) and sertraline (5 or 10 mg / kg) were administered three times at intervals of 24, 5 and 1 hour prior to the start of the test. Separate groups were injected with pramipexole at the above-mentioned doses together with sertraline (5 or 10 mg / kg) in the same three times as described above. Each group of animals consisted of 10 rats.

Results

In the discussed forced swimming test ("Forced swimming test"), pramipexole in a dose of 0.1 mg / kg does not change the length of immobilization time, while in higher doses (0.3 mg) it significantly shortens the immobilization time. Sertraline 5 mg / kg alone did not shorten the immobilization time either. However , the combined administration of 5 mg / kg sertraline and 0.1 mg / kg pramipexole resulted in a marked reduction in immobilization time. The effect was generally more pronounced at the higher doses of sertraline. Sertraline 10 mg / kg was inactive in the Forced Swimming Test, but was adequate in combination with pramipexole (0.1, 0.3 mg / kg). This effect is enhanced with higher doses of pramipexole. Pramipexole at a dosage of 0.05 mg / kg did not have any effect on the immobilization time, but in combination with sertraline showed a reduction in immobilization time.

These results demonstrate the unexpected synergistic effect of pramipexole when used in combination with sertraline as an antidepressant.

Ta bale a 1

Effect of pramipexole (0.1 and 0.3 mg / kg) alone or in combination with sertraline (5 mg / kg) on ​​immobilization time in the "Forced swimming test" in rats

<td rowspan="2">Compounds (mg / kg)</td><td colspan="2">Time (s) of immobilization</td>

<td>Mean ± SEM</td><td>P.</td>

<td>1.Vehiculum</td><td> 239,9 ± 3,1</td><td> -</td>

<td>2. Sertraline 5</td><td> 257,0 ± 7,0</td><td>not significant, see above 1</td>

<td>3. Pramipexole 0.1</td><td> 223,4 ± 6,2</td><td>not significant, see above 1</td>

<td>4. Pramipexole 0.3</td><td> 171,5 ± 9,2</td><td>&lt;0.001, see above 1</td>

<td>5. Sertraline 5 + pramipexole 0.1</td><td> 96,10 ± 10,3</td><td>&lt;0.001, see above 3</td>

<td>6. Sertraline 5 + pramipexole 0.3</td><td> 18,10 ± 3,5</td><td>&lt;0.001, see above 4</td>

Pramipexole (0.1 or 0.3 mg / kg sc) and sertraline (5 mg / kg ip) were administered 3 times (24, 5 and 1 hour) prior to testing.

This bale a 2

Effect of pramipexole (0.1 and 0.3 mg / kg) alone or in combination with sertraline (10 mg / kg) on ​​immobilization in a "Forced swimming test" in rats

<td rowspan="2">Compounds (mg / kg)</td><td colspan="2">Time (s) of immobilization</td>

<td>Mean ± SEM</td><td>P.</td>

<td>1. Vehicle</td><td> 237,9 ± 2,7</td><td> -</td>

<td>2. Sertraline 10</td><td> 223,6 ± 9,9</td><td>not significant, see above 1</td>

<td>3. Pramipexole 0.1</td><td> 212,5 ± 6,9</td><td>unchanged, see above 1</td>

<td>4. Pramipexole 0.3</td><td> 142,9 ± 7,9</td><td>&lt;0.001, see above 1</td>

<td>5. Sertraline 10 + pramipexole 0.1</td><td> 133,3 ± 6,9</td><td>&lt;0.001, see above 3</td>

<td>6. Sertraline 10 + pramipexole 0.3</td><td> 11,8 ± 2,3</td><td>&lt;0.001, see above 4</td>

PL 195 043 B1

Pramipexole (0.1 or 0.3 mg / kg sc) and sertraline (10 mg / kg ip) were administered 3 times (24, 5 and 1 hour) prior to testing.

This bel a 3

Effect of pramipexole (0.05 mg / kg) alone or in combination with sertraline (5 and 10 mg / kg) on ​​immobilization time in the "Forced swimming test" in rats

<td rowspan="2">Compounds (mg / kg)</td><td colspan="2">Time (s) of immobilization</td>

<td>Mean ± SEM</td><td>P.</td>

<td>1. Vehicle</td><td> 235,3 ± 4,8</td><td> -</td>

<td>2. Pramipexole 0.05</td><td> 245,5 ± 7,8</td><td>not significant, see above 1</td>

<td>3. Sertraline 5</td><td> 247,5 ± 3,0</td><td>not significant, see above 1</td>

<td>4. Sertraline 10</td><td> 223,7 ± 2,8</td><td>not significant, see above 1</td>

<td>5. Sertraline 5 + pramipexole 0.05</td><td> 187,7 ± 11,2</td><td>&lt;0.001, see above 2</td>

<td>6. Sertraline 10 + pramipexole 0.05</td><td> 163,9 ± 10,0</td><td>&lt;0.001, see above 2</td>

Pramipexole (0.05 mg / kg sc) and sertraline (5 and 10 mg / kg ip) were administered 3 times (24, 5 and 1 hour) prior to testing.